（2026.V1）NCCN临床实践指南：B细胞淋巴瘤

指南血液内科· 淋巴瘤与骨髓瘤 · 2026

NCCN Guidelines Version 1.2026

B-Cell Lymphomas

NCCN Guidelines Index Table of Contents Discussion

*Andrew D. Zelenetz, MD, PhD/Chair †b

Memorial Sloan Kettering Cancer Center

*Leo I. Gordon, MD/Vice Chair ‡ § Robert H. Lurie Comprehensive Cancer Center of Northwestern University

Jeremy S. Abramson, MD, MMSc ‡‡ Mass General Cancer Center

Ranjana H. Advani, MD ‡ Stanford Cancer Institute

Alaa Altahan, MD ‡† b St. Jude Children's Research Hospital/The University of Tennessee Health Science Center

Babis Andreadis, MD, MSCE ‡ ‡ UCSF Helen Diller Family Comprehensive Cancer Center

Nancy L. Bartlett, MD † Sisteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

L. Elizabeth Budde, MD, PhD ‡ ξ City of Hope National Medical Center

Paolo F. Caimi, MD ‡† ξ Case Comprehensive Cancer Center/ University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute

Sven DeVos, MD, PhD ‡†b UCLA Jonsson Comprehensive Cancer Center

Bhagirathbhai Dholaria, MD ‡† θ Vanderbilt-Ingram Cancer Center

Luis E. Fayad, MD ‡‡ $\blacktriangleright$ The University of Texas MD Anderson Cancer Center

Sameh Gaballa, MD ‡ Moffitt Cancer Center

Thomas M. Habermann, MD $ξ Mayo Clinic Comprehensive Cancer Center

Francisco Hernandez-ilizaliturri, MD † Roswell Park Comprehensive Cancer Center

Boyu Hu, MD ‡ ‡†

Huntsman Cancer Institute at the University of Utah

Yasmin Karimi, MD ‡ University of Michigan Rogel Cancer Center

Christopher R. Kelsey, MD § Duke Cancer Institute

Rebecca King, MD ≠ Mayo Clinic Comprehensive Cancer Center

Justin Kline, MD † The UChicago Medicine Comprehensive Cancer Center

Susan Krivacic, MPAff ¥ Patient advocate

Ann S. LaCasce, MD, MMSc † Dana-Farber/Brigham and Women's Cancer Center

Daniel Landsburg, MD † Abramson Cancer Center at the University of Pennsylvania

Megan Lim, MD, PhD ≠ Memorial Sloan Kettering Cancer Center

Marcus Messmer, MD ‡‡ Fox Chase Cancer Center

Priyanka Pophali, MD ‡ University of Wisconsin Carbone Cancer Center

Rachel Rabinovitch, MD § University of Colorado Cancer Center Praveen Ramakrishnan, MD, MS ‡ UT Southwestern Simmons Comprehensive Cancer Center

Erin Reid, MD †‡ UC San Diego Moores Cancer Center

Kenneth B. Roberts, MD § Yale Cancer Center/Smilow Cancer Hospital

Aditi Saha, MD ‡ O'Neal Comprehensive Cancer Center at UAB

Naoyuki G. Saito, MD, PhD § Indiana University Melvin and Bren Simon Comprehensive Cancer Center

Yazeed Sawalha, MD

The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute

Stephen D. Smith, MD ‡ Fred Hutchinson Cancer Center

Lode J. Swinnen, MBChB, MD †‡§ Johns Hopkins Kimmel Cancer Center

Joseph Tuscano, MD ‡ UC Davis Comprehensive Cancer Center

Julie M. Vose, MD, MBA ‡ § Fred & Pamela Buffett Cancer Center

NCCN Mary Dwyer, MS Hema Sundar, PhD

* ξ Bone marrow * transplantation # Hematology/ Hematology oncology # Internal medicine # Medical oncology

NCCN Guidelines Version 1.2026 B-Cell Lymphomas

Version 1.2026, 12/22/25 © 2025 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Index Table of Contents Discussion

NCCN B-Cell Lymphomas Panel Members

Summary of the Guidelines Updates

• Diagnosis (DIAG-1)

• Follicular Lymphoma (FOLL-1)

• Marginal Zone Lymphomas (MZL-1)

• Mantle Cell Lymphoma (MANT-1)

• Diffuse Large B-Cell Lymphoma (BCEL-1)

• Primary Mediastinal Large B-Cell Lymphoma (PMBL-1)

• Histologic Transformation of Indolent Lymphomas to DLBCL (HTBCEL-1)

• High-Grade B-Cell Lymphomas (HGBL-1)

• Burkitt Lymphoma (BURK-1)

• HIV-Related B-Cell Lymphomas (HIVLYM-1)

• Lymphoblastic Lymphoma (BLAST-1)

• Post-Transplant Lymphoproliferative Disorders (PTLD-1)

• Use of Immunophenotyping/Molecular Analysis in Differential Diagnosis of Mature

B-Cell Neoplasms (NHODG-A)

• Supportive Care for B-Cell Lymphomas (NHODG-B)

• Lugano Response Criteria for Non-Hodgkin Lymphoma (NHODG-C)

• Principles of Radiation Therapy (NHODG-D)

Classification and Staging (ST-1)

Abbreviations (ABBR-1)

Primary CNS Lymphoma (NCCN Guidelines for CNS)

NCCN Guidelines for Castleman Disease

Waldenström Macroglobulinemia/Lymphoplasmacytic Lymphoma (NCCN Guidelines

for WM/LPL)

The NCCN Guidelines® are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to

treatment. Any clinician seeking to apply or consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network® (NCCN®) makes no representations or warranties of any kind regarding their content, use or application and disclaims any responsibility for their application or use in any way. The NCCN Guidelines are copyrighted by National Comprehensive Cancer Network®. All rights reserved. The NCCN Guidelines and the illustrations herein may not be reproduced in any form without the express written permission of NCCN. ©2025.

Find an NCCN Member Institution: https://www.nccn.org/home/memberinstitutions.

NCCN Categories of Evidence and

Consensus: All recommendations are category 2A unless otherwise indicated.

See NCCN Categories of Evidence and Consensus.

NCCN Categories of Preference:

All recommendations are considered

appropriate.

See NCCN Categories of Preference.

NCCN Guidelines Version 1.2026 B-Cell Lymphomas

NCCN Guidelines Index Table of Contents Discussion

Continued UPDATES

Updates in Version 1.2026 of the NCCN Guidelines for B-Cell Lymphomas:Global changes

• References for suggested treatment regimens were updated.

• Modifications made throughout the Guidelines related to terminology for biomarker testing and results.

• "Karyotype" removed.

• "Next-generation sequencing (NGS) panel" changed to "Multigene panel testing (MGPT)".

• "T-cell engager therapy" changed to "T-cell mediated therapy"

• Workup bullet revised: Pregnancy testing in patients of childbearing age (if chemotherapy or radiation therapy [RT] planned)

• Footnote revised: Fertility preservation options include: sperm banking, semen cryopreservation, in vitro fertilization (IVF), or ovarian tissue or oocyte cryopreservation.

• Removed section for "Guidance for Treatment of Patients with Chimeric Antigen Receptor (CAR) T-Cell Therapy" and directed to NCCN Guidelines for Management of CAR T-Cell and Lymphocyte Engager-Related Toxicities.

Follicular Lymphoma

FOLL-2

• Workup,

Essential, 8th bullet revised: PET/CT scan (preferred) or chest/abdomen/pelvis (C/A/P) CT with contrast of diagnostic quality if systemic therapy is planned. (Also for

EMZLNG-1, NMZL-1 and MANT-1)

Useful, 1st bullet moved from Essential: Bone marrow biopsy + aspirate (to document clinical stage I–II disease if involved-site radiation therapy [ISRT] planned, or to

evaluate unexplained cytopenias. (Also for NMZL-1)

Useful, 6th bullet revised: Serum protein electrophoresis (SPEP) with serum immunofixation electrophoresis (SIFE) and/or quantitative Ig levels

Useful, removed bullet: PET/CT scan if RT planned for stage I, II disease. (Also for NMZL-1)

FOLL-3

• Non-contiguous stage II, Active surveillance moved as first option and "if indications for treatment present" added to "Anti-CD20 mAb ± chemotherapy..." (Also for

NMZL-2)

FOLL-4

• After indication present,

"PET/CT scan" removed. (Also for NMZL-3)

"Palliative ISRT" revised as "very low-dose ISRT."

FOLL-5

• For both CR and PR, removed: Consolidation (Also for NMZL-4)

• For both PR and NR or progressive disease, 3rd option revised: In third-line systemic therapy or later: T-cell–engager therapy (Also for NMZL-4)

• Second-line and subsequent therapy, after indication present, 3rd option revised: Palliative ISRT Very low dose ISRT (Also for NMZL-4)

FOLL-A

• Footnote removed: FLIPI-2 (Federico M, Bellei M, Marcheselli L, et al. Follicular lymphoma international prognostic index 2: a new prognostic index for follicular

lymphoma developed by the international follicular lymphoma prognostic factor project. J Clin Oncol 2009;27:4555-4562) predicts for outcomes after active therapy; see Discussion.

FOLL-B (1 of 6)

• First-line therapy for older or infirm, Other recommended regimens removed:

Chlorambucil ± Rituximab

Cyclophosphamide ± Rituximab

NCCN Guidelines Version 1.2026 B-Cell Lymphomas

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Continued

UPDATES

Updates in Version 1.2026 of the NCCN Guidelines for B-Cell Lymphomas:Follicular Lymphoma (continued)

FOLL-B (2 of 6)

• Second-line therapy

Added: Lenalidomide + Rituximab + Epcoritamab-bysp (category 1)

Lenalidomide + Rituximab + Tafasitamab-cxix changed from a category 2A to a category 1

Lenalidomide + Rituximab moved from Preferred to Other recommended

• Second-line therapy for older or infirm, Other recommended regimen removed:

Cyclophosphamide ± Rituximab

• Removed: Second-line consolidation therapy with High-dose therapy with autologous stem cell rescue (HDT/ASCR)

FOLL-B (3 of 6)

• Third-line and subsequent therapy

Statement revised from "Subsequent systemic therapy options include second-line therapy regimens (FOLL-B 2 of 6) that were not previously given" to

"Second-line therapy regimens (FOLL-B 2 of 6) that were not previously given can also be used as options for third-line and subsequent therapy."

FOLL-B (4 of 6)

• Footnote f revised by removing: The clinical trial evaluating this regimen included obinutuzumab maintenance. The use without maintenance was an extrapolation of the data.

• Footnote k revised: In the setting of CD20-negative lymphomas, the activity efficacy of CD3 x CD20 bispecific antibody therapy is unclear poor. Rebiopsy to confirm

CD20 positivity is recommended prior to initiating CD3 x CD20 bispecific antibody therapy. If clinically feasible, repeat biopsy to confirm antigen expression prior to the initiation of T-cell mediated therapy. (Also for MANT-A 3 of 5, BCEL-C 5 of 7, HTBCEL-A 2 of 2)

• Footnote m revised: It is unclear unknown if tafasitamab-cxix or loncastuximab tesirine-lpyl...If clinically feasible, repeat biopsy to confirm antigen expression prior to the initiation of CD19-directed CAR T-cell therapy. (Also for BCEL-C 5 of 7, HTBCEL-A 2 of 3)

EMZL of the Stomach

EMZLG-1

• Additional diagnostic testing

Bullet revised and moved from Essential to Useful: Flow cytometry with peripheral blood and/or biopsy specimen in the presence of lymphocytosis: kappa/lambda,...

• Workup

Bullet revised and moved from Useful to Essential: SPEP with SIFE and/or quantitative Ig levels. (Also for EMZLNG-1, NMZL-1, SMZL-1)

Useful, 1st bullet revised: Bone marrow biopsy ± aspirate (to document clinical stage I–II disease if ISRT planned or to evaluate unexplained cytopenias)

• Footnote g added: PET/CT scan may be negative in marginal zonal lymphomas. In such cases, CT scan is recommended. (Also for EMZLNG-1, NMZL-1, SMZL-1)

• Footnote h added: Bilateral or unilateral provided core biopsy is >2 cm. If active surveillance is initial therapy, bone marrow biopsy may be deferred. (Also for

EMZLNG-1, NMZL-1, SMZL-1)

EMZLG-2

• Initial therapy

Revised: Rituximab (if ISRT is contraindicated or unavailable)

EMZLG-3

• After indication present,

"Palliative ISRT" changed to "ISRT preferred if disease can be encompassed in a single field"

"First-line Therapy for Marginal Zone Lymphomas (MZL-A 1 of 4)" changed to "Manage per advanced-stage NMZL (NMZL-3)"

• Footnote r added: Optional second-line extended therapy (obinutuzumab maintenance for rituximab-refractory disease) if treated with bendamustine + obinutuzumab for recurrent disease (MZL-A 2 OF 4).(Also for EMZLNG-3, SMZL-3)

EMZLG-6

• Footnote w added: Optional first-line extended therapy (rituximab maintenance 375 mg/m2 one dose every 8–12 weeks for up to 2 years) for patients treated with

single-agent rituximab (MZL-A 1 of 4). (Also for EMZLNG-3, SMZL-3)

NCCN Guidelines Version 1.2026 B-Cell Lymphomas

NCCN Guidelines Index Table of Contents Discussion

Continued

UPDATES

Updates in Version 1.2026 of the NCCN Guidelines for B-Cell Lymphomas:Extranodal MZL of Nongastric Sites (Noncutaneous)

EMZLNG-1

• Workup

Useful, 2nd bullet revised: Bone marrow biopsy ± aspirate (to document clinical stage I–II disease if ISRT planned or to evaluate unexplained cytopenias)

Nodal Marginal Zone Lymphoma

NMZL-1

• Workup,

Removed: Evaluation to rule out extranodal primary sites

• Footnote removed: NMZL is rare and occurs most commonly as spread from extranodal sites; must also be distinguished from nodal FL, MCL, lymphoplasmacytic lymphoma (LPL), and chronic lymphocytic leukemia (CLL), all of which are more common.

Splenic Marginal Zone Lymphoma

SMZL-1

• Workup, Useful, 1st bullet revised by adding: if cytopenias are present and considering splenectomy to ensure adequate bone marrow hematopoiesis

• Footnote a revised: SMZL is most definitively diagnosed at splenectomy, since the immunophenotype is nonspecific and morphologic features on the bone marrow may not be diagnostic. However, The presumptive diagnosis of SMZL may be based on peripheral blood involvement ± bone marrow ± peripheral blood involvement by...and...NGS MGPT panel...SMZL is most definitively diagnosed at splenectomy, since the immunophenotype is nonspecific and morphologic features on the bone marrow may not be diagnostic.

Marginal Zone Lymphomas

MZL-A (1 of 4)

• First-line therapy

Preferred split by NMZL and SMZL.

Other recommended, lenalidomide + rituximab for NMZL changed from a category 2B to category 2A recommendation.

• First-line therapy for older or infirm

Preferred, added: ISRT for local disease

Other Recommended regimen removed: Chlorambucil ± Rituximab

MZL-A (2 of 4)

• Second-line and subsequent therapy

Added: For sequencing of therapy, see Discussion.

Other Recommended regimen removed: Ibrutinib (Also for second-line and subsequent therapy for older or infirm)

Moved from Preferred to Other recommended (Also for second-line and subsequent therapy for older or infirm)

◊ Bendamustine + Obinutuzumab (not recommended if treated with prior bendamustine)

◊ Acalabrutinib

◊ Pirtobrutinib

Other Recommended regimen removed: Chlorambucil ± Rituximab for second-line and subsequent therapy for older or infirm

• Removed: Second-line consolidation therapy with HDT/ASCR

MZL-A (3 of 4)

• Third-line and subsequent therapy

Statement revised from, "Subsequent systemic therapy options include second-line therapy regimens (MZL-A 2 of 4) that were not previously given" to "Second-line

therapy regimens (MZL-A 2 of 4) that were not previously given can also be used as options for third-line and subsequent therapy"

Preferred, added: Lisocabtagene maraleucel (CD19-directed) (if not previously given) (category 2A)

Axicabtagene ciloleucel moved from Preferred to Other recommended

• Footnote d added: If absolute lymphocyte count (ALC) is >25,000 mcL: 1) consider split dosing for rituximab of 100 mg, flat dose on day 1 and the remainder of the

375 mg/m2 on day 2; 2) consider additional glucocorticoid premedication prior to rituximab (50 mg at bedtime day prior, 50 mg morning of, and 50 mg immediately prior to infusion) to reduce infusion-related reactions.

• Footnote h added: If clinically feasible, repeat biopsy to confirm antigen expression prior to the initiation of CD19-directed CAR T-cell therapy.

NCCN Guidelines Version 1.2026 B-Cell Lymphomas

NCCN Guidelines Index Table of Contents Discussion

Continued

UPDATES

Updates in Version 1.2026 of the NCCN Guidelines for B-Cell Lymphomas:Mantle Cell Lymphoma

MANT-1

• Stage clarified: Stage II bulky and/or noncontiguous; Stage III, IV. (Also for MANT-3)

MANT-2

• Footnote removed: In the treatment plan, early referral for HDT/ASCR is advisable. (Also for MANT-3, MANT-4, MANT-5)

MANT-4

• Classical TP53 wild type Stage II bulky noncontiguous; Stage III, IV

◊ After aggressive induction therapy, CR revised by adding "uMRD6" and "dMRD6"

– uMRD6 goes to "Rituximab maintenance ± covalent BTKi (MANT-A)"

– dMRD6 goes to "Consider HDT/ASCR" then "Rituximab maintenance ± covalent BTKi (MANT-A)"

• Footnotes

Footnote n added: Determination of measurable residual disease (MRD) using a sensitive assay (with a limit of detection of at least 10-6 tumor cells) will stratify

patients who do not benefit from HDT/SCR. Patients achieving CR with undetectable MRD (uMRD; <10-6, uMRD6) should not receive HDT/ASCR.

Footnote o revised: Patients who have achieved near CR can proceed to HDT/ASCR. Patients who have achieved minimal PR with substantial disease should be

treated as having refractory or progressive disease. Patients who have achieved a very good PR may be treated with additional therapy to achieve CR with dMRD6

(detectable MRD; >10-6) with the goal of proceeding to HDT/ASCR.

Footnote p revised: Benefit of 2 years of ibrutinib maintenance and 3 years of rituximab maintenance after alternating RCHOP + ibrutinib/RDHAP was shown in the

TRIANGLE study......

MANT-6

• Header revised: Relapsed/Refractory or Progressive Disease

• Recommendations separated by "cBTKi naïve or Late relapse (>24 months) after prior cBTKi-containing regimen (MANT-6A)" and "Progression on cBTKi or Early

relapse (<24 months) after prior cBTKi-containing regimen (MANT-6B)"

MANT-A (1 of 5)

• Stage I or Stage II nonbulky (contiguous or noncontiguous) or Classical TP53 wildtype: Stage II bulky noncontiguous; Stage III, IV

Preferred, 1st option revised: Acalabrutinib (continuous)/Bendamustine + Rituximab followed by Rituximab maintenance (2y)

Other recommended, added: Ibrutinib (continuous) + Rituximab followed by Rituximab maintenance (2y) (category 2A)

Moved from Preferred to Other recommended: CHOP + Rituximab followed by Rituximab maintenance; Lenalidomide (continuous) + Rituximab; VR-CAP

Moved from Other recommended to Preferred: Acalabrutinib (continuous) + Rituximab

• Classical TP53 wildtype: Stage II bulky noncontiguous; Stage III, IV

Triangle regimen: Use of alternate BTKis, acalabrutinib and zanubrutinib, changed from a category 2B to a category 2A recommendation. Added: followed by

maintenance with Rituximab + covalent BTKi (Also for Classical TP53 mutated: Stage II bulky noncontiguous; Stage III, IV)

Removed: HyperCVAD

• Classical TP53 mutated: Stage II bulky noncontiguous; Stage III, IV

Not suitable for aggressive induction therapy,

◊ Removed: Less aggressive induction therapy regimens (as recommended for classical TP53 wildtype)

◊ Added: Acalabrutinib (continuous) + Rituximab

NCCN Guidelines Version 1.2026 B-Cell Lymphomas

NCCN Guidelines Index Table of Contents Discussion

Continued

UPDATES

Updates in Version 1.2026 of the NCCN Guidelines for B-Cell Lymphomas:

MANT-A (2 of 5)

• Maintenance after HDT/ASCR or aggressive induction therapy

Use of alternate covalent BTKis, acalabrutinib and zanubrutinib, changed from a category 2B to a category 2A recommendation.

• Maintenance after less aggressive induction therapy

1st bullet, added: ± Acalabrutinib

2nd bullet revised: Maintenance Rituximab following VR-CAP or RBAC500 has not been evaluated

• Second-line and or subsequent therapy

Progressive disease after prior covalent BKTi

◊ Added: Mosunetuzumab-axgb + polatuzumab vedotin-piiq (category 2A)

◊ Glofitamab-gxbm removed qualifier "Progressive disease after CAR T-cell therapy and pirtobrutinib or ineligible for CAR T-cell therapy" and changed from a category 2B to a category 2A recommendation.

MANT-A 3 of 5

• Footnote f revised ... In patients intended to receive HDT/ASCR, CAR T-cell therapy...

• Footnote o added: In selected circumstances, an alternate CAR T-cell therapy can be used upon disease progression. (Also for BCEL-C 5 of 7, HTBCEL-A 2 of 2)

• Footnote removed: In patients intended to receive HDT/ASCR, bendamustine should be used with caution as there are conflicting data regarding ability to collect peripheral progenitor cell collection. In patients intended to receive HDT/ASCR, CAR T-cell therapy

Diffuse Large B-Cell Lymphoma

BCEL-4

• Footnote i added: In testicular lymphoma, after completion of chemoimmunotherapy, scrotal RT should be given. See Principles of Radiation Therapy (NHODG-D).

(Also BCEL-5)

BCEL-5

• For CR, "initial dose" removed after ISRT.

• For PR, "higher dose" removed after ISRT.

BCEL-7

• Relapsed disease <12 mo or Primary refractory disease,

Candidates for CAR T-cell therapy, additional therapy,

◊ Added: Clinical trial

◊ Revised: CAR T-cell therapy with bridging pre/postpheresis therapy...

Non-candidates for CAR T-cell therapy, after complete response, removed: Consolidation with HDT/ ASCR ± ISRT (optional)

• Footnote dd revised by adding: When using holding therapy (prepheresis), potential complications of the holding therapy regimen on the collection of T-cells should be considered. Delay bendamustine until after CAR-T leukapheresis. If holding or bridging (postpheresis) therapy

• Footnote ff added: In patients who do not have access to CAR T-cell therapy or bispecific antibodies, optional consolidation with HDT/ASCR can be considered if CR is achieved after 2L therapy regimens (BCEL-C 3 of 7 - Intention to Proceed to Transplant). Additional RT can be given before or after transplant to sites of previous positive disease.

• Footnote removed: If patient's clinical situation improves markedly and patient becomes eligible for HDT/ASCR. This may include patients who do not have access to CAR T-cell therapy. Additional RT can be given before or after transplant to sites of previous positive disease.

BCEL-9

• Footnote w revised by removing: Surveillance imaging at 12 mo has treatment implications.

• Footnote mm revised: If not a candidate for T-cell engager mediated therapy or clinical trial.

BCEL-10

• Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type

Initial and second-line therapy, removed "RCHOP"; added "R-CHP-Pola" (category 2A)

NCCN Guidelines Version 1.2026 B-Cell Lymphomas

NCCN Guidelines Index Table of Contents Discussion

UPDATES

Continued

Updates in Version 1.2026 of the NCCN Guidelines for B-Cell Lymphomas:

BCEL-B (1 of 2)

• ALK-positive large B-cell lymphomas (ALK+ LBCL)

Relapsed/refractory disease, added:

◊ If CD-19 positive, consider (CD19-directed) CAR T-cell therapy:

– Axicabtagene ciloleucel (category 2A)

– Lisocabtagene maraleucel (category 2A)

– Tisagenlecleucel (category 2A)

BCEL-C 1 of 7

• First-line therapy

Patients with Poor Left Ventricular Function and Very Frail Patients and Patients >80 Years of Age with Comorbidities

◊ Removed: CEPP

• Concurrent presentation with CNS disease

1st bullet revised: Parenchymal: systemic high-dose Methotrexate (≥3 g/m2 given with CHOP + Rituximab anthracycline-based chemoimmunotherapy cycle that has

been supported by growth factors). Different schedules have been used for the integration of high-dose Methotrexate with CHOP + Rituximab anthracycline-based

chemoimmunotherapy cycle;...

2nd bullet revised: Leptomeningeal: IT Cytarabine/Methotrexate/Hydrocortisone, consider Ommaya reservoir placement. Systemic high-dose Methotrexate (3–3.5

g/ m2) can be given in combination with CHOP + Rituximab anthracycline-based chemoimmunotherapy or as consolidation after CHOP + Rituximab anthracyclinebased chemoimmunotherapy cycle + IT Cytarabine/Methotrexate/Hydrocortisone

Added: Consider consolidation with HDT/ASCR

BCEL-C 2 of 7

• Second-line therapy regimens, Relapsed disease <12 mo or primary refractory disease

Candidates for CAR T-Cell Therapy,

◊ Bridging therapy clarified as postpheresis therapy and holding therapy (prepheresis) options added

Non-Candidates for CAR T-Cell Therapy,

◊ Preferred

– Added: GEMOX + Polatuzumab vedotin-piiq + Rituximab (category 2A)

◊ Other recommended regimens

– 5th bullet revised: GemOx ± rituximab (if unable to receive epcoritamab-bysp, glofitamab-gxbm or polatuzumab vedotin-piiq) (Also for BCEL-C 3 of 7)

– Removed: MINE (Mesna/Ifosfamide/Mitoxantrone/Etoposide) ± Rituximab

◊ Useful in certain circumstances

– Revised: Brentuximab vedotin for CD30+ disease (Also for BCEL-C 3 of 7)

BCEL-C 3 of 7

• Second-line therapy regimens, Relapsed disease >12 mo

Intention to Proceed to Transplant

◊ Other recommended, removed: MINE ± Rituximab

No Intention to Proceed to Transplant

◊ Preferred

– Changed: GEMOX + Glofitamab-gxbm from a category 1 to a category 2A

– Added: GEMOX + Polatuzumab vedotin-piiq + Rituximab (category 2A)

NCCN Guidelines Version 1.2026 B-Cell Lymphomas

NCCN Guidelines Index Table of Contents Discussion

Updates in Version 1.2026 of the NCCN Guidelines for B-Cell Lymphomas:

UPDATES

BCEL-C 4 of 7

• Third-line and subsequent therapy

Statement revised from, "Subsequent systemic therapy options include second-line therapy regimens (BCEL-C 2 of 7 and BCEL-C 3 of 7) that were not previously

used" to "Second-line therapy regimens (BCEL-C 2 of 7 and BCEL-C 3 of 7) that were not previously given can also be used as options for third-line and subsequent

therapy."

Preferred

◊ Revised qualifier for CAR T-cell therapy (preferred if not previously given)

◊ Revised qualifier for bispecific antibody therapy: (only after at least two lines of systemic therapy; including patients with disease progression after transplant or CAR T-cell therapy)

Other recommended

◊ Revised: Brentuximab vedotin + lenalidomide + rituximab (for CD30+ disease)

BCEL-C 5 of 7

• Footnote removed: Responses with BV have been seen in patients with a low level of CD30 positivity and any level of CD30 positivity is acceptable for the use of BVbased regimens.

Histologic Transformation of Indolent Lymphomas to DLBCL

HTBCEL-2

• PR or NR or progressive disease

CAR T-cell therapy option clarified: ... with or without bridging pre/postpheresis therapy if eligible

HTBCEL-3

• PR pathway: Revised qualifier for CAR T-cell therapy (preferred if not previously given)

HTBCEL-A

• Systemic therapy regimens

No intention to proceed to transplant, added: Lenalidomide + Brentuximab vedotin + Rituximab (category 2A)

High-Grade B-Cell Lymphomas (HGBL)

HGBL-1

• Footnote a added: TdT expression has prognostic implications but doesn't change therapy.

Continued

NCCN Guidelines Version 1.2026 B-Cell Lymphomas

NCCN Guidelines Index Table of Contents Discussion

Updates in Version 1.2026 of the NCCN Guidelines for B-Cell Lymphomas:

UPDATES

Burkitt Lymphoma

BURK-A 1 of 3

• Induction therapy

≥60 y, High risk, removed: Initiate treatment with the portion of the systemic therapy that contains CNS-penetrating drugs

• Footnote e added: Patients with active CSF involvement as determined by flow cytometry and/or cytology received treatment with methotrexate intrathecally twice

weekly for at least 4 weeks, then weekly for 6 weeks, and then monthly for 6 months. Intravenous methotrexate was not permitted (Roschewski M, et al. J Clin Oncol 2020;38:2519-2529).

BURK-A 2 of 3

• Second-line therapy

Other recommended

◊ Revised: DA-EPOCH + Rituximab for 6 cycles (if not previously given) + intensive IT methotrexate (for patients presenting with symptomatic CNS disease)

Useful in certain circumstances

◊ Added: Glofitamab + Polatuzumab as a bridge to transplant in candidates for allogeneic HCT

• Footnote f added: Refer to package insert for full prescribing information, dose modifications, and monitoring for adverse reactions: https://www.accessdata.fda.gov/scripts/cder/daf/index. cfm. In the setting of CD20-negative lymphomas, the efficacy of CD3 x CD20 bispecific antibody therapy is poor. If clinically feasible, repeat

biopsy to confirm antigen expression prior to the initiation of T-cell mediated therapy.

• Removed bullet: For patients presenting with symptomatic CNS disease; initiate treatment with the portion of the systemic therapy that contains CNS-penetrating

drugs).

HIV-Related B-Cell LymphomasHIVLYM-2

• Workup

9th bullet revised: SPEP with SIFE and/or quantitative Ig levels

HIVLYM-4

• Plasmablastic lymphoma, 4th bullet added: Consider consolidation ISRT in patients with localized disease.

HIVLYM-A

• EPOCH regimens, added: with dose adjustment (HIVLYM-B)

• Plasmablastic lymphoma

Added: EPOCH with dose adjustment (HIVLYM-B) + Daratumumab

• Footnote removed: Recommendations for EPOCH ± Rituximab Dose Adjustments for Non-Burkitt Lymphomas (HIVLYM-B).

Lymphoblastic LymphomaBLAST-1

• Additional diagnostic workup, Useful, added: FISH: Ph-like

Post-Transplant Lymphoproliferative DisordersPTLD-1

• Workup

7th bullet added: SPEP with SIFE and/or quantitative Ig levels

PTLD-2

• Footnote n added: Monitoring EBV PCR viral load may have utility but frequency and duration of monitoring are undefined. (Also for PTLD-3)

PTLD-A

• Concurrent chemoimmunotherapy

Added: GCVP + Rituximab (category 2A)

Removed: CEPP + Rituximab

NCCN Guidelines Version 1.2026 B-Cell Lymphomas

NCCN Guidelines Index Table of Contents Discussion

Updates in Version 1.2026 of the NCCN Guidelines for B-Cell Lymphomas:

UPDATES

Supportive Care for B-Cell LymphomasNHODG-B 3 of 5

• Additional Rare Complications of Monoclonal Antibody Therapy, 3rd bullet added: Consider premedication to reduce infusion-related reactions associated with mAbs.

Principles of Radiation TherapyNHODG-D 3 of 4

• General dose guidelines, Definitive RT

• Marginal zone lymphoma (MZL):

Revised from "EMZL of the stomach: 24 Gy in 16 fractions (1.5 Gy/fractions) to minimize acute GI toxicity. 4 Gy in 2 fractions has been used.21 However, additional

20 Gy is needed for some patients and careful follow-up is needed. Orbital and salivary gland MZL: 4 Gy in 2 fractions may be considered as an alternative to 24

Gy. Careful regular follow-up (physical exam and imaging as appropriate) with radiation oncologist and ophthalmologist is essential when using this very-low-dose

regimen. Definitive doses are recommended for incomplete response or relapsed disease" to

◊ Conventional: 24 Gy (local control >95%)

◊ Dose-adapted: 4 Gy initially (local control 60-80%); 20-24 Gy sequentially for poor response or relapsed disease. Preferred for orbital MZL to reduce risk of

xerophthalmia; supported by prospective studies. Strongly consider for parotid MZL to reduce risk of long-term xerostomia. Can be considered for other sites

depending upon patient preference, site-dependent risks of RT, patient age, compliance with follow-up, etc. Closer monitoring required given higher risk of local failure.

• MCL:

Primary treatment (without chemoimmunotherapy) revised from 36 Gy to 24-36 Gy

Consolidation after chemoimmunotherapy revised PR from 36 Gy to 24–36 Gy

• DLBCL/HGBL/PMBL/MGZL

Consolidation after chemoimmunotherapy revised CR from 30–36 Gy to CR (5-PS 1–3) - 20 Gy for DLBCL/HGBL; 30–36 Gy for MGZL/PBL/PMBL

• Footnotes

Footnote b added: Gastric EMZL- 1.5 Gy fractions often utilized to minimize acute GI toxicity.

Footnote c added: Median follow-up 2-3 years. Longer follow-up needed to confirm results.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

B-Cell Lymphomas

NCCN Guidelines Index Table of Contents Discussion

DIAGNOSIS

ADDITIONAL DIAGNOSTIC $TESTING^{b}$

* Excisional or incisional biopsy is preferred for the definitive diagnosis or histologic grading of lymphoma.

* A fine-needle aspiration (FNA) biopsy is insufficient for the initial diagnosis or histologic grading of lymphoma. Core needle biopsy (multiple biopsies preferred) is an appropriate alternative to excisional or incisional biopsy especially in certain circumstances (when a lymph node is not easily accessible for excisional or incisional biopsy or if surgical biopsy would cause significant morbidity or substantial treatment delays); a combination of core needle biopsy (multiple biopsies preferred) and FNA biopsy in conjunction with appropriate ancillary techniques for the differential diagnosis (immunohistochemistry [IHC], flow cytometry, molecular analysis to detect immunoglobulin [lg] gene rearrangements, fluorescence in situ hybridization [FISH] for major translocationsa) may be sufficient for diagnosis.

$\bullet$ Hematopathology review of all slides with at least one paraffin block representative of the lesion. Rebiopsy if consult material is nondiagnostic, preferably the most FDG-avid, accessible lymph node.

* Follicular lymphoma (FL) $\rightarrow$ FOLL-1

$\bullet$ Extranodal marginal zone lymphoma (EMZL) $\rightarrow$ EMZLG-1 of the stomach

* EMZL of nongastric sites (noncutaneous) $\rightarrow$ EMZLNG-1

$\bullet$ Nodal marginal zone lymphoma (NMZL) $\rightarrow$ NMZL-1

$\bullet$ Splenic marginal zone lymphoma (SMZL) $\rightarrow$ SMZL-1

$\bullet$ Mantle cell lymphoma (MCL) $\rightarrow$ MANT-1

* Diffuse large B-cell lymphoma (DLBCL) BCEL-1

* High-grade B-cell lymphomas (HGBL)

$\bullet$ Burkitt lymphoma (BL) $\rightarrow$ BURK-1

$\bullet$ HIV-related B-cell lymphomas $\rightarrow$ HIVLYM-1

$\cdot$ Lymphoblastic lymphoma (LL) $\rightarrow$ BLAST-1

$\bullet$ Post-transplant

$\bullet$ Post-transplant lymphoproliferative disorders (PTLD) $\rightarrow$ PTLD-1

a If a high suspicion of a clonal process remains and other techniques have not resulted in a clear identification of a clonal process, then multigene panel testing (MGPT) can be used.

$^{a}$ Use of Immunophenotyping/Molecular Analysis in Differential Diagnosis of Mature B-Cell and NK/T-Cell Neoplasms (NHODG-A).

Note: All recommendations are category 2A unless otherwise indicated.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Follicular Lymphoma

NCCN Guidelines Index Table of Contents Discussion

ADDITIONAL DIAGNOSTIC TESTING$^{a}$

In the 2022 WHO classification (WHO5), follicular lymphoma (FL) grades 1, 2, and 3A are termed as classic FL (cFL). International Consensus classification (ICC) has retained the grading for FL (1–2, 3A, and 3B). FL1–2 (ICC) are managed according to the treatment recommendations for cFL (WHO5). FL3B (ICC)/follicular large B-cell lymphoma (FLBCL; WHO5) is commonly treated as DLBCL (BCEL-1). Any area of DLBCL in FL of any grade should be diagnosed and treated as a DLBCL (BCEL-1). The management of FL3A (ICC) is controversial and treatment should be individualized.

ESSENTIAL:

$\bullet$ Adequate immunophenotyping to establish diagnosis$^{e}$

$\bullet$ IHC panel: CD20, CD3, CD5, CD10, BCL2, C BCL6, CD21, or CD23, with or without

$\bullet$ Flow cytometry with peripheral blood and/or biopsy specimen: kappa/lambda, CD19, CD20, CD5, CD23, CD10

USEFUL UNDER CERTAIN CIRCUMSTANCES:

$\bullet$ Molecular analysis to detect: Ig gene rearrangements; BCL2 rearrangements

$\bullet$ FISH: t(14;18)$^{c}$; BCL6, 1p36,$^{d}$ IRF4/MUM1 rearrangements$^{e}$

$\bullet$ IHC panel: Ki-67f; IRF4/MUM1 for FL grade 3, cyclin D1

$\bullet$ MGPT including CREBBP, EZH2, MAP2K1, TNFRSF14, and STAT6 mutation

![graph TD\n A1[Classic FL(cFL; WHO5)] --> A2[Workup(FOLL-2)]\n A3[BCLL2-R negative, CD23-positive follicle center lymphoma(ICC)/FL with predominantly diffuse growth pattern(dFL)(WHO5)d] --> A4[Manage as cFL(FOLL-2)]\n A5[Large B-cell lymphoma(LBCL) with IRF4/MUM1 rearrangement] --> A6[BCEL-2]\n A7[Pediatric-type FL(PTFL)(in adults)c] --> A8[FOLL-6]\n](1/parseimages/figurecb04eb1891b3469fa1a51c493a3edb4e_0_15.png) a Germinal center (GC) or follicular center cell phenotype is not equivalent to FL and occurs in BL and some DLBCL.

b Typical immunophenotype: CD10+, BCL2+, CD23+/-, CD43-, CD5-, CD20+, BCL6+. Rare cases of FL may be CD10- or BCL2-.

c In young patients with localized disease that lacks BCL2 expression or t(14;18), differential diagnosis should include PTFL in adults; BCL2-R negative, CD23-positive follicle center lymphoma (ICC)/dFL (WHO5), and LBCL with IRF4/MUM1 rearrangement.

d BCL2-R negative, CD23-positive follicle center lymphoma (ICC)/dFL (WHO5) has a predominantly diffuse pattern, pelvis/inguinal location, and common STAT6 mutations along with 1p36 deletion or TNFRSF14 mutation.

e LBCL with IRF4/MUM1 rearrangement are usually DLBCL but occasionally are purely FL3B (ICC/FLBCL [WHO5]) and often DLBCL with FL3B. Patients typically present with Waldeyer's ring involvement and are often children/young adults. These lymphomas are locally aggressive but respond well to chemotherapy ± radiation therapy (RT). They do not have a BCL2 rearrangement and should not be treated as low-grade FL.

$^{f}$ There are reports showing that FL1-2 with a Ki-67 proliferation fraction of >30% may be associated with a more aggressive clinical behavior, but there is no evidence that this should guide treatment decisions.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Classic Follicular Lymphoma

NCCN Guidelines Index Table of Contents Discussion

WORKUP

ESSENTIAL:

* Physical exam: attention to node-bearing areas, including Waldeyer's ring, and to size of liver and spleen

* Performance status

* B symptoms

* Complete blood count (CBC) with differential

$\bullet$ Lactate dehydrogenase (LDH)

* Comprehensive metabolic panel

$\bullet$ Hepatitis B testing$^{9}$

$\bullet$ PET/CT scan (preferred) or chest/abdomen/pelvis (C/A/P) CT with contrast of diagnostic quality if therapy is planned

* Pregnancy testing in patients of childbearing age (if therapy planned)

USEFUL IN SELECTED CASES:

$\bullet$ Bone marrow biopsy + aspirate (to document clinical stage I-II disease if involved-site radiation therapy [ISRT] planned, or to evaluate unexplained cytopenias)$^{n}$

$\bullet$ Echocardiogram or multigated acquisition (MUGA) scan if anthracycline-based regimen is indicated

* Neck CT with contrast

$\bullet$ Beta-2-microglobulin (necessary for calculation of FLIPI-2)

$\bullet$ Uric acid

$\bullet$ Serum protein electrophoresis (SPEP) with serum immunofixation electrophoresis (SIFE) and/or quantitative Ig levels

$\bullet$ Hepatitis C testing

$\bullet$ Discuss fertility preservation$^{1}$

![StageInitial TherapyI,Il(FOLL-3Initial TherapyStageIII,IV(FOLL-4\n](1/parseimages/figure71b5848d8a08490c8538f91cd84a318c_0_24.png) $^{9}$ Hepatitis B testing is indicated because of the risk of reactivation with immunotherapy + chemotherapy. Tests include hepatitis B surface antigen (HBsAg) and core antibody for a patient with no risk factors. For patients with risk factors or previous history of hepatitis B, add e-antigen (NHODG-B). If positive, check viral load and consider consult with gastroenterologist.

h Bilateral or unilateral provided core biopsy is >2 cm. If active surveillance is initial therapy, bone marrow biopsy may be deferred.

i Fertility preservation options include: sperm banking, in vitro fertilization (IVF), or ovarian tissue or oocyte cryopreservation.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Classic Follicular Lymphoma

NCCN Guidelines Index Table of Contents Discussion

![graph TD\n A1[Stage I, II] --> A2[Non-contiguous stage II]\n A1 --> A3[Stage I or Contiguous stage II]\n A2 --> A4[Active surveillance]\n A2 --> A5[If indications for treatment present, anti-CD20 mAb± chemotherapy(FOLL-B)±ISRT for local palliation]\n A3 --> A6[ISRTk(preferred)]\n A3 --> A7[or ISRTk + anti-CD20 monoclonal antibody(mAb)± chemotherapy(FOLL-B)m or Anti-CD20 mAb± chemotherapy(FOLL-B)m in certain circumstancesn]\n A4 --> A8[ Clinical.H&P labsevery 3-6 mo for 5 y and then annually or as clinically indicated.Surveillance imagingrUp to 2 y postcompletion of treatment: C/A/P CT scan with contrast no more than every 6 mo>2y: No more than annually]\n A5 --> A12[Consider ISRTk if not previously given]\n A6 --> A9[CR or PR]\n A6 --> A10[NR]\n A7 --> A11[CR or PR]\n A7 --> A14[NR]\n A9 --> A8\n A10 --> A13[See Stage III, IV(FOLL-4)or If histologic transformation, see HTBCEL-1]\n A11 --> A8\n A12 --> A15[CR or PR]\n A12 --> A16[NR]\n A14 --> A17[See NR or progressive disease(FOLL-5)or If histologic transformation, see HTBCEL-1]\n A15 --> A8\n A16 --> A18[See NR or progressive disease(FOLL-5) or If histologic transformation, see HTBCEL-1]\n](1/parseimages/figureeb995b1422dd4d20957d462b9f77bb57_0_4.png) $^{1}$ Active surveillance may be appropriate in circumstances where potential toxicity of ISRT or systemic therapy outweighs potential clinical benefit in consultation with a radiation oncologist.

k Principles of Radiation Therapy (NHODG-D).

$^{1}$ Anti-CD20 mAbs include rituximab or obinutuzumab. Obinutuzumab is not indicated as single-agent therapy.

m Initiation of systemic therapy can improve failure-free survival (FFS), but has not been shown to improve overall survival. These are options for initial therapy.

n Eg, for patients with bulky intra-abdominal or mesenteric stage I disease.

° Lugano Response Criteria for Non-Hodgkin Lymphoma (NHODG-C). PET/CT scan should be interpreted via the PET Five-Point Scale (5-PS).

P Consider possibility of histologic transformation in patients with progressive disease, especially if LDH levels are rising, single site is growing disproportionately, extranodal disease develops, or there are new B symptoms. If clinical suspicion of transformation, FDG-PET may help identify areas suspicious for transformation. FDG-PET scan demonstrating marked heterogeneity or sites of intense FDG avidity may indicate transformation, and biopsy should be directed biopsy at the most FDG-avid area. Functional imaging does not replace biopsy to diagnose transformation. If transformation is histologically confirmed, treatment options should be directed towards the large cell transformation, see HTBCEL-1.

9. Follow-up includes diagnostic tests and imaging using the same modalities performed during workup as clinically indicated. Imaging should be performed whenever there are clinical indications. For surveillance imaging, see Discussion for consensus imaging recommendations.

「Surveillance image is used for monitoring asymptomatic patients. When a site of disease can only be visualized on PET/CT scan (eg, bone), it is appropriate to proceed with PET/CT scans for surveillance.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Classic Follicular Lymphoma

NCCN Guidelines Index Table of Contents Discussion

![graph TD\n A1[Stage III, IV] --> A2[Evaluate for indications for treatment: • Candidate for clinical trial • Symptoms • Threatened end-organ function • Clinically significant or progressive cytopenia secondary to lymphoma • Clinically significant bulky diseasea • Steady or rapid progressionb]\n A2 --> A3[Indication present]\n A3 --> A4[Active surveillance （category 1）]\n A3 --> A5[See Suggested Regimens （FOLL-B）or Clinical trial and/or Very low-dose ISRTk]\n A4 --> A6[No indication]\n A4 --> A7[Clinical • H&P and labs every 3-6 mo for 5 y and then annually or as clinically indicated • Up to 2 y: C/A/P CT scan with contrast no more than every 6 mo • >2 y: CT scan no more than annually]\n A5 --> A8[Response Assessment and Additional Therapy （FOLL-5）]\n A6 --> A2\n A7 --> A8\n A9[Progressivediseaseor If histologic transformation, see HTCEL-1] --> A5\n](1/parseimages/figureb1ca5ca363e345dfb1b029b670b7ed7a_0_4.png) k Principles of Radiation Therapy (NHODG-D).

$^{0}$ Lugano Response Criteria for Non-Hodgkin Lymphoma (NHODG-C). PET/CT scan should be interpreted via the PET 5-PS.

P Consider possibility of histologic transformation in patients with progressive disease, especially if LDH levels are rising, single site is growing disproportionately, extranodal disease develops, or there are new B symptoms. If clinical suspicion of transformation, FDG-PET may help identify areas suspicious for transformation. FDG-PET scan demonstrating marked heterogeneity or sites of intense FDG avidity may indicate transformation, and biopsy should be directed biopsy at the most FDG-avid area. Functional imaging does not replace biopsy to diagnose transformation. If transformation is histologically confirmed, options should be directed towards the large cell transformation, see HTBCEL-1.

$^{9}$ Follow-up includes diagnostic tests and imaging using the same modalities performed during workup as clinically indicated. Imaging should be performed whenever there are clinical indications. For surveillance imaging, see [Discussion] for consensus imaging recommendations.

* Surveillance imaging is used for monitoring asymptomatic patients. When a site of disease can only be visualized on PET/CT scan (eg, bone), it is appropriate to proceed with PET/CT scans for surveillance.

$^{s}$ GELF criteria (FOLL-A).

Note: All recommendations are category 2A unless otherwise indicated.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Classic Follicular Lymphoma

NCCN Guidelines Index Table of Contents Discussion

![graph TD\n A1[PET/CT （preferred）or C/A/P CT scan with contrast] --> A2[CR⁰]\n A1 --> A4[PR⁰,t]\n A2 --> A3[Extended therapy （optional）（FOLL-B）or Active surveillance]\n A3 --> A6[Clinical • H&P and labs every 3–6 mo for 5 y and then annually or as clinically indicated • Up to 2 y post completion of treatment: C/A/P CT scan with contrast no more than every 6 mo • >2 y: CT scan no more than annually]\n A4 --> A5[Extended therapy （optional）（FOLL-B）or Active surveillance or Third-line systemic therapy or later （FOLL-B）]\n A5 --> A6\n A6 --> A7[Relapsed or Progressive disease⁸,⁹ or If histologic transformation, see HTBCEL-1]\n A7 --> A8[Evaluate for indications for treatment⁶: • Candidate for clinical trial • Symptoms • Threatened end-organ function • Clinically significant or progressive cytopenia secondary to lymphoma • Clinically significant bulky disease⁶ • Steady or rapid progression⁶]\n A8 --> A9[No indication]\n A8 --> A12[Indication present]\n A9 --> A10[Active surveillance]\n A10 --> A11[See Suggested Regimens （FOLL-B）or Clinical trial or Very low-dose ISRT⁸]\n A12 --> A13[PET/CT scan⁹]\n A13 --> A14[No histologic transformation • If histologic transformation, see HTBCEL-1 • Third-line systemic therapy or later （FOLL-B）]\n A13 --> A15[See Suggested Regimens （FOLL-B）or Clinical trial or Very low-dose ISRT⁸]\n A14 --> A11\n A15 --> A1\n](1/parseimages/figure76d346ea80b04982b2f65d2d90f80f4d_0_4.png) k Principles of Radiation Therapy (NHODG-D).

* Lugano Response Criteria for Non-Hodgkin Lymphoma (NHODG-C). PET/CT scan should be interpreted via the PET 5-PS.

s GELF criteria (FOLL-A).

t APET-positive PR is associated with a shortened progression-free survival (PFS) (Discussion); however, additional treatment at this juncture has not been shown to change outcome.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Pediatric-Type Follicular Lymphoma

NCCN Guidelines Index Table of Contents Discussion

PEDIATRIC-TYPE FOLLICULAR LYMPHOMA IN ADULTS

PATHOLOGIC AND CLINICAL PRESENTATION$^{c,u}$

STAGING WORKUP

TREATMENT

* Pathologic * Morphology: expansile follicles, effacement of architecture, absence of diffuse area * Expresses: BCL6, CD10, ± IRF4/ MUM1 (~20%) * Proliferation index (Ki-67/MIB-1) >30% * No rearrangement of BCL2, BCL6, IRF4/MUM1 * Clinical * Localized disease (stage I, II) * Head and neck (tonsillar, cervical, submandibular, submental, postauricular, or periparotid lymph nodes) or less common inguinal lymph nodes * Male sex predominant * Younger age than typical FL (though can occur in adults >60 years)

![graph TD\n A1[PET/CT scan • Bone marrow biopsy （optional）] --> A2[Stage Ⅰ,Ⅱu]\n A2 --> A3[Excision （preferred）或 ISRTk 或 RCHOP for patients with extensive local disease who are not candidates for excision or ISRT]\n A3 --> A4[Active surveillancev]\n A3 --> A5[Restage with PET/CT]\n A5 --> A6[CR⁰]\n A5 --> A7[<CR]\n A6 --> A4\n A7 --> A8[NR or Progressive disease （FOLL-5）]\n](1/parseimages/figure58ac8b3000d240f287c26428e406783b_0_9.png) $^{c}$ In young patients with localized disease that lacks BCL2 expression or t(14;18), differential diagnosis should include PTFL in adults; BCL2-R negative, CD23-positive follicle center lymphoma (ICC)/dFL (WHO5), and LBCL with IRF4/MUM1 rearrangement.

k Principles of Radiation Therapy (NHODG-D).

$^{0}$ Lugano Response Criteria for Non-Hodgkin Lymphoma (NHODG-C). PET/CT scan should be interpreted via the PET 5-PS.

$^{u}$ Localized disease (stage I, II) is the most common presentation. If the patient has disease >stage II, it is by definition not PTFL.

$\bullet$ Patients typically have an excellent prognosis and therefore, the majority of patients will not require surveillance imaging. There are no data to support maintenance therapy.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Classic Follicular Lymphoma

NCCN Guidelines Index Table of Contents Discussion

|GELF $CRITERIA^{a,b}$| |---| |• Involvement of ≥3 nodal sites, each with a diameter of ≥3 cm • Any nodal or extranodal tumor mass with a diameter of ≥7 cm • B symptoms • Splenomegaly • Pleural effusions or peritoneal ascites • Cytopenias (leukocytes <1.0 x 10$^{9}$/L and/or platelets <100 x 10$^{9}$/L) • Leukemia (>5.0 x 10$^{9}$/L malignant cells)|

|FLIPI - 1 CRITERIA$^{a,c}$|||| |---|---|---|---| |RISK FACTORS|RISK FACTORS|RISK GROUPS|RISK GROUPS| |• Age|≥60 y||Number of factors| |• Ann Arbor Stage|III-IV|Low|0-1| |• Hemoglobin level|<12 g/dL|Intermediate|2| |• Serum LDH level|>ULN|High|≥3| |• Number of nodal $sites^{d}$|≥5|||

ULN = upper limit of normal

![Nodal AreasLeft CervicaRight CervicaPreauricularPreauricularUpper CervicaUpper CervicaMedian or LowerMedian or LowerPostcervicalPostcervicaSupraclavicularSupraclavicularMediastinaParatracheaMediastinalHilarLeft AxillaryRight AxillaryLeft EpitrochleaRight EpitrochlearPara-AorticMesentericPara-AorticMesentericCommon lliacSplenic HilarExternal IliacPortaCeliacRight InguinaLeft InguinaInguinaInguinaFemoraFemoralRight PoplitealLeft PopliteaLegend for labelsBlue = BilateralBlack = Midline\n](1/parseimages/figurebf2f3d89b6bb4aa889f375d6f850cfaa_0_7.png) Mannequin used for counting the number of involved areas.d

All rights reserved. Permission is hereby granted for copying this image by photocopy or similar process for use in the practice of medicine or for research purposes. No other use is permitted which will infringe for use in the practice of medicine or for research purposes. No other use is permitted which will infringe for use in the practice of medicine or for research purposes. No other use is permitted which will infringe for use in the practice of medicine or for research purposes. No other use is permitted which will infringe for use in the practice of medicine or for research purposes. No other use is permitted which will infringe for use in the practice of medicine or for research purposes. No other use is permitted which will infringe for use in the practice of medicine or for research purposes. No other use is permitted which will infringe for use in the practice of medicine or for research purposes. No other use is permitted which will infringe for use in the practice of medicine or for research purposes. No other use is permitted which will infringe for use in the practice of medicine or for research purposes. No other use is permitted which will infringe for use in the practice of medicine or for research purposes. No other use is permitted which will infringe for use in the practice of medicine or for research purposes. No other use is permitted which will infringe for use in the practice of medicine or for research purposes. No other use is permitted which will infringe for use in the practice of medicine or for research purposes. No other use is permitted which will infringe for use in the practice of medicine or for research purposes. No other use is permitted which will infringe for use in the practice of medicine or for research purposes. No other use is permitted which will infringe for use in the practice of medicine or for research purposes. No other use is permitted which will infringe for use in the practice of medicine or for research purpose

a These criteria may be clinically useful to guide initiation of treatment.

b Solal-Celigny P, Lepage E, Brousse N, et al. Doxorubicin-containing regimen with or without interferon alfa 2b for advanced follicular lymphomas: final analysis of survival and toxicity in the Groupe d'Etude des Lymphomes Folliculaire 86 trial. J Clin Oncol 1998;16:2332-2338.

c This research was originally published in Blood. Solal-Celigny P, Roy P, Colombat P, et al. Follicular lymphoma international prognostic index. Blood 2004;104:1258-1265. © the American Society of Hematology.

d The map is used to determine the number of nodal sites in FLIPI-1 criteria and is different than the conventional Ann Arbor site map.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Classic Follicular Lymphoma

NCCN Guidelines Index Table of Contents Discussion

SUGGESTED TREATMENT REGIMENSa,b,c

|FIRST-LINE THERAPY|FIRST-LINE THERAPY| |---|---| |Preferred, high tumor burden (in alphabetical order)|| |Bendamustine$^{d}$ + Obinutuzumab$^{e,f}$ or Rituximab|| |CHOP (Cyclophosphamide/Doxorubicin/Vincristine/Prednisone) + Obinutuzumab$^{e,f}$ or Rituximab|| |CVP (Cyclophosphamide/Vincristine/Prednisone) + Obinutuzumab$^{e,f}$ or Rituximab|| |Lenalidomide + Rituximab|| |Preferred, low tumor burden|| |Rituximab (375 mg/m$^{2}$ weekly for 4 doses)$^{g}$|| |Other recommended|Other recommended| |Lenalidomide + Obinutuzumab (category 2B)||

FIRST-LINE THERAPY FOR OLDER OR INFIRM

(if none of the above are expected to be tolerable in the opinion of treating physician)

Preferred

$\bullet$ Rituximab (375 mg/m$^{2}$ weekly for 4 doses)

FIRST-LINE EXTENDED THERAPY (optional)

Preferred following chemoimmunotherapy

$\bullet$ Rituximab maintenance 375 mg/m$^{2}$ one dose every 8–12 weeks for 2 years for patients initially presenting with high tumor burden (category 1)$^{h}$

$\bullet$ Obinutuzumab maintenance (1 g every 8 weeks for 12 doses)

Other recommended

$\bullet$ If initially treated with single-agent Rituximab, Rituximab maintenance 375 mg/m$^{2}$ one dose every 8 weeks for 4 doses

Consider prophylaxis for tumor lysis syndrome (NHODG-B)

See monoclonal antibody and viral reactivation (NHODG-B)

Footnotes Second-line Therapy on FOLL-B 2 of 6

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 1.2026 Classic Follicular Lymphoma

NCCN Guidelines Index Table of Contents Discussion

SECOND-LINE THERAPYi

Preferred (in alphabetical order)

• Bendamustined,j + Obinutuzumabe,f or Rituximab (not recommended if treated with prior Bendamustine)

• CHOP + Obinutuzumabe,f or Rituximab

• CVP + Obinutuzumabe,f or Rituximab

• Lenalidomide + Rituximab + Epcoritamab-byspk,l (category 1)

• Lenalidomide + Rituximab + Tafasitamab-cxixl,m (≥1 prior systemic therapy including an anti-CD20 mAb)(category 1)

Other recommended (in alphabetical order)

• Lenalidomide (if not a candidate for anti-CD20 mAb therapy)

• Lenalidomide + Obinutuzumab or Rituximab

• Obinutuzumab

• Rituximab

SECOND-LINE THERAPY FOR OLDER OR INFIRM

(if none of the therapies are expected to be tolerable in the opinion of treating physician)

Preferred• Rituximab (375 mg/m2 weekly for 4 doses)

• Tazemetostatl (irrespective of EZH2 mutation status)

SECOND-LINE EXTENDED THERAPY (optional)

Preferred• Rituximab maintenance 375 mg/m2 one dose every 12 weeks for 2 years (category 1)

• Obinutuzumab maintenance for rituximab-refractory disease (1 g every 8 weeks for total of 12 doses)

Note: All recommendations are category 2A unless otherwise indicated.

FOLL-B 2 OF 6

SUGGESTED TREATMENT REGIMENSa,b,c

Consider prophylaxis for tumor lysis syndrome (NHODG-B)See monoclonal antibody and viral reactivation (NHODG-B)

Third-line and Subsequent Therapy on FOLL-B 3 of 6 Footnotes

NCCN Guidelines Version 1.2026 Classic Follicular Lymphoma

NCCN Guidelines Index Table of Contents Discussion

THIRD-LINE AND SUBSEQUENT THERAPY

Second-line therapy regimens (FOLL-B 2 of 6) that were not previously given can also be used as options for third-line and subsequent therapy

Preferred (in alphabetical order)

• T-cell mediated therapyk

Bispecific antibody therapyl

◊ Epcoritamab-bysp

◊ Mosunetuzumab-axgb

Chimeric antigen receptor (CAR) T-cell therapym,n◊ Axicabtagene ciloleucel (CD19-directed)

◊ Lisocabtagene maraleucel (CD19-directed)◊ Tisagenlecleucel (CD19-directed)

Other recommended

• EZH2 inhibitor

Tazemetostatl (irrespective of EZH2 mutation status)

• BTK inhibitor (BTKi)

Zanubrutinibl + Obinutuzumab

• Loncastuximab tesirine-lpylm,l + Rituximab (category 2B)

Note: All recommendations are category 2A unless otherwise indicated.

FOLL-B 3 OF 6

SUGGESTED TREATMENT REGIMENSa,b,c

Consider prophylaxis for tumor lysis syndrome (NHODG-B)See monoclonal antibody and viral reactivation (NHODG-B)

THIRD-LINE CONSOLIDATION THERAPY

Useful in Certain Circumstances• Allogeneic hematopoietic cell transplantation (HCT) in selected caseso

Footnotes

NCCN Guidelines Version 1.2026 Classic Follicular Lymphoma

NCCN Guidelines Index Table of Contents Discussion

Note: All recommendations are category 2A unless otherwise indicated.

FOLL-B 4 OF 6

SUGGESTED TREATMENT REGIMENS FOOTNOTES

a See references for regimens on FOLL-B 5 of 6 and FOLL-B 6 of 6.b An FDA-approved biosimilar is an appropriate substitute for any recommended systemic biologic therapy in the NCCN Guidelines. Rituximab and hyaluronidase

human injection for subcutaneous use may be substituted for rituximab after patients have received the first full dose of rituximab by intravenous infusion.

c The choice of therapy requires consideration of many factors, including age, comorbidities, and future treatment possibilities (eg, high-dose therapy [HDT] with

autologous stem cell rescue [ASCR]). Therefore, treatment selection is highly individualized.

d In the GALLIUM study, there was an increased risk of mortality from opportunistic infections and secondary malignancies in patients receiving bendamustine.

Increased risk of mortality occurred over the entire treatment program and extending beyond maintenance. Prophylaxis for pneumocystis jirovecii pneumonia (PJP) and varicella zoster virus (VZV) should be administered; see NCCN Guidelines for Prevention and Treatment of Cancer-Related Infections.

e The clinical trial evaluating this regimen included obinutuzumab maintenance. The use without maintenance was an extrapolation of the data.f Obinutuzumab is preferred for patients with rituximab refractory disease, which includes disease progressing on or within 6 months of prior rituximab therapy.g Rituximab may be appropriate if active surveillance was initial therapy and for patients with progression of low tumor burden disease not meeting GELF criteria

(FOLL-A). Immediate initial therapy with rituximab in patients not meeting GELF criteria has not improved overall survival (Ardeshna K, et al. Lancet Oncol

2014;15:424-435).

h This is based on the PRIMA study for patients with high tumor burden following treatment with RCVP and RCHOP. There are no data for rituximab maintenance

following other regimens.

i Generally, a first-line regimen is not repeated.j In patients intended to receive CAR T-cell therapy or CD3 x CD20 bispecific antibody therapy, bendamustine should be used with caution. Delay bendamustine until

after CAR-T leukapheresis.

k In the setting of CD20-negative lymphomas, the efficacy of CD3 x CD20 bispecific antibody therapy is poor. If clinically feasible, repeat biopsy to confirm antigen

expression prior to the initiation of T-cell mediated therapy.

l Refer to package insert for full prescribing information, dose modifications, and monitoring for adverse reactions: https://www.accessdata.fda.gov/scripts/cder/daf/index.

cfm.

m It is unknown if tafasitamab-cxix or loncastuximab tesirine-lpyl or if any other CD19–directed therapy would have a negative impact on the efficacy of subsequent antiCD19 CAR T-cell therapy. If clinically feasible, repeat biopsy to confirm antigen expression prior to the initiation of CD19-directed CAR T-cell therapy.

n NCCN Guidelines for Management of CAR T-Cell and Lymphocyte Engager-Related Toxicities.o Selected cases include mobilization failures and persistent bone marrow involvement.

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Classic Follicular Lymphoma

NCCN Guidelines Index Table of Contents Discussion

SUGGESTED TREATMENT REGIMENS REFERENCES

First-line Therapy Bendamustine + rituximab Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indental and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet 2013;381:1203-1210. Flinn IW, van der Jagt R, Kahl BS, et al. Open-label, randomized, noninferiority study of bendamustine-rituximab or R-CHOP/R-CVP in first-line treatment of advanced indolent NHL or MCL: the BRIGHT study. Blood 2014;123:2944-2952. Bendamustine + obinutuzumab Marcus R, Davies A, Ando K, et al. Obinutuzumab for the first-line treatment of follicular lymphoma. N Engl J Med 2017;377:1331-1344. RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) Czuczman MS, Weaver R, Alkuzweny B, et al. Prolonged clinical and molecular remission in patients with low-grade or follicular non-Hodgkin's lymphoma treated with rituximab plus CHOP chemotherapy: 9-year follow-up. J Clin Oncol 2004;22:4711-4716. Hiddemann W, Kneba M, Dreyling M, et al. Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood 2005;106:3725-3732. CHOP + obinutuzumab Marcus R, Davies A, Ando K, et al. Obinutuzumab for the first-line treatment of follicular lymphoma. N Engl J Med 2017;377:1331-1344. RCVP (rituximab, cyclophosphamide, vincristine, prednisone) Marcus R, Imrie K, Solal-Celigny P, et al. Phase III study of R-CVP compared with cyclophosphamide, vincristine, and prednisone alone in patients with previously untreated advanced follicular lymphoma. J Clin Oncol 2008;26:4579-4586. CVP + obinutuzumab Marcus R, Davies A, Ando K, et al. Obinutuzumab for the first-line treatment of follicular lymphoma. N Engl J Med 2017;377:1331-1344. RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) Marcus R, Davies A, Ando K, et al. Obinutuzumab for the first-line treatment of follicular lymphoma. N Engl J Med 2017;377:1331-1344. Rituximab Witzig TE, Vukov AM, Habermann TM, et al. Rituximab therapy for patients with newly diagnosed, advanced-stage, follicular grade I non-Hodgkin's lymphoma: a phase II trial in the North Central Cancer Treatment Group. J Clin Oncol 2005;23:1103-1108. Martinelli G, Schmitz SF, Utiger U, et al. Long-term follow-up of patients with follicular lymphoma receiving single-agent rituximab at two different schedules in trial SAKK 35/98. J Clin Oncol 2010;28:4480-4484. Northend M, Wilson W, Ediriwickrema K, et al. Early rituximab monotherapy versus watchful waiting for advanced stage, asymptomatic, low tumour burden follicular lymphoma: long-term results of a randomised, phase 3 trial. Lancet Haematol 2025;12:e335-e345.

Cartron G, Bachy E, Tilly H, Randomized phase III Trial evaluating subcutaneous rituximab for the first-line treatment of low-tumor burden follicular lymphoma: Results of a LYSA study. J Clin Oncol 2023;41:3523-3533. Erratum in: J Clin Oncol 2023;41:4187.

Kahl BS, Jegede OA, Peterson C, et al. Long-Term Follow-Up of the RESORT Study (E4402): A Randomized Phase III Comparison of Two Different Rituximab Dosing Strategies for Low-Tumor Burden Follicular Lymphoma. J Clin Oncol 2024;42:774-778.

Northend M, Wilson W, Clifton-Hadley L, et al. Long term follow-up of international randomised phase 3 study of rituximab versus a watch and wait approach for patients with asymptomatic, low tumour burden follicular lymphoma shows rituximab is highly effective at delaying time to new treatment without detrimental impact following next line of therapy [abstract]. Blood 2022;140:1456-1458.

Lenalidomide + rituximab

Martin P, Jung SH, Pitcher B, et al. A phase II trial of lenalidomide plus rituximab in previously untreated follicular non-Hodgkin's lymphoma (NHL): CALGB 50803 (Alliance). Ann Oncol 2017;28:2806-2812.

Fowler N, Davis R, Rawal S, et al. Safety and activity of lenalidomide and rituximab in untreated indolent lymphoma: an open-label, phase 2 trial. Lancet Oncol 2014;15:1311-1318.

Morschhauser F, Fowler NH, Feugier P, et al. Rituximab plus lenalidomide in advanced untreated follicular lymphoma. N Engl J Med 2018;379:934-947.

Lenalidomide + obinutuzumab

Bachy E, Houot R, Feugier P, et al. Obinutuzumab plus lenalidomide (GALEN) in advanced, previously untreated follicular lymphoma in need of systemic therapy: a LYSA study. Blood 2022;139:2338-2346.

First-line Extended Dosing

Chemmoimmunotherapy followed by rituximab maintenance

Bachy E, Seymour JF, Feugier P, et al. Sustained progression-free survival benefit of rituximab maintenance in patients with follicular lymphoma: Long-term results of the PRIMA Study. J Clin Oncol 2019;37:2815-2824.

Extended dosing with rituximab

Ghielmini M, Schmitz SH, Cogliatti SB, et al. Prolonged treatment with rituximab in patients with follicular lymphoma significantly increases event-free survival and response duration compared with the standard weekly x 4 schedule. Blood 2004;103:4416-4423.

Obinutuzumab-based chemoimmunotherapy followed by obinutuzumab maintenance Marcus R, Davies A, Ando K, et al. Obinutuzumab for the first-line treatment of follicular lymphoma. N Engl J Med 2017;377:1331-1344.

Continued

FOLL-B 5 OF 6

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Classic Follicular Lymphoma

NCCN Guidelines Index Table of Contents Discussion

SUGGESTED TREATMENT REGIMENS REFERENCES

Second-line and Subsequent Therapy

Bendamustine + obutinuzumab

Sehn LH, Chua N, Mayer J, et al. Obinutuzumab plus bendamustine versus bendamustine monotherapy in patients with rituximab-refractory indolent non-Hodgkin lymphoma (GADOLIN): a randomised, controlled, open-label, multicentre, phase 3 trial. Lancet Oncol 2016;17:1081-1093.

Lenalidomide ± rituximab

Leonard JP, Jung SH, Johnson J, et al. Randomized trial of lenalidomide alone versus lenalidomide plus plus rituximab in patients with recurrent follicular lymphoma: CALGB 50401 (Alliance). J Clin Oncol 2015;33:3635-3640.

Leonard JP, Trneny M, Izutsu K, et al. AUGMENT: A phase III study of lenalidomide plus rituximab versus placebo plus rituximab in relapsed or refractory indolent lymphoma. J Clin Oncol 2019;37:1188-1199.

Lenalidomide + obinutuzumab

Morschhauser F, Le Gouill S, Feugier P, et al. Obinutuzumab combined with lenalidomide for relapsed or refractory follicular B-cell lymphoma (GALEN): a multicentre, single-arm, phase 2 study. Lancet Haematol 2019;6:e429-e437.

Lenalidomide + Rituximab + Epcoritamab-bysp

Falchi L, Nijland M, Huang H, et al. Epcoritamab, lenalidomide, and rituximab versus rituximab and rituximab for refractory follicular lymphoma (EPCORE FL-1): a global, open-label, randomised, phase 3 trial. The Lancet 2025:Online Ahead of Print.

Rituximab

McLaughlin P, Grillo-Lopez AJ, Link BK, et al. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol 1998;16:2825-2833.

Lenalidomide + rituximab + tafasitamab-cxix

Sehn LH, Hübel K, Luminari S, et al. Tafasitamab, lenalidomide, and rituximab in relapsed or refractory follicular lymphoma (inMIND): a global, phase 3, randomised controlled trial. Lancet 2025:Online ahead of print.

Tazemetostat

Morschhauser F, Tilly H, Chaidos A, et al. Tazemetostat for patients with relapsed or refractory follicular lymphoma: an open-label, single-arm, multicentre, phase 2 trial. Lancet Oncol 2020;21:1433-1442.

Second-line Extended Dosing

Zunadomide

Lanecet Maatamabat

van Oers MHJ, Van Glabbeke M, Giurgea L, et al. Rituximab maintenance treatment of relapsed/ resistant follicular non-hodgkin's lymphoma: Long-term outcome of the EORTC 20981 Phase III randomized Intergroup Study. J Clin Oncol 2010;28:2853-2858.

Obinutuzumab maintenance for rituximab refractory disease

Note: All recommendations are category 2A unless otherwise indicated.

Third-line and Subsequent Therapy

Loncastuximab tesirine-lpyl + rituximab

Aideruccio JP, Alencar AJ, Schatz JH, et al. Loncastuximab tesirine with rituximab in patients with relapsed or refractory follicular lymphoma: A single-centre, single-arm, phase 2 trial. Lancet Haematol 2025;12:e23-e34.

Zanubrutinib + obutunuzumab

Zinzani PL, Mayer J, Flowers CR, et al. ROSEWOOD: A phase II randomized study of zanubrutinib plus obinutuzam versus obinutuzumab monotherapy in patients with relapsed or refractory follicular lymphoma. J Clin Oncol 2023;41:5107-5117.

Zinzani PL, Mayer J, Flowers C, et al. Final analysis of the randomized phase 2 ROSEWOOD study of zanubrutinib + obinutuzumab vs obinutuzumab monotherapy in patients with relapsed/refractory follicular lymphoma [abstract]. Blood 2025;146:Abstract 227.

T-Cell-Mediated Therapy

CAR T-Cell Therapy

Axicabtagene cilolecue1

Neelapu SS, Chavez JC, Seghal AR, et al. Three-year follow-up analysis of axicabtagene ciloleucel in relators/refractory indolent non-Hodgkin lymphoma (ZUMA-5). Blood 2024;143:496-506.

Lisocabtagene maraleucel

Morschhauser F, Dahiya S, Palomba ML, et al. Lisocabtagene maraleucel in follicular lymphoma: the phase 2 TRANSCEND FL study. Nat Med 2024;30:2199-2207.

Ahmed S, Martin Garcia-Sancho A, Reguera JL, et al. Three-Year Efficacy and Longitudinal Safety of Liscabtagene Maraleucel (liso-cel) in Patients With Third-Line or Later (3L+) Follicular Lymphoma (FL) From TRANSCEND FL [abstract]. Blood 2025;146:Abstract 467.

Tisagenleuclei

Dreyling, M, Fowler NH, Dickinson M, et al. Durable response after tisagenlecleucel in adults with relapsed/refractory follicular lymphoma: ELARA trial update. Blood 2024;143:1713-1725.

Schuster S, Thieblemont C, Dickinson M, et al. Clinical outcomes of tisagenlecleucel in patients with relapsed/refractory follicular lymphoma (rr(rL)); Phase 2 ELARA 5-year update [abstract]. Blood 2025;146:Abstract 468.

Bispecific Antibody Therapy

Epocritamab-bysp

Linson KM, Vitolo U, Jurczak W, et al. Epcoritamab monotherapy in patients with relapsed or refractory follicular lymphoma (EPCORE NHL-1): a phase 2 cohort of a single-arm, multicentre study. Lancet Haematol 2024;11:433-1442.

Mosunetuzumab-axgb

Sehn LH, Bartlett NL, Matasar MJ, et al. Long-term 3-year follow-up of mosunetuzumab in relapsed or refractory follicular lymphoma after >=2 prior therapies. Blood 2025;145:708-719.

Budde E, Sehn L, Matasar M, et al. Fixed treatment duration mosunetuzumab continues to demonstrate clinically meaningful outcomes in patients with relapsed/refractory (R/R) follicular lymphoma (FL) after ≥2 prior therapies: 5-year follow-up of a pivotal Phase II study [abstract]. Blood 2025;146:Abstract 5352.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Marginal Zone Lymphomas

NCCN Guidelines Index Table of Contents Discussion

![graph TD\n A1[Extranodal marginal zone lymphoma (EMZL)] --> A2[EMZL of the stomach]\n A1 --> A3[EMZL of nongastric sites(noncutaneous)]\n A1 --> A4[Cutaneous]\n A2 --> A5[Diagnosis and Workup (EMZLG-1)]\n A3 --> A6[Diagnosis and Workup (EMZLNG-1)]\n A4 --> A7[Primary Cutaneous Marginal Zone Lymphoma in NCCN Guidelines for Cutaneous Lymphomas]\n](1/parseimages/figurefa83e76fe8674164bb9834ca625ee90b_0_4.png) Nodal marginal zone lymphoma (NMZL) $\rightarrow$ Diagnosis and Workup (NMZL-1)

Splenic marginal zone lymphoma (SMZL) $\rightarrow$ Diagnosis and Workup (SMZL-1)

Histologic transformation to DLBCL $\rightarrow$ HTBCEL-1

Note: All recommendations are category 2A unless otherwise indicated.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Extranodal Marginal Zone B-Cell Lymphoma

NCCN Guidelines Index Table of Contents Discussion

ADDITIONAL DIAGNOSTIC TESTING$^{a,b}$

ESSENTIAL:

* Diagnosis of EMZL of the stomach requires an endoscopic biopsy. An FNA is never adequate.

$\bullet$ Adequate immunophenotyping to establish $diagnosis^{c}$

$\blacktriangleright$ IHC panel: CD20, CD3, CD5, CD10, BCL2, kappa/lambda, CD21 or CD23, cyclin D1, d BCL6

* Helicobacter pylori stain (gastric), if positive, then FISH for MALT1 rearrangements$^{e}$

USEFUL UNDER CERTAIN CIRCUMSTANCES:

* Flow cytometry with peripheral blood and/or biopsy specimen in the presence of lymphocytosis: kappa/lambda, CD19, CD20, CD5, CD23, CD10

$\bullet$ Molecular analysis to detect: Ig gene rearrangements; MYD88 mutation status to help differentiate Waldenström macroglobulinemia (WM) (90%) versus MZL (10%) if plasmacytic differentiation present

* FISH: t(1;14); t(3;14); t(11;14)d; t(14;18)

WORKUP

ESSENTIAL:

* Physical exam

* Performance status

$\bullet$ CBC with differential

* Comprehensive metabolic panel

$\bullet$ LDH

$\bullet$ If H. pylori negative by histopathology, then use noninvasive H. pylori testing (stool antigen test or urea breath test)

$\bullet$ Hepatitis B testingf

$\bullet$ Hepatitis C testing

$\bullet$ SPE with SIFE and/or quantitative Ig levels

C/A/P CT with contrast of diagnostic quality or PET/CT scan$^{9}$ (especially if ISRT anticipated)

Pregnancy testing in patients of childbearing age (if therapy planned)

USEFUL IN SELECTED CASES:

$\bullet$ Bone marrow biopsy ± aspirate (to document clinical stage I-II disease if ISRT planned, or to evaluate unexplained cytopenias)$^{h}$

* Echocardiogram or MUGA scan if anthracycline-based regimen is indicated

$\bullet$ Endoscopy with ultrasound (if available) with multiple biopsies of anatomical sites$^{1}$

* Discuss fertility preservation$^{1}$

a Nondiagnostic atypical lymphoid infiltrates that are H. pylori positive should be rebiopsied to confirm or exclude lymphoma prior to treatment of H. pylori.

b Any area of DLBCL should be treated as DLBCL (BCEL-1).

c Typical immunophenotype: CD10-, CD5-, CD20+, cyclin D1-, with BCL2-follicles.

d In CD5+ cases, concurrent IHC positivity for cyclin D1 is more compatible with the diagnosis of MCL. FISH for t(11;14) is helpful to exclude the diagnosis of MCL; see MANT-1.

e Locally advanced disease is more likely in patients with EMZL of the stomach with t(11;18), and is a predictor for lack of tumor response (<5%) to antibiotic therapy.

f Hepatitis B testing is indicated because of the risk of reactivation with immunotherapy + chemotherapy. Tests include HBsAg and core antibody for a patient with no risk factors. For patients with risk factors or previous history of hepatitis B, add e-antigen (NODG-B). If positive, check viral load and consider consult with gastroenterologist.

9 PET/CT scan may be negative in marginal zonal lymphomas. In such cases, CT scan is recommended.

h Bilateral or unilateral provided core biopsy is >2 cm. If active surveillance is initial therapy, bone marrow biopsy may be deferred.

i This is particularly useful for H. pylori-positive cases because the likelihood of tumor response is related to depth of tumor invasion.

f. Fertility preservation options include: sperm banking, IVF, or ovarian tissue or oocyte cryopreservation.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Extranodal Marginal Zone B-Cell Lymphoma Extranodal MZL of the Stomach

NCCN Guidelines Index Table of Contents Discussion

![graph TD\n A1[Stage II or Stage IV (distant nodal, advanced stage)] --> A2[EMZLG-3]\n A3[Stage I or Stage II] --> A4[H. pylori positive, t(11;18) positive]\n A3 --> A5[H. pylori negative]\n A3 --> A6[H. pylori positive, t(11;18) negative or t(11;18) unknown]\n A4 --> A7[Currently accepted antibiotic therapy for H. pylori and ISRTn (preferred) or Rituximab(if ISRT is contraindicated or unavailable)]\n A5 --> A10[ISRTn,o (preferred) or Rituximab(if ISRT is contraindicated or unavailable)]\n A6 --> A8[Currently accepted antibiotic therapy for H. pylori]\n A7 --> A9[EMZLG-5]\n A8 --> A9\n A10 --> A9\n A11[EMZL of the stomach] --> A12[Manage as Diffuse Large]\n](1/parseimages/figurecf21fadc00e24b388159d1aec81bb0f9_0_4.png) $^{k}$ Staging of EMZL of the Stomach: Comparison of Different Systems (EMZLG-A).

$^{1}$ Involvement of submucosa or regional lymph nodes are much less likely to respond to antibiotic therapy. If there is persistent disease after evaluation, RT may be considered earlier in the course.

$m$ t(11;18) is a predictor for lack of tumor response (<5%) to antibiotic therapy. Antibiotic therapy is used in these patients to eradicate the H. pylori infection. These patients should be considered for alternative therapy for lymphoma. Liu H, et al. Gastroenterology 2002;122:1286-1294.

$^{n}$ Principles of Radiation Therapy (NHODG-D).

° If H. pylori negative by both histology and serum antibodies, ISRT is recommended.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Extranodal Marginal Zone B-Cell Lymphoma

Extranodal MZL of the Stomach

NCCN Guidelines Index Table of Contents Discussion

![graph TD\n A1[Evaluate for indications for treatment: • Candidate for clinical trial® • Symptoms • Gastrointestinal(GI) bleeding • Threatened end-organ function • Clinically significant bulky disease • Steady or rapid progression] -->|No indication| A2[Active surveillance]\n A1 -->|Indication present§| A3[ISRT preferred if disease can be encompassed in a single field¨ or Manage per advanced-stage NMZL(NMZL-3)]\n A2 --> A1\n A3 --> A4[Evaluate with endoscopy, if evidence of recurrence(MZL), Second-line and Subsequent Therapy for Marginal Zone Lymphomas(MZL-A 2 of 4 and MZL-A 3 of 4)r • If histologic transformation, see HTBCEL-1]\n](1/parseimages/figure8fc39f4b2f8343cfbb42b4adfb0c7f83_0_4.png) NCCN 授权医脉通提供NCCN指南全文下载。wmlsyy于2025/12/23,21:20在医脉通平台下载,仅供个人使用,严禁分发。2025 美国国家综合癌症网络版权所有。

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Extranodal Marginal Zone B-Cell Lymphoma

Extranodal MZL of the Stomach

NCCN Guidelines Index Table of Contents Discussion

RESTAGING WITH ENDOSCOPY/BIOPSY

![graph TD\n A1[Restage at 6 mo with endoscopy/biopsy, for H. pylori/lymphoma after antibiotics] --> A2[H. pylori negative, Lymphoma negative]\n A1 --> A3[H. pylori negative, Lymphoma positive]\n A1 --> A4[H. pylori positive, Lymphoma negative]\n A1 --> A5[H. pylori positive, Lymphoma positive]\n A2 --> A6[EMZLG-6]\n A3 --> A7[Repeat endoscopy and biopsy after 3 mo or ISRTn]\n A3 --> A6\n A4 --> A10[Second-line antibiotic treatment and reassess]\n A5 --> A11[Stable disease]\n A5 --> A12[Progressive or symptomatic disease]\n A7 --> A6\n A8[Asymptomatic] --> A9[ISRTn]\n A9 --> A6\n A10 --> A6\n A11 --> A10\n A12 --> A13[ISRTn and second-line antibiotic treatment and reassess]\n A13 --> A6\n](1/parseimages/figure3dd81048a0c64be7a7a7d3a9fb9ef739_0_5.png) $^{n}$ Principles of Radiation Therapy (NHODG-D).

$^{s}$ If symptomatic, restaging should be done as clinically indicated.

† Reassessment to rule out H. pylori by institutional standards. Biopsy to rule out large cell lymphoma. Any area of DLBCL should be treated as DLBCL (BCEL-1). $^{u}$ If re-evaluation suggests slowly responding disease or asymptomatic nonprogression, continued active surveillance may be warranted. Complete responses may be achieved as early as 3 months after initial therapy, but can take longer to achieve (up to 18 months) (category 2B).

Note: All recommendations are category 2A unless otherwise indicated.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Extranodal Marginal Zone B-Cell Lymphoma Extranodal MZL of the Stomach

Extranodal MZL of the Stomach

NCCN Guidelines Index Table of Contents Discussion

RESTAGING WITH ENDOSCOPY/BIOPSY

AFTER ISRT OR RITUXIMAB

![graph TD\n A1[Restage at 6 mo with endoscopy and biopsy if <1 or rituximab] --> A2[H. pylori negative Lymphoma negative]\n A1 --> A3[H. pylori positive Lymphoma negative]\n A1 --> A4[H. pylori negative Lymphoma positive]\n A1 --> A5[H. pylori positive Lymphoma positive]\n A2 --> A6[EMZLG-6]\n A3 --> A7[Second-line antibiotic treatment and reassess]\n A4 --> A6\n A5 --> A8[Second-line antibiotic treatment and reassess]\n](1/parseimages/figuredcf18d9a1a9d420a82ede3e09a41211b_0_7.png) $^{s}$ If symptomatic, restaging should be done as clinically indicated.

† Reassessment to rule out H. pylori by institutional standards. Biopsy to rule out large cell lymphoma. Any area of DLBCL should be treated as DLBCL (BCEL-1).

$^{u}$ If re-evaluation suggests slowly responding disease or asymptomatic nonprogression, continued active surveillance may be warranted. Complete responses may be achieved as early as 3 months after initial therapy, but can take longer to achieve (up to 18 months) (category 2B).

Note: All recommendations are category 2A unless otherwise indicated.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Extranodal Marginal Zone B-Cell Lymphoma

Extranodal MZL of the Stomach

NCCN Guidelines Index Table of Contents Discussion

![NCCN\n#NCCN Guidelines Version 1.2026\n##Extranodal Marginal Zone B-Cell Lymphoma\n##Extranodal MZL of the Stomach\n##Response after completion of antibiotic treatment, ISRT, or $rituximab^{t,u}$ $H.$ pylori negative $H.$ pylori positive, Lymphoma negative $H.$ pylori positive, Lymphoma negative $H.$ pylori positive, Lymphoma positive $H.$ pylori positive, Lymphoma positive $H.$ pylori positive, Lymphoma positive $H.$ pylori positive, Lymphoma positive $H.$ pylori positive, Lymphoma positive $H.$ pylori positive, Lymphoma positive\n\n### Recurrence post ISRT or rituximab\n#### EmZLG-3\nSystemic recurrence recurrence\nLocal recurrence recurrence\nISRT$^{n}$\nIndication for*sum\n######ISRT\nIndication for*sum\n#######ISRT\nIndication for*sum\n#######ISRT\nIndication for*sum\n#######ISRT\nIndication for*sum\n#######ISRT\nIndication for*sum\nIndication for*sum\nIndication for*sum\nIndication for*sum\nIndication for*sum\nIndication for*sum\nIndication for*sum\nIndication for*sum\nIndication for*sum\nIndication for*sum\nIndication for*sum\nIndication for*sum\nIndication for*sum\nIndication for*sum\nIndication for*sum\nIndica\n](1/parseimages/figurefb5b93b80acd4fc486fba3f99284db74_0_4.png) $^{n}$ Principles of Radiation Therapy (NHODG-D).

† Reassessment to rule out H. pylori by institutional standards. Biopsy to rule out large cell lymphoma. Any area of DLBCL should be treated as DLBCL (BCEL-1).

$\bullet$ Optimal interval for follow-up endoscopy and imaging is not known. Follow-up endoscopy and imaging using the modalities performed during workup is driven by symptoms. Relapse rates are higher after treatment with rituximab and may warrant serial endoscopy.

W Optional first-line extended therapy (rituximab maintenance 375 mg/m$^{2}$ one dose every 8–12 weeks for up to 2 years) for patients treated with single-agent rituximab (MZL-A 1 of 4).

Note: All recommendations are category 2A unless otherwise indicated.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Extranodal Marginal Zone B-Cell Lymphoma Extranodal MZL of the Stomach

NCCN Guidelines Index Table of Contents Discussion

STAGING OF EMZL OF THE STOMACH: COMPARISON OF DIFFERENT SYSTEMS

|Lugano Staging System for Gastrointestinal Lymphomas|Lugano Modification of Ann Arbor Staging System|TNM Staging System Adapted for Gastric Lymphoma|Tumor Extension|| |---|---|---|---|---| |Stage I|Confined to Gl $tract^{a}$|||| |Stage I|$I_{1}$ = mucosa, submucosa|$I_{E}$|T1 N0 M0|Mucosa, submucosa| |Stage I|$I_{2}$ = muscularis propria, serosa|$I_{E}$|T2 N0 M0|Muscularis propria| |Stage I|$I_{2}$ = muscularis propria, serosa|$I_{E}$|T3 N0 M0|Serosa| |Stage II|Extending into abdomen|||| |Stage II|$II_{1}$ = local nodal involvement|$II_{E}$|T1-3 N1 M0|Perigastric lymph nodes| |Stage II|$II_{2}$ = distant nodal involvement|$II_{E}$|T1-3 N2 M0|More distant regional lymph nodes| |Stage IIE|Penetration of serosa to involve adjacent organs or tissues|$II_{E}$|T4 N0 M0|Invasion of adjacent structures| |Stage $IV^{b}$|Disseminated extranodal involvement or concomitant supradiaphragmatic nodal involvement||T1-4 N3 M0|Lymph nodes on both sides of the diaphragm/distant metastases (eg, bone marrow or additional extranodal sites)| |Stage $IV^{b}$|Disseminated extranodal involvement or concomitant supradiaphragmatic nodal involvement|IV|T1-4 N0-3 M1|Lymph nodes on both sides of the diaphragm/distant metastases (eg, bone marrow or additional extranodal sites)|

Zucca E, Bertoni F, Yahalom J, Isaacson P. Extranodal Marginal Zone B-cell Lymphoma of Mucosa-Associated Lymphoid Tissue (MALT lymphoma) in Armitage, et al, eds. Non-Hodgkin's Lymphomas. Philadelphia: Lippincott, 2010:242. (http://lww.com)

a Single primary or multiple, noncontiguous.

b Involvement of multiple extranodal sites in MALT lymphoma appears to be biologically distinct from multiple extranodal involvement in other lymphomas, and these patients may be managed by treating each site separately with excision or RT. In contrast, cases with disseminated nodal involvement appear to behave more like nodal marginal zone lymphoma or like disseminated follicular lymphoma.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Extranodal Marginal Zone B-Cell Lymphoma

Extranodal MZL of Nongastric Sites (Noncutaneous)

ADDITIONAL DIAGNOSTIC TESTING$^{a,b}$

WORKUP

ESSENTIAL:

* Physical exam with attention to nongastric sites$^{a}$

* Performance status

$\bullet$ CBC with differential

$\bullet$ Comprehensive metabolic panel

$\bullet$ LDH

$\bullet$ Hepatitis B testing$^{d}$

$\bullet$ Hepatitis C testing

$\bullet$ SPEP with SIFE and/or quantitative Ig levels

$\bullet$ PET/CT scan® or C/A/P CT with contrast of diagnostic quality if therapy is planned

* Pregnancy testing in patients of childbearing age (if therapy planned) USEFUL IN SELECTED CASES:

![InitialTherapy(EMZLNG-2)\n](1/parseimages/figure29b8adee6c0643678763644b64453428_0_18.png)

ESSENTIAL:

$\bullet$ Adequate immunophenotyping to establish diagnosis$^{c}$

$\bullet$ IHC panel: CD20, CD3, CD5, CD10, BCL2, kappa/ lambda, CD21 or CD23, cyclin D1 with or without

$\bullet$ Flow cytometry with peripheral blood and/or biopsy specimen: kappa/lambda, CD19, CD20, CD5, CD23, CD10

USEFUL UNDER CERTAIN CIRCUMSTANCES:

* FISH: t(11;18), t(11;14), t(3;14); t(14;18)

* Echocardiogram or MUGA scan if anthracycline-based regimen is indicated

$\bullet$ Bone marrow biopsy ± aspirate (to document clinical stage I–II disease if ISRT planned, or to evaluate unexplained cytopenias)$^{f}$

$\bullet$ Endoscopy with multiple biopsies of anatomical sites$^{9}$

$\bullet$ MRI with contrast for neurologic evaluation or if CT with contrast is contraindicated

* MRI of head/neck, cranial, and ocular adnexa

* Neck CT scan with contrast particularly if RT planned for stage I, II disease

* Evaluation for autoimmune disease (eg, Sjogren's)

$\bullet$ Discuss fertility preservation$^{n}$

a Typical nongastric sites include the following: bowel (small and large), breast, head and neck, lung, dural, ocular adnexa, ovary, parotid, prostate, and salivary gland. Infectious agents have been reported to be associated with many nongastric sites, but testing for these infectious organisms is not required for management in the United States.

b This guideline pertains to EMZL of nongastric sites (noncutaneous); for primary cutaneous marginal zone lymphoma (PCMZL), see NCCN Guidelines for Cutaneous Lymphomas.

c Typical immunophenotype: CD10-, CD5-, CD20+, CD23-/+, CD43-/+, cyclin D1-, with BCL2- follicles.

d Hepatitis B testing is indicated because of the risk of reactivation with immunotherapy + chemotherapy. Tests include HBsAg and core antibody for a patient with no risk factors. For patients with risk factors or previous history of hepatitis B, add e-antigen (NHODG-B). If positive, check viral load and consider consult with gastroenterologist.

e PET/CT scan may be negative in marginal zonal lymphomas. In such cases, CT imaging is recommended.

f Bilateral or unilateral provided core biopsy is >2 cm. If active surveillance is initial therapy, bone marrow biopsy may be deferred.

g In cases where primary site is thought to be in head/neck or lungs, upper GI endoscopy should be considered.

h Fertility preservation options include: sperm banking, IVF, or ovarian tissue or oocyte cryopreservation.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Extranodal Marginal Zone B-Cell Lymphoma

Extranodal MZL of Nongastric Sites (Noncutaneous)

NCCN Guidelines Index Table of Contents Discussion

![STAGE\n\nINITIAL THERAPY^{i}\n\nStRT^{j} (preferred) or Surgery may be considered for certain sites$^{k}$ (lung, breast [lumpectomy], thyroid, colon/small bowel) or Rituximab in selected cases or Active surveillance in selected cases$^{l}$\n\nStage IE or contiguous stage IIE\n\nStage IV\n\n| ISRT^{j},m| or | Active surveillance in selected cases| or | Manage per advanced-stage NMZL (NMZL-3)\n\n| EMZL of nongastric sites with concurrent large cell transformation | Manage as Diffuse Large B-Cell Lymphoma (BCEL-1)\n]() $^{1}$ Based on anecdotal responses to antibiotics in ocular and cutaneous marginal zone lymphomas, some physicians will give an empiric course of doxycycline prior to initiating other therapy.

$^{1}$ Principles of Radiation Therapy (NHODG-D).

$^{k}$ Surgical excision for adequate diagnosis may be appropriate treatment for disease.

$^{1}$ Active surveillance may be considered for patients whose diagnostic biopsy was excisional, or where RT could result in significant morbidity.

m Definitive treatment of multiple sites may be indicated (eg, bilateral orbital disease without evidence of disease elsewhere) or palliative treatment of symptomatic sites.

Note: All recommendations are category 2A unless otherwise indicated.

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Extranodal Marginal Zone B-Cell Lymphoma

Extranodal MZL of Nongastric Sites (Noncutaneous)

NCCN Guidelines Index Table of Contents Discussion

FOLLOW-UP

![Local recurrence\n\nISRT if not previously given or Manage per advanced-stage NMZL (NMZL-3)\n\nClinical follow-up every 3-6 mo for 5 y and then annually or as clinically indicated^{n,0}\n\nSystemic recurrence\n\nEvaluate for indications for treatment:\nCandidate for clinical trial\nSymptoms\nGl bleeding\nThreatened end-organ function\nClinically significant bulky disease\nSteady or rapid progression\n\nIndication present\n\nTo: All recommendations are category 2A unless otherwise indicated.\n\nEMZL-A 2 of 4)\n\n(1) In: 2026, 12/22/25 © 2025 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.\n](1/parseimages/figure3ddb389aa0db43fd9cbb8ccd4302e28e_0_6.png) $^{1}$ Principles of Radiation Therapy (NHODG-D).

$^{n}$ Follow-up includes diagnostic tests and imaging previously used as clinically indicated.

° Optional first-line extended therapy (rituximab maintenance 375 mg/m$^{2}$ one dose every 8–12 weeks for up to 2 years) following CR or PR for patients treated with single-agent rituximab (MZL-A 1 of 4).

$^{p}$ Optional second-line extended therapy (obinutuzumab maintenance for rituximab-refractory disease) following CR or PR if treated with bendamustine + obinutuzumab for recurrent disease (MZL-A 2 of 4).

Note: All recommendations are category 2A unless otherwise indicated.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Nodal Marginal Zone Lymphoma

NCCN Guidelines Index Table of Contents Discussion

ADDITIONAL DIAGNOSTIC TESTING

ESSENTIAL:

$\bullet$ Adequate immunophenotyping to establish diagnosisª

$\bullet$ IHC panel: CD20, CD3, CD5, CD10, BCL2, kappa/ lambda, CD21 or CD23, cyclin D1 with or without

$\bullet$ Flow cytometry with peripheral blood and/or biopsy specimen:

kappa/lambda, CD19, CD20, CD5, CD23, CD10

$\bullet$ Pediatric NMZL should be considered with localized disease in a young patient.

USEFUL UNDER CERTAIN CIRCUMSTANCES:

$\bullet$ Molecular analysis to detect: Ig gene rearrangements; MYD88 mutation status to help differentiate WM (90%) versus MZL (10%) if plasmacytic differentiation present; CXCR4 mutation status to help differentiate WM versus MZL; FISH for MALT1 rearrangements

* FISH: t(11;18), t(1;14), del(13q), del(7q); t(14;18)

WORKUP

ESSENTIAL:

$\bullet$ Physical exam with performance status

* CBC with differential

* Comprehensive metabolic panel

$\bullet$ LDH

$\bullet$ Hepatitis B testing$^{b}$

$\bullet$ Hepatitis C testing

$\bullet$ PET/CT scan (preferred)$^{c}$ or C/A/P CT with contrast of diagnostic quality if therapy is planned

diagnostic quality if therapy is planned

* Pregnancy testing in patients of childbearing age (if therapy planned)

USEFUL IN SELECTED CASES:

$\bullet$ Bone marrow biopsy + aspirate (to document clinical stage - II disease if ISRT planned, or to evaluate unexplained cytopenias)$^{d}$

$\bullet$ Echocardiogram or MUGA scan if anthracycline-based regimen is indicated

$\bullet$ Additional imaging as needed based on clinical presentation or symptoms$^{e}$

$\bullet$ SPEP with SIFE and/or quantitative Ig levels

$\bullet$ Discuss fertility preservation$^{f}$

a Typical immunophenotype: CD10-, CD5-, CD20+, CD23-/+, CD43-/+, and cyclin D1-, may have BCL2- follicles.

b Hepatitis B testing is indicated because of the risk of reactivation with immunotherapy + chemotherapy. Tests include HBsAg and core antibody for a patient with no risk factors. For patients with risk factors or previous history of hepatitis B, add e-antigen (NHODG-B). If positive, check viral load and consider consult with gastroenterologist.

c PET/CT scan may be negative in marginal zonal lymphomas. In such cases, CT imaging is recommended.

d Bilateral or unilateral provided core biopsy is >2 cm. If active surveillance is initial therapy, bone marrow biopsy may be deferred.

e In NMZL, extranodal involvement is common: Neck nodes: ocular, parotid, thyroid, and salivary gland; axillary nodes: lung, breast, and skin; mediastinal/hilar nodes: lung; abdominal nodes: splenic and Gl; inguinal/iliac nodes: Gl and skin.

f Fertility preservation options include: sperm banking, IVF, or ovarian tissue or oocyte cryopreservation.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Nodal Marginal Zone Lymphoma

NCCN Guidelines Index Table of Contents Discussion

![STAGE\nINITIAL THERAPY\nRESPONSE TO THERAPY $^{1,m}$\nFOLLOW-UP $^{n}$\nStage I or Contiguous stage II $^{9}$ → ISRT $^{h}$ + anti-CD20 $mAb^{i}$ ± chemotherapy (MZL-A) $^{j}$ or Anti-CD20 $mAb^{i}$ ± chemotherapy (MZL-A) in certain circumstances $^{k}$R\nAive surveillance $^{9}$R\nActive surveillance $^{9}$R\nC\nI, II\nAive surveillance $^{9}$R\nI, II\nAive surveillance $^{9}$R\nI, II\nAive surveillance $^{9}$R\nI, II\nAive surveillance $^{9}$R\nI, II\nAive surveillance $^{9}$R\nI, II\nAive surveillance $^{9}$R\nI, II\nAive surveillance $^{9}$R\nI, II\nAive surveillance $^{9}$R\nI, II\nAive surveillance $^{9}$R\nI, II\nAive surveillance $^{9}$R\nI, II\nAive surveillance $^{9}$R\nI, II\nAive surveillance $^{9}$R\nI, II\nAive surveillance $^{9}$R\nI, II\nAive surveillance $^{9}$R\nI, II\nAive surveillance $^{9}$R\nI, II\nAive su\n](1/parseimages/figure721ae9ffb50f4f70baf57e9a5829b5a1_0_4.png) m Consider possibility of histologic transformation in patients with progressive disease, especially if LDH levels are rising, single site is growing disproportionately, extranodal disease develops, or there are new B symptoms. If clinical suspicion of transformation, FDG-PET may help identify areas suspicious for transformation. FDG-PET scan demonstrating marked heterogeneity or sites of intense FDG avidity may indicate transformation, and biopsy should be directed biopsy at the most FDG-avid area. Functional imaging does not replace biopsy to diagnose transformation. If transformation is histologically confirmed, treatment options should be directed towards the large cell transformation. See [HTBCEL-1].

$^{9}$ Active surveillance may be appropriate in circumstances where potential toxicity of ISRT or systemic therapy outweighs potential clinical benefit in consultation with a radiation oncologist.

h Principles of Radiation Therapy (NHODG-D).

$^{1}$ Anti-CD20 mAbs include rituximab or obinutuzumab. Obinutuzumab is not indicated as single-agent therapy.

$^{1}$ Initiation of systemic therapy can improve FFS, but has not been shown to improve overall survival. These are options for initial therapy.

k Eg, for patients with bulky intra-abdominal or mesenteric stage I disease.

$^{1}$ Lugano Response Criteria for Non-Hodqkin Lymphoma (NHODG-C). PET/CT scan should be interpreted via the PET 5-PS.

PET/CT scan should be interpreted via the PET 5-PS.

met a result is a result that the result is a result that the result is a result that the result is a result that the result is a result that the result is a result that the result is a result that the result is a result that the result is a result that the result is a result that the result is a result that the result is a result that the result is a result that the result is a result that the result is a result that the result is a result that the result is a result that the result is a result

Follow-up includes diagnostic tests and imaging using the same modalities performed during workup as clinically indicated. Imaging should be performed whenever there are clinical indications. For surveillance imaging, see [Discussion] for consensus imaging recommendations.

$\circ$ Surveillance imaging is used for monitoring asymptomatic patients. When a site of disease can only be visualized on PET/CT scan (eg, bone), it is appropriate to proceed with PET/CT scans for surveillance.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Nodal Marginal Zone Lymphoma

NCCN Guidelines Index Table of Contents Discussion

STAGE

MANAGEMENT AND FOLLOW-UP$^{n}$

![Stage III, IV\n\nEvaluate for indications for treatment$^{p}$:\nCandidate for clinical trial\nSymptoms\nThreatened end-organ function\nClinically significant or progressive cytopenia secondary to lymphoma\nClinically significant bulky disease$^{p}$\nSteady or rapid progression$^{m}$\n\nIndication\n\nNo indication\n\nActive surveillance category 1\n\nClinical\n\nH&P and labs every 3-6 mo for 5 y and then annually or as clinically indicated Surveillance imaging$^{o}$\n\nUp to 2 y: C/A/P CT scan with contrast no more than every 6 mo\n\n>2 y: CT scan no more than annually\n\nProgressive disease, see HTBCEL-1\n\nSee Suggested Regimens (MZL-A) or\nClinical trial and/or\nVery low-dose ISRT$^{h}$\n\n| Response\n| = | | | | | | | | | | | | | |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | \n](1/parseimages/figure4bfb231adc97471fba0c67adfbc68a99_0_6.png) NCCN 授权医脉通提供NCCN指南全文下载。wlsyy于2025/12/23,21:20在医脉通平台下载,仅供个人使用,严禁分发。2025美国国家综合癌症网络版权所有。

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Nodal Marginal Zone Lymphoma

NCCN Guidelines Index Table of Contents Discussion

![RESPONSE ASSESSMENT$^{1}$ AND ADDITIONAL THERAPY\n\nExtended therapy (optional) for patients treated with single-agent Rituximab (MZL-A) or Active surveillance\n\nClinical H&P and labs every 3-6 mo for 5 y and then annually or as clinically indicated Surveillance imaging$^{0}$\n\nUp to 2 y post completion of treatment: C/A/P CT scan with single-agent Rituximab (MZL-A) or Active surveillance\n\n4C/A/P CT scan with contrast\n\nPR$^{1}$,q → PR$^{1}$,q → 4C\n\nExtended therapy (optional) for patients treated with single-agent Rituximab with single-agent Rituximab (MZL-A) or Active surveillance (MZL-A 3 of 4)\n\n4C/A/P CT scan with contrast\n\n4C/A-P CT scan with contrast\n\nNR or progressive disease$^{1}$,m → Rebiopsy → No histologic transformation, 2025 美国国家综合癌症网络版权所有。\nFOLLOW-UP$^{n}$\n\nClinical H&P and labs every 3-6 mo for 5 y and then annually or as clinically indicated Surveillance imaging$^{0}$\n\nRelapsed or Progressive disease$^{1}$,m → Prebiopsy → No histologic transformation, 2025 美国国家综合癌症网络版权所有。\n4C/A/P CT scan with contrast\n\n4C/A/P CT scan with contrast was the HTBCEL-1\n\n4C/A/P CT scan with contrast was the HTBCEL-1\n\n4C/A/P CT scan with contrast was the HTBCEL-1\n\n4C/A/P CT scan with contrast was the HTBCEL-1\n\n4C/A/P CT scan with contrast was the HTBCEL-1\n\n4C/A/P CT scan with contrast was the HTBCEL-1\n\n4C/A/P CT scan with contrast was the HTBCEL-1\n\n4C/A/P CT scan with contrast was the HTBCEL-1\n\n4C/A/P CT scan with contrast was the HTBCEL-1\n\n4C/A/P CT scan with contrast was the HTBCEL-1\n\n4C/A/P CT scan with contrast was the HTBCEL-1\n\n4C/A/P CT scan with contrast was the HTBCEL-1\n\n4C/A/P CT scan with contrast was the HTBCEL-1\n\n4C/A/P CT scan with contrast was the HTBCEL-1\n\n4C/A/P CT scan with contrast was the HTBCEL-1\n\n4C/A/P CT scan with contrast was the HTBCEL-1\n\n4C/A/P CT scan with contrast was the HTBCEL-1\n\n4C/A/P CT scan with contrast was the HTBCEL-1\n\n4C/A/P CT scan with contrast was the HTBCEL-1\n\n4C/A/P CT scan with contrast was the HTBCEL-1\n\n4C/A/P CT scan with contrast was \n](1/parseimages/figure1bf40b7e7e8e412bbf96f2b5375536bb_0_4.png) h Principles of Radiation Therapy (NHODG-D).

$^{1}$ Lugano Response Criteria for Non-Hodgkin Lymphoma (NHODG-C). PET/CT scan should be interpreted via the PET 5-PS.

m Consider possibility of histologic transformation in patients with progressive disease, especially if LDH levels are rising, single site is growing disproportionately, extranodal disease develops, or there are new B symptoms. If clinical suspicion of transformation, FDG-PET may help identify areas suspicious for transformation. FDG-PET scan demonstrating marked heterogeneity or sites of intense FDG avidity may indicate transformation, and biopsy should be directed biopsy at the most FDG-avid area. Functional imaging does not replace biopsy to diagnose transformation. If transformation is histologically confirmed, treatment options should be directed towards the large cell transformation. See [HTBCEL-1].

$^{n}$ Follow-up includes diagnostic tests and imaging using the same modalities performed during workup as clinically indicated. Imaging should be performed whenever there are clinical indications. For surveillance imaging, see [Discussion] for consensus imaging recommendations.

° Surveillance imaging is used for monitoring asymptomatic patients. When a site of disease can only be visualized on PET/CT scan (eg, bone), it is appropriate to proceed with PET/CT scans for surveillance.

P GELF criteria (FOLL-A).

$^{9}$ A PET-positive PR is associated with a shortened PFS (see Discussion); however, additional treatment at this juncture has not been shown to change outcome.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Splenic Marginal Zone Lymphoma

NCCN Guidelines Index Table of Contents Discussion

ADDITIONAL DIAGNOSTIC TESTING$^{a}$

ESSENTIAL:

$\bullet$ Adequate immunophenotyping to establish diagnosis$^{e}$ $\rightarrow$ IHC panel: CD20, CD3, CD5, CD10, BCL2, kappa/ lambda, CD21 or CD23, cyclin D1, IgD, CD43, annexin A1; with or without

$\blacktriangleright$ Flow cytometry with peripheral blood and/or biopsy specimen: kappa/lambda, CD19, CD20, CD5, CD23, CD10, CD43, CD103

USEFUL UNDER CERTAIN CIRCUMSTANCES:

$\bullet$ Molecular analysis to detect: Ig gene rearrangements; MYD88 mutation status to help differentiate WM (90%) versus MZL (10%) if plasmacytic differentiation present$^{c}$; BRAF mutation status (by IHC or sequencing) to differentiate MZL from hairy cell leukemia (HCL); FISH for MALT1 rearrangements

* FISH: chronic lymphocytic leukemia (CLL) panel; t(11;18), t(11;14), del(7q); t(14;18)

a The presumptive diagnosis of SMZL may be made based on peripheral blood involvement ± bone marrow by small lymphoid cells with lg light chain restriction that lack characteristic features of other small B-cell neoplasms (ie, CD5, CD10, cyclin D1). In patients with lymphocytosis (>3), evaluation of peripheral blood with flow cytometry and MGPT panel including MYD88, NOTCH2, and KLF2 mutations may be adequate to confirm the diagnosis. Plasmacytoid differentiation with cytoplasmic Ig detectable on paraffin sections may occur. In such cases, the differential diagnosis may include LPL. With a characteristic intrasinusoidal lymphocytic infiltration of the bone marrow, the diagnosis can strongly be suggested on bone marrow biopsy alone, if the immunophenotype is consistent. SMZL is most definitively diagnosed at splenectomy, since the immunophenotype is nonspecific and morphologic features on the bone marrow may not be diagnostic.

WORKUP

ESSENTIAL:

$\bullet$ Physical exam with performance status

$\bullet$ CBC with differential

* Comprehensive metabolic panel

$\bullet$ LDH

$\bullet$ Hepatitis B testing$^{d}$

$\bullet$ Hepatitis C testing

$\bullet$ PET/CT scan$^{e}$ or C/A/P CT or other suspected sites with contrast of diagnostic quality

* SPEP with SIFE and/or quantitative Ig levels

$\bullet$ Pregnancy testing in patients of childbearing age (if therapy planned)

USEFUL IN SELECTED CASES:

$\bullet$ Bone marrow biopsy ± aspirate if cytopenias are present and considering splenectomy to ensure adequate bone marrow hematopoiesis$^{f}$

* Additional imaging as needed based on clinical presentation or symptoms

$\bullet$ Cryoglobulins

$\bullet$ Direct Coombs testing

* Discuss fertility preservation$^{9}$

b Typical immunophenotype: CD10-, CD5-, CD20+, CD23-/+, CD43-/+, and cyclin D1-, with BCL2- follicles, annexin A1, and CD103- (distinction from HCL) with expression of both IgM and IgD.

c NOTCH2 and KLF2 mutation status may be helpful to differentiate SMZL from other B-cell lymphoma subtypes.

e PET/CT scan may be negative in marginal zonal lymphomas. In such cases, CT imaging is recommended.

f Bilateral or unilateral provided core biopsy is >2 cm. If active surveillance is initial therapy, bone marrow biopsy may be deferred.

$^{9}$ Fertility preservation options include: sperm banking, IVF, or ovarian tissue or oocyte cryopreservation.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Splenic Marginal Zone Lymphoma

NCCN Guidelines Index Table of Contents Discussion

CLINICAL PRESENTATION

MANAGEMENT

FOLLOW-UP

![Asymptomatic, without progressive cytopenia, no splenomegaly\n\nFollow-up (SMZL-3)\n\nNo contraindications for treatment of hepatitis\n\nAppropriate treatment\n\nCR/PR\n\nPROFLOW-UP\n\nSplenomegaly\n\nHepatitis C positive^h\n\nHepatology\n\nconsult\n\nContraindications for treatment of hepatitis\n\nRecontraindications for treatment of hepatitis\n\nSplenomegaly\n\nCytopenias or Symptoms\n\nRituximab^i (preferred) or Splenectomy^i (category 2B)\n\nHepatitis C\n\nnegative\n\nNo symptoms\n\nActive surveillance\n\nh If hepatitis C positive, treat with an appropriate regimen for hepatitis C.\n\nTsimberidou AM, et al. Cancer 2006;107:125-135.\n\nj Pneumococcal, meningococcal, haemophilus influenza, and hepatitis B vaccination should be given at least 2 weeks before splenectomy.\n\nNote: All recommendations are category 2A unless otherwise indicated.\n](1/parseimages/figured456905086594ad6bf4150c9ac2232fb_0_7.png) h If hepatitis C positive, treat with an appropriate regimen for hepatitis C.

$^{i}$ Tsimberidou AM, et al. Cancer 2006;107:125-135.

j Pneumococcal, meningococcal, haemophilus influenza, and hepatitis B vaccinations should be given at least 2 weeks before splenectomy.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Splenic Marginal Zone Lymphoma

NCCN Guidelines Index Table of Contents Discussion

FOLLOW-UP

![Clinical follow-up every 3-6 mo for 5 y and then annually or as clinically indicated^{k,l}^{NCC}$Recurrence\nIf histologic transformation, see HTBCEL-1\n\nEvaluate for indications for treatment:\nCandidate for clinical trial\nSymptoms\nThreatened end-organ function\nCytopenias including autoimmune cytopenia\nClinically significant bulky disease\nSteady or rapid progression\n\nNo indication\n\nActive surveillance\n\nTreatment naive, then see First-line Therapy for Marginal Zone Lymphomas (MZL-A 1 of 4)$^{1}$ or Prior treatment with rituximab, then see Second-line and Subsequent Therapy for Marginal Zone Lymphomas (MZL-A 2 of 4 and MZL-A 3 of 4)$^{m}$ or Splenectomy$^{j}$ or Very low-dose ISRT$^{n}$\n](1/parseimages/figure7df9f0bd11b74e80bc9a6f6182d535d2_0_5.png) $^{1}$ Optional first-line extended therapy (rituximab maintenance 375 mg/m$^{2}$ one dose every 8–12 weeks for up to 2 years) following CR or PR for patients treated with single-agent rituximab (MZL-A 1 of 4).

$m$ Optional second-line extended therapy (obinutuzumab maintenance for rituximab-refractory disease) following CR or PR if treated with bendamustine + obinutuzumab for recurrent disease (MZL-A 2 of 4).

$^{n}$ Principles of Radiation Therapy (NHODG-D).

Note: All recommendations are category 2A unless otherwise indicated.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Marginal Zone Lymphomas

NCCN Guidelines Index Table of Contents Discussion

SUGGESTED TREATMENT REGIMENSa,b,c

|FIRST-LINE THERAPYd| |---| |Preferred (in alphabetical order)| |● NMZL| |▶ Bendamustine + Rituximab| |▶ CHOP + Rituximab| |▶ CVP + Rituximab| |▶ Rituximab (375 mg/m² weekly for 4 doses) for low tumor burden| |● SMZL| |▶ Rituximab (375 mg/m² weekly for 4 doses)| |Other recommended| |● Lenalidomide + Rituximab for NMZL| |● Rituximab (375 mg/m² weekly for 4 doses) for EMZL (multifocal)|

|FIRST-LINE THERAPY FOR OLDER OR INFIRM (if none of the above are expected to be tolerable in the opinion of treating physician)| |---| |Preferred| |• Rituximab (375 mg/m² weekly for 4 doses)| |• ISRT for local disease| |Other recommended| |• Cyclophosphamide ± Rituximab|

|FIRST-LINE EXTENDED THERAPY (optional)$^{d}$| |---| |• Rituximab maintenance 375 mg/m$^{2}$ one dose every 8–12 weeks for up to 2 years|

Footnotes Second-line and Subsequent Therapy on MZL-A 2 of 4

Consider prophylaxis for tumor lysis syndrome (NHODG-B) See monoclonal antibody and viral reactivation (NHODG-B)

Note: All recommendations are category 2A unless otherwise indicated.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Marginal Zone Lymphomas

NCCN Guidelines Index Table of Contents Discussion

SUGGESTED TREATMENT REGIMENSa,b,c

SECOND-LINE AND SUBSEQUENT THERAPY$^{d}$

For sequencing of therapy, see Discussion.

Preferred (in alphabetical order)

$\bullet$ Bendamustine$^{e}$ + Rituximab (not recommended if treated with prior Bendamustine)

$\cdot$ BTKis

$\blacktriangleright$ Covalent BTKi

$\bullet$ Zanubrutinib (continuous)$^{f}$ (after at least one prior anti-CD20 mAb-based regimen)

$\bullet$ CHOP + Rituximab

$\bullet$ CVP + Rituximab

$\bullet$ Lenalidomide + Rituximab

Other recommended (in alphabetical order)

$\bullet$ Bendamustine$^{e}$ + Obinutuzumab (not recommended if treated with prior Bendamustine)

$\bullet$ BTKis

$\blacktriangleright$ Covalent BTKi

$\bullet$ Acalabrutinib (continuous)$^{f,9}$

$\blacktriangleright$ Non-covalent BTKi

$\bullet$ Pirtobrutinib (continuous) (after prior covalent BTKi)

Lenalidomide + Obinutuzumab

$\bullet$ Rituximab (if longer duration of remission)

SECOND-LINE AND SUBSEQUENT THERAPY FOR OLDER OR INFIRM⁺ (if combination chemoimmunotherapy is not expected to be tolerable in the opinion of treating physician)

Preferred (in alphabetical order)

$\bullet$ BTKis

$\bullet$ Covalent BTKi

◇ Zanubrutinib (continuous)f (after at least one prior anti-CD20 mAb-based regimen)

$\bullet$ Lenalidomide + Rituximab

$\bullet$ Rituximab (375 mg/m$^{2}$ weekly for 4 doses)

Other recommended (in alphabetical order)

$\bullet$ BTKis

$\bullet$ Covalent BTKi

$\bullet$ Acalabrutinib (continuous)$^{f,9}$

$\bullet$ Non-covalent BTKi

$\bullet$ `Pirtobrutinib (continuous) (after prior covalent BTKi)`

$\bullet$ Cyclophosphamide ± Rituximab

Preferred

$\bullet$ If treated with Bendamustine + Obinutuzumab for recurrent disease, then Obinutuzumab maintenance for Rituximab-refractory disease (1 g every 8 weeks for total of 12 doses)

Consider prophylaxis for tumor lysis syndrome (NHODG-B) See monoclonal antibody and viral reactivation (NHODG-B)

Footnotes

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 1.2026 Marginal Zone Lymphomas

NCCN Guidelines Index Table of Contents Discussion

Note: All recommendations are category 2A unless otherwise indicated.

MZL-A 3 OF 4

SUGGESTED TREATMENT REGIMENSa,b,c

a See references for regimens (MZL-A 4 of 4).b An FDA-approved biosimilar is an appropriate substitute for any recommended systemic biologic therapy in the NCCN Guidelines. Rituximab and hyaluronidase

human injection for subcutaneous use may be substituted for rituximab after patients have received the first full dose of rituximab by intravenous infusion.

c The choice of therapy requires consideration of many factors, including age, comorbidities, and future treatment possibilities (eg, HDT/ASCR). Therefore, treatment

selection is highly individualized.

d If absolute lymphocyte count (ALC) is >25,000 mcL: 1) consider split dosing for rituximab of 100 mg, flat dose on day 1 and the remainder of the 375 mg/m2 on day 2; 2) consider additional glucocorticoid premedication prior to rituximab (50 mg at bedtime day prior, 50 mg morning of, and 50 mg immediately prior to infusion) to reduce infusion-related reactions.

e In patients intended to receive CAR T-cell therapy, bendamustine should be used with caution. Delay bendamustine until after CAR-T leukapheresis.f Refer to package insert for full prescribing information, dose modifications, and monitoring for adverse reactions: https://www.accessdata.fda.gov/scripts/cder/daf/index.

cfm.

g Studies of acalabrutinib excluded concomitant use of warfarin or equivalent vitamin K antagonists. h If clinically feasible, repeat biopsy to confirm antigen expression prior to the initiation of CD19-directed CAR T-cell therapy.i NCCN Guidelines for Management of CAR T-Cell and Lymphocyte Engager-Related Toxicities.j Selected cases include mobilization failures and persistent bone marrow involvement.

Consider prophylaxis for tumor lysis syndrome (NHODG-B)

See monoclonal antibody and viral reactivation (NHODG-B)

THIRD-LINE AND SUBSEQUENT THERAPY

• Second-line therapy regimens (MZL-A 2 of 4) that were not previously given can also be used as options for third-line and subsequent therapy

Preferred

• CAR T-cell therapyh

Lisocabtagene maraleuceli (CD19-directed)

Other recommended

• CAR T-cell therapyh

Axicabtagene ciloleuceli (CD19-directed)

THIRD-LINE CONSOLIDATION THERAPY (optional)

• Allogeneic HCT in highly selected casesj

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Marginal Zone Lymphomas

NCCN Guidelines Index Table of Contents Discussion

SUGGESTED TREATMENT REGIMENS REFERENCES

First-line Therapy RCHOP/RCVP/BR Rummel MJ, Niederle N, Maschermeyer G, et al. Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet 2013;381:1203-1210. Finn IW, van der Jagt R, Kahl BS, et al. Randomized trial of bendamustine-rituximab or R-CHOP/R-CVP in first-line treatment of indolent NHL or MCL: the BRIGHT study. Blood 2014;123:2944-2952. Salar A, Domingo-Domenech E, Paniz C, et al. Long-term results of a phase 2 study of rituximab and bendamustine for mucosa-associated lymphoid tissue lymphoma. Blood 2017;130:172-1774. Lenalidomide + rituximab Fowler NH, Davis RE, Rawal, et al. Safety and activity of lenalidomide and rituximab in untreated indolent lymphoma: an open-label, phase 2 trial. Lancet Oncol 2014;15:1311-1318. Kiesewetter B, Willenbacher W, et al. A phase 2 study of rituximab plus lenalidomide for mucosa-associated lymphoid tissue lymphoma. Blood 2017;129:383-385. Rituximab (preferred for SMZL) Tsinterdub AM, Catovsky D, Schlette E, et al. Outcomes in patients with splenic marginal zone lymphoma and marginal zone lymphoma treated with rituximab with or without chemotherapy or chemotherapy alone. Cancer 2006;107:125-135. Else M, Marin-Niebla A, de la Cruz F, et al. Rituximab, used alone or in combination, is superior to other treatment modalities in splenic marginal zone lymphoma. Br J Haematol 2012;159:322-328. Kalpadakis C, Pangalis GA, Angelopoulou MK, et al. Treatment of splenic marginal zone lymphoma with rituximab monotherapy; progress report and comparison with splenectomy. Oncologist 2013;18:190-197. First-line Extended Therapy (optional) Extended dosing with rituximab Williams ME, Hong F, Gascoyne RD, et al. Rituximab extended schedule or retreatment trial for low tumour burden non-follicular indolent B-cell non-Hodgkin lymphomas: Eastern Cooperative Oncology Group Protocol E4402. Br J Haematol 2016;173:867-875.

Second-line and Subsequent Therapy

Acaalrutinib

Strati P, Coleman M, Champion R, et al. A phase 2, multicentre, open-label trial (ACE-LY-003) of acalabrutinib in patients with relapsed or refractory marginal zone Lymphoma. Br J Haematol 2022;19:76-85.

Bendamustine + obutizumab

Lenalidomide + rituximab

Lansigan F, Andorsky DJ, Coleman M, et al. P1156: Magnify phase 3b study of lenalidomide + rituximab (R2) followed by maintenance in relapsed/refractory indent non-hodgkin lymphoma: complete induction phase analysis. HemaSphere 2022;6:1043-1044.

Leonard JP, Treny M, Izutsu K, et al. AUGMENT: A phase iii study of tenalidomide plus rituximab versus placebo plus rituximab in relapsed or refractory indolent lymphoma. J Clin Oncol 2019;37:1188-1199.

Sacchi S, Marcheselli R, Bari A, et al. Safety and efficacy of lenalidomide in combination with rituximab in recurrent indent non-follicular lymphoma: final results of a phase II study conducted by the Fontazione Italiana Linfomi. Haematologica 2016;101:e196.

Pirtobrutinib

Patel K, Vose JM, Nasta SD, et al. Pirtobrutinib, a highly selective, non-covalent (Reversible) BTK inhibitor in relapsed/refractory marginal zone lymphoma: Results from phase 1/2 BRUIN study [abstract]. Blood 2023;142:Abstract 1660.

Zanubrutinib

Opat S, Tedeschi A, Hu B, et al. Safety and efficacy of zanubrutinib in relapsed/refractory marginal zone lymphoma: the lymphoma: final analysis of the MAGNOLIA study. Blood Adv 2023;7:6801-6811-6811.

Second-line Extended Dosing (optional)

Third-line and Subsequent Therapy

CAR T-cell therapy

Axicabtagene ciloleucel

Neelapu SS, Chavez JC, Sehgal AR, et al. Three-year follow-up analysis of axicabtagene ciloleucel in relapse/refractory indolent non-Hodgkin lymphoma (ZUMA-5). Blood 2024;143:496-506.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Mantle Cell Lymphoma

NCCN Guidelines Index Table of Contents Discussion

ADDITIONAL DIAGNOSTIC TESTING

ESSENTIAL:

* Adequate immunophenotyping to establish diagnosisa

$\bullet$ IHC panel: CD20, CD3, CD5, cyclin D1, CD10, CD21, CD23, BCL2, BCL6, SOX11, Ki-67$^{b}$ with or without

$\bullet$ Flow cytometry with peripheral blood and/or biopsy specimen:

kappa/lambda, CD19, CD20, CD5, CD23, CD10, CD200

$\bullet$ TP53 sequencing$^{c}$

USEFUL UNDER CERTAIN CIRCUMSTANCES:

$\bullet$ IHC: LEF1 may help distinguish from variant CLL; SOX11 or IGHV sequencing may be useful for determination of clinically indolent MCL$^{d}$; may also help in diagnosis of CCND1- MCL

$\bullet$ FISH: t(11;14); FISH for CCND2 and CCND3 gene fusions may also help in diagnosis of CCND1- MCL

WORKUP

ESSENTIAL:

* Physical exam: Attention to node-bearing areas, including Waldeyer's ring, and to size of liver and spleen

$\bullet$ Performance status

* B symptoms

$\bullet$ CBC with differential

* Comprehensive metabolic panel

$\bullet$ LDH

* PET/CT scan (preferred) or C/A/P CT with contrast of diagnostic quality if therapy is planned

$\bullet$ Hepatitis B testinge

* Echocardiogram or MUGA scan if anthracycline-based regimen is indicated

Pregnancy testing in patients of childbearing age (if therapy planned)

USEFUL UNDER CERTAIN CIRCUMSTANCES:

* Endoscopy/colonoscopyf

$\bullet$ Bone marrow biopsy ± aspirate

* Neck CT with contrast

* Uric acid

* Beta-2-microglobulin

$\bullet$ Hepatitis C testing

$\bullet$ Lumbar puncture (for plastic variant or central nervous system [CNS] symptoms)

$\bullet$ Discuss fertility preservation$^{5}$

a Typical immunophenotype: CD5+, CD20+, CD43+, CD23-/+, cyclin D1+, CD10-/+. Note: Some cases of MCL may be CD5- or CD23+. If the diagnosis is suspected, cyclin D1 staining or FISH for t(11;14) should be done. There are rare cases of CCND1- MCL (<5%) with an otherwise typical immunophenotype.

b Ki-67 proliferation fraction of <30% in lymph nodes is associated with a more favorable prognosis.

c TP53 mutation has been associated with poor prognosis in patients treated with conventional therapy, including transplant. Clinical trial is strongly recommended for these patients. TP53 sequencing is preferred; however, in the front-line setting, p53 by IHC can be used as a surrogate but should be confirmed with sequencing.

d Most common biomarker for indolent disease: SOX11- [IGHV mutated]. Typical clinical presentation: leukemic non-nodal CLL-like with splenomegaly, low tumor burden, Ki-67 proliferation fraction <10%.

e Hepatitis B testing is indicated because of the risk of reactivation with immunotherapy + chemotherapy. Tests include HBsAg and core antibody for a patient with no risk factors. For patients with risk factors or previous history of hepatitis B, add e-antigen (NHODG-B). If positive, check viral load and consider consult with gastroenterologist.

f Essential for confirmation of stage I-II disease. See Discussion for details.

$^{9}$ Fertility preservation options include: sperm banking, IVF, or ovarian tissue or oocyte cryopreservation.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Mantle Cell Lymphoma

NCCN Guidelines Index Table of Contents Discussion

![STAGE\n\nINDUCTION THERAPY\n\nINITIAL RESPONSE\n\nFOLLOW-UP$^{1}$/ADDITIONAL THERAPY\n\nFOLLOW-UP$^{1}$/ADDITIONAL THERAPY\n\nSECOND-LINE THERAPY\n\nStage I or Stage II, nonbulky contiguous\n\n[Stage I, nonbulky contiguous]\n\n[Step I, nonbulky contiguous]\n\n[Step I, nonbulky contiguous]\n\n[Step I, nonbulky contiguous]\n\n[Step I, nonbulky previous and text. ] = 0\n\n[Step I, nonbulky previous and text. ] = 0\n\n[Step I, nonbulky previous and text. ] = 0\n\n[Step I, nonbulky previous and text. ] = 0\n\n[Step I, nonbulky previous and text. ] = 0\n\n[Step I, nonbulky previous and text. ] = 0\n\n[Step I, nonbulky previous and text. ] = 0\n\n[Step I, nonbulky previous and text. ] = 0\n\n[Step I, nonbulky previous and text. ] = 0\n\n[Step I, nonbulky previous and text. ] = 0\n\n[Step I, nonbulky previous and text. ] = 0\n\n[Step I, nonbulky previous and text. ] = 0\n\n[Step I, nonbulky previous and text. ] = 0\n\n[Step I, nonbulky previous and text. ] = 0\n\n[Step I, nonbulky previous and text. ] = 0\n\n[Step I, nonbulky previous and text. ] = 0\n\n[Step I, nonbulky previous and text. ] = 0\n\n[Step I, nonbulky previous and text. ] = 0\n\n[Ste\n](1/parseimages/figure4c855d7cfde749eea65e2f2575e6aa3e_0_4.png) h Localized presentation is extremely rare.

$^{1}$ Principles of Radiation Therapy (NHODG-D).

$^{1}$ Leitch HA, et al. Ann Oncol 2003;14:1555-1561.

k Lugano Response Criteria for Non-Hodgkin Lymphoma (NHODG-C).

$^{1}$ Follow-up includes diagnostic tests and imaging using the same modalities performed during workup as clinically indicated.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Mantle Cell Lymphoma

NCCN Guidelines Index Table of Contents Discussion

MANAGEMENT AND FOLLOW-UP$^{1}$

![NCCN 授权医脉通提供NCCN指南全文下载。wmlsyy于2025/12/23,21:20在医脉通平台下载,仅供个人使用,严禁分发。2025 美国国家综合癌症网络版权所有。\n\nNCCN Guidelines Index\nTable of Contents\n#NCCN Guidelines Network®\nMANAGEMENT AND FOLLOW-UP1\n\nClassical TP53 → MANT-4\n\nClassical TP53 mutateds have been associated with poor prognosis in patients treated with conventional therapy including transplant\nClinical trial is strongly recommended\nIn absence of clinical trial, consider the induction therapy options listed on MANT-A.\n\nStage\nIl bulky and/or noncontiguous;\nStage III, IV\n\nModelentm\n\nCommon presentations include:\nLeukemic non-nodal CLL-like with splenomegaly\nGl or blood/bone marrow involvement only\nLow tumor burden,\nKi-67 proliferation fraction <10%\n\nSymptomatic or other indication for treatment\nEvaluate for clinical concern of transformation Rebiopsy and TP53 sequencing\nTreat as described above based on the TP53 mutation status\nAsymptomatic, no other indication for treatment\nActive surveillance\n](1/parseimages/figure117e4111bc49499da3461a3f37035005_0_5.png) $^{1}$ Follow-up includes diagnostic tests and imaging using the same modalities performed during workup as clinically indicated. $^{m}$ Most common biomarker for indolent disease: SOX11- (IGHV mutated).

Note: All recommendations are category 2A unless otherwise indicated.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Mantle Cell Lymphoma

NCCN Guidelines Index Table of Contents Discussion

![INDUCTION THERAPY\n\nMaintenance therapy (Rituximab ± covalent BTKi)$^{p}$\n\nCR$^{k,n}$\n\nCR$^{k,n}$\n\ndMRD6\n\nConsider therapy (Rituximab ± covalent BTKi)$^{p}$\n\nMaintenance therapy (MANT-A)\n\nMaintenance therapy (MANT-A)\n\nMaintenance therapy (MANT-A)\n\nMaintenance therapy (MANT-A)\n\nMaintenance therapy (Rituximab ± covalent BTKi)$^{p}$\n\nControling and controling and controling\n\nSuitable for aggressive induction therapy\n\nSuitable for aggressive induction therapy\n\nSuitable for aggressive induction therapy\n\nSuitable for aggressive induction therapy\n\nSuitable for aggressive induction therapy\n\nSuitable for aggressive induction therapy\n\nSuitable for aggressive induction therapy\n\nSuitable for aggressive induction therapy\n\nSuitable for aggressive induction therapy\n\nSuitable for aggressive induction therapy\n\nSuitable for aggressive induction therapy\n\nSuitable for aggressive induction therapy\n\nSuitable for aggressive induction therapy\n\nSuitable for aggressive induction therapy\n\nSuitable for aggressive induction therapy\n\nSuitable for negative failure therapy\n\nSuitable for negative failure therapy\n\nSuitable for negative failure therapy\n\nSuitable for negative failure therapy\n\nSuitable for negative failure therapy\n\nSuitable for negative failure therapy\n\nSuitable for negative failure therapy\n\nSuitable for negative failure therapy\n\nSuitable for negative failure therapy\n\nSabove for negative failure therapy\n\nSabe for negative failure therapy\n\nSabe for negative failure therapy\nSabe for negative failure therapy\nSabe for negative failure therapy\nSabe for negative failure therapy\nSabe for negative failure therapy\nSabe for negative failure therapy\nSabe for negative failure therapy\nSabe for negative failure therapy\nSabe for negative failure therapy\nSabe for negative failure therapy\nSabe for negative failure therapy\nSabe for negative failure therapy\nSabe for negative failure therapy\nSabe for negative failure therapy\nSabe for negative failure therapy\nSabe for negative failure therapy\nSabe for negat\n](1/parseimages/figure01201aec64a345388e650f7f51b079bf_0_4.png) k Lugano Response Criteria for Non-Hodgkin Lymphoma (NHODG-C).

$^{1}$ Follow-up includes diagnostic tests and imaging using the same modalities performed during workup as clinically indicated.

$^{1}$ Determination of measurable residual disease (MRD) using a sensitive assay (with a limit of detection of at least $10^{-6}$ tumor cells) will stratify patients who do not benefit from HDT/SCR. Patients achieving CR with undetectable MRD (uMRD; <$10^{-6}$, uMRD6) should not receive HDT/ASCR.

° Patients who have achieved minimal PR with substantial disease should be treated as having refractory or progressive disease. Patients who have achieved a very good PR may be treated with additional therapy to achieve CR with dMRD6 (detectable MRD; >10⁻$^{6}$) with the goal of proceeding to HDT/ASCR.

P Benefit of 2 years of irutinib maintenance and 3 years of rituximab maintenance after alternating RCHOP + ibrutinib/RDHAP was shown in the TRIANGLE study (Dreyling M, et al. Lancet 2024;403:2293-2306). The value of irutinib maintenance after other aggressive induction therapy regimens has not been established. Alternate covalent BTKi (acalabrutinib and zanubrutinib) were not evaluated in the TRIANGLE study.

Note: All recommendations are category 2A unless otherwise indicated.

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Mantle Cell Lymphoma

NCCN Guidelines Index Table of Contents Discussion

![NCCN\nNational Comprehensive Cancer Network®\nADDITIONAL THERAPY\nFOLLOW-UP1\nSECOND-LINE THERAPY\nClassical TP53 wild type Stage II bulky and/or noncontiguous; Stage III, IV\nNot suitable for aggressive induction therapy\nClinical maintenance (category 1 following RCHOP) (MANT-A)\nCRk→\nConsider rituximab maintenance (category 1 following RCHOP) (MANT-A)\nChemoimmunotherapy (MANT-A) to achieve CR\nPrk,q→\nConder rituximab maintenance (category 1 following RCHOP) (MANT-A)\nRelapsed/ Refractory or Progressive Disease\ncBTKi naïve or Late relapse (>24 mo) after prior cBTKi-containing regimen (MANT-6A)\nNo response or progressive disease\n| diseasek|\n](1/parseimages/figure2b5d9397c35243e987b72576dcb037ea_0_4.png) k Lugano Response Criteria for Non-Hodgkin Lymphoma (NHODG-C).

$^{1}$ Follow-up includes diagnostic tests and imaging using the same modalities performed during workup as clinically indicated.

$^{9}$ Active surveillance is recommended for patients who have achieved a very good PR or consider rituximab maintenance. Patients who have achieved minimal PR with substantial disease should be treated as having refractory or progressive disease.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Mantle Cell Lymphoma

NCCN Guidelines Index Table of Contents Discussion

![RELAPSED/REFRACTORY OR PROGRESSIVE DISEASE\n\nCONSOLIDATION/ ADDITIONAL THERAPY\n\nFOLLOW-UP†\n\nRELAPSE #2 OR GREATER\n\ncBTKi naïve or Late relapse (>24 months) after prior cBTKi-containing regimen\n\nR\n\nNR or progressive disease\n\nNCCN Guidelines Version 1.2026\nMantle Cell Lymphoma\n\nCLOSOLIDATION/ ADDITIONAL THERAPY\n\nFOLLOW-UP†\n\nRELAPSE #2 OR GREATER\n\ncBTKi naïve or Late relapse (>24 months) after prior cBTKi-containing regimen\n\nR\n\nNR or progressive disease\n\nIClinical trial\n\nNortileal therapy (MANT-A) (MANT-A) (MANT-A) followed by allogeneic HCT in selected cases if CR or PR is achieved $^{s}$ ± ISRT†\n\nLugano Response Criteria for Non-Hodgkin Lymphoma (NHODG-C).\n\nFholdation of regresin regimens [Suggested Regimens (MANT-A)] or ISRTi\n\nFixed-duration regimens [Suggested Regimens (MANT-A)] or ISRTi\n\nPRk,r\n\nPRk,r\n\nCAR T-cell therapy (MANT-A) or C-1\n\nNon-covalent BTKi (MANT-A) or C-1\n\nClinical follow-up every 3-6 mo for 5 y and then annually or as clinically indicated\n\nRelapse or Progressive disease\n\nCAR T-cell therapy (MANT-A) (MANT-A) or C-1\n\nCMLInG follow-up every 3-6 mo for 5 y and then annually or as clinically indicated\n\nCAR T-cell therapy (MANT-A) or C-1\n\nR\n\nCAR T-cell therapy (MANT-A) (MANT-A) or C-1\n\nNortileal therapy (MANT-A) (MANT-A) or C-1\n\nNortileal therapy (MANT-A) (MANT-A) or C-1\n\nNortileal therapy (MANT-A) or C-1\n\nNortileal therapy (MANT-A) (MANT-A) or C-1\n\nNortileal therapy (MANT-A) (MANT-A) or C-1\n\nNortileal therapy (MANT-A) (MANT-A) or C-1\n\nNortileal therapy (MANT-A) (MANT-A) or C-1\n\nNortileal therapy (MANT-A) (MANT-A) or C-1\n\nNortileal therapy (MANT-A) (MANT-A) or C-1\n\nNortileal therapy (MANT-A) (MANT-A) or C-1\n\nNortileal therapy (MANT-A) (MANT-A) or C-1\n\nNortileal therapy (MANT-A) (MANT-A) or C-1\n\nNortileal therapy (MANT-A) (MANT-A) or C-1\n\nNortileal therapy (MANT-A) (MANT-A) or C-1\n\nNortileal therapy (MANT-A) (MANT-A) or C-1\n\nNortileal therapy (MANT-A) (MANT-A) or C-1\n\nNortileal therapy (MANT-A) (MANT-A) or C-1\n\nNortileal therapy (MANT-A) (MANT-A) or C-1\n\nN\n](1/parseimages/figure9e6a104224844e0db5d96ce4f9afb0c8_0_4.png) Note: All recommendations are category 2A unless otherwise indicated.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Mantle Cell Lymphoma

NCCN Guidelines Index Table of Contents Discussion

![RELAPSED/REFRACTORY OR PROGRESSIVE DISEASE\n\n### $$\text{SCN}\text{Gulendelines Version 1.2026}$$\n### RELAPSED/REFRACTORY OR PROGRESSIVE DISEASE\n\n### $$\text{SCN}\text{Gulendelines Version 1.2026}$$\n###RELAPSED/REFRACTORY OR PROGRESSIVE DISEASE\n\n#### $$\text{SCN}\text{Gulendelines Version 1.2026}$$\n#####RELAPSED/REFRACTORY OR PROGRESSIVE DISEASE\n\n########################################################################################################################################################\n](1/parseimages/figure18753da133a34642948cf35b7850e3f4_0_4.png) Note: All recommendations are category 2A unless otherwise indicated.

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Mantle Cell Lymphoma

NCCN Guidelines Index Table of Contents Discussion

SUGGESTED TREATMENT REGIMENSa,b

|INDUCTION THERAPY|INDUCTION THERAPY|INDUCTION THERAPY| |---|---|---| |Stage I or Stage II nonbulky (contiguous or noncontiguous)$^{c}$ or Classical TP53 wildtype: Stage II bulky and/or noncontiguous; Stage III, IV|Classical TP53 wildtype: Stage II bulky and/or noncontiguous; Stage III, IV|Classical TP53 mutated: Stage II bulky and/or noncontiguous; Stage III, IV| |Less Aggressive Induction Therapy Preferred • Acalabrutinib$^{d,e}$ (continuous)/ Bendamustine$^{f}$ + Rituximab followed by Rituximab maintenance (2 y) • Acalabrutinib$^{d,e}$ (continuous) + Rituximab • Bendamustine$^{f}$ + Rituximab$^{g}$ Other recommended • CHOP$^{h}$ + Rituximab followed by Rituximab maintenance • Ibrutinib (continuous) + Rituximab followed by Rituximab maintenance (2 y) • Lenalidomide (continuous) + Rituximab • VR-CAP (Bortezomib/ Cyclophosphamide/Doxorubicin/ Prednisone) + Rituximab|Aggressive Induction Therapy Preferred (in alphabetical order) • Bendamustine$^{f}$ + Rituximab followed by high-dose Cytarabine + Rituximab • LyMA regimen: DHA (Dexamethasone/Cytarabine) + platinum (Carboplatin, Cisplatin, or Oxaliplatin) + Rituximab x 4 cycles followed by CHOP + Rituximab for non-PET CR • NORDIC regimen: Dose-intensified induction immunochemotherapy with maxi-CHOP (Cyclophosphamide/Doxorubicin/Vincristine/Prednisone) + Rituximab alternating with high-dose Cytarabine + Rituximab • TRIANGLE regimen (fixed duration): CHOP/covalent BTKi (Acalabrutinib, Ibrutinib, or Zanubrutinib)$^{d}$ + Rituximab alternating with DHA (Dexamethasone/Cytarabine) + platinum (Carboplatin, Cisplatin, or Oxaliplatin) + Rituximab • Hadiabutinib$^{d,e}$ (continuous) + Rituximab Other recommended • RBAC500 (Bendamustine$^{f}$/Low-dose Cytarabine) + Rituximab|Suitable for all patients • Venetoclax/Zanubrutinib + Obinutuzumab Suitable for aggressive induction therapy: • TRIANGLE regimen (fixed duration): CHOP/ covalent BTKi (Acalabrutinib, Ibrutinib, or Zanubrutinib)$^{d}$ + Rituximab alternating with DHA (Dexamethasone/Cytarabine) + platinum (Carboplatin, Cisplatin, or Oxaliplatin) + Rituximab followed by maintenance with Rituximab + covalent BTKi Not suitable for aggressive induction therapy: • Acalabrutinib$^{d,e}$ (continuous) + Rituximab|

Consider prophylaxis for tumor lysis syndrome (NHODG-B) See monoclonal antibody and viral reactivation (NHODG-B)

Footnotes Second-line or Subsequent Therapy on MANT-A 2 of 5

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 1.2026 Mantle Cell Lymphoma

NCCN Guidelines Index Table of Contents Discussion

SECOND-LINE OR SUBSEQUENT THERAPY

Preferred (in alphabetical order)

• Covalent BTKi (continuous)d,j

Acalabrutinibe

Zanubrutinib

• Lenalidomide (continuous) + Rituximab

Other recommended

• Covalent BTKi (continuous)d Ibrutinibk ± Rituximab

Useful in Certain Circumstances (in alphabetical order)

• Bendamustinef + Rituximab (not recommended if treated with prior

Bendamustine)

• Bortezomib ± Rituximab

• DHA (Dexamethasone/Cytarabine) + platinum (Carboplatin, Cisplatin, or Oxaliplatin) + Rituximab (if not previously given)

• GEMOX (Gemcitabine/Oxaliplatin) + Rituximab

• Ibrutinibd (continuous)/Venetoclax

• RBAC500 (not recommended if treated with prior Bendamustine)

• Venetoclaxd (continuous) ± Rituximab

• Progressive disease after prior covalent BTKi

Non-covalent BTKi (continuous)

◊ Pirtobrutinibd,l

T-Cell Mediated Therapym,n

◊ CAR T-cell therapyo

– Brexucabtagene autoleucel (CD19-directed)

– Lisocabtagene maraleucel (CD19-directed)

◊ Bispecific antibody therapy

– Glofitamab-gxbmd

– Mosunetuzumab-axgb + Polatuzumab vedotin-piiqd

Note: All recommendations are category 2A unless otherwise indicated.

MANT-A 2 OF 5

Consider prophylaxis for tumor lysis syndrome (NHODG-B)See monoclonal antibody and viral reactivation (NHODG-B)

Footnotes

MAINTENANCE AFTER HDT/ASCR OR AGGRESSIVE INDUCTION THERAPY

• Rituximab every 8 weeks x 3 years ± Covalent BTKi (fixed duration; Acalabrutinib, Ibrutinib, or Zanubrutinib)d x 2 yearsi

MAINTENANCE AFTER LESS AGGRESSIVE INDUCTION THERAPY

• Rituximab every 8 weeks for 2–3 years following CHOP + Rituximab (category 1) or Bendamustine + Rituximab ± Acalabrutinib

• Maintenance Rituximab following VR-CAP has not been evaluated

SUGGESTED TREATMENT REGIMENSa,b

NCCN Guidelines Version 1.2026 Mantle Cell Lymphoma

NCCN Guidelines Index Table of Contents Discussion

Note: All recommendations are category 2A unless otherwise indicated.

MANT-A 3 OF 5

a See references for regimens MANT-A 4 of 5 and MANT-A 5 of 5.b An FDA-approved biosimilar is an appropriate substitute for any recommended systemic biologic therapy in the NCCN Guidelines. Rituximab and hyaluronidase

human injection for subcutaneous use may be substituted for rituximab after patients have received the first full dose of rituximab by intravenous infusion.

Obinutuzumab can optionally be substituted for rituximab at the discretion of the treating physician.

c In selected cases, relapsed disease may be managed with induction therapy recommended for newly diagnosed advanced stage MCL.d Refer to package insert for full prescribing information, dose modifications, and monitoring for adverse reactions: https://www.accessdata.fda.gov/scripts/cder/daf/

index.cfm.

e Studies of acalabrutinib excluded concomitant use of warfarin or equivalent vitamin K antagonists.f In patients intended to receive HDT/ASCR, bendamustine should be used with caution as there are conflicting data regarding ability to collect peripheral progenitor cell collection. In patients intended to receive HDT/ASCR, CAR T-cell therapy or CD3 x CD20 bispecific antibody therapy, bendamustine should be used with

caution. Delay bendamustine until after CAR-T leukapheresis.

g Addition of ibrutinib to BR followed by continuous ibrutinib maintenance was shown in the SHINE study to have a superior PFS but overall survival was

compromised by excess non-lymphoma deaths (Wang ML, et al. N Engl J Med 2022;386:2482-2494).

h There is a randomized trial that demonstrated that RCHOP was not superior to CHOP.i Benefit of 2 years of ibrutinib maintenance after alternating RCHOP + ibrutinib/RDHAP was shown in the TRIANGLE study (Dreyling M, et al. Blood 2022;140:1-

3). The value of ibrutinib maintenance after other aggressive induction therapy regimens has not been established. Alternate covalent BTKi (acalabrutinib and

zanubrutinib) were not evaluated in the TRIANGLE study.

j Acalabrutinib and zanubrutinib have not been shown to be effective for ibrutinib-refractory MCL with BTK C481S mutations. Pirtobrutinib is effective for the

management of resistance to covalent BTKi, including in patients with BTK C481 mutations (which are uncommon in MCL). Patients with intolerance to a BTKi will often be successfully treated with an alternate BTKi (covalent or non-covalent).

k Head-to-head clinical trials in other B-cell malignancies have demonstrated a more favorable toxicity profile for acalabrutinib and zanubrutinib compared to ibrutinib without compromising efficacy.

l Pirtobrutinib can be given as second-line therapy for disease progression during induction or maintenance therapy with covalent BTKi-based regimens.m In the setting of CD20-negative lymphomas, the efficacy of CD3 x CD20 bispecific antibody therapy is poor. If clinically feasible, repeat biopsy to confirm antigen

expression prior to the initiation of T-cell mediated therapy.

n Bispecific antibodies are associated with higher incidence of cytokine release syndrome (CRS) in patients with MCL than that reported in patients with DLBCL.

NCCN Guidelines for Management of CAR T-Cell and Lymphocyte Engager-Related Toxicities.

o In selected circumstances, an alternate CAR T-cell therapy can be used upon disease progression.

FOOTNOTES

SUGGESTED TREATMENT REGIMENS

National Cancer Network®

NCCN Guidelines Version 1.2026 Mantle Cell Lymphoma

NCCN Guidelines Index Table of Contents Discussion

SUGGESTED TREATMENT REGIMENS REFERENCES

Induction Therapy Aggressive therapy TRIANGLE regimen: Alternating RCHOP + ibrutinib/RDHA (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone, ibrutinib)/(rituximab, dexamethasone, cytarabine) + platinum (carbopatin, cisplatin, or oxalilatin) Dreyling M, Doorduijn J, Gine E, et al. Ibrutinib combined with immunochemotherapy with or without autologous stem-cell transplantation versus immunochemotherapy and autologous stem-cell transplantation in previously untreated patients with mantle cell lymphoma (TRIANGLE): a three-arm, randomised, open-label, phase 3 superiority trial of the European Mantle Cell Lymphoma Network. Lancet 2024;403:2293-2306. Dreyling M, Doorduijn JK, Gine E, et al. Role of autologous stem cell transplantation in the context of ibrutinib-containing first-line treatment in younger patients with mantle cell lymphoma: Results from the randomized triangle trial by the European MCL network [abstract]. Blood 2024;144:Abstract 240. Nordic trial regimen (Dose-intensified induction immunochemotherapy with rituximab + cyclophosphamide, vincristine, doxorubicin, prednisone [maxi-CHOP] alternating with rituximab + high-dose cytarabine) Geisler CH, Kolstad A, Herrell A, et al. Long-term progression-free survival of mantle cell lymphoma following intensive front-line immunochemotherapy with in vivo-purged stem cell resone: A non-randomized phase-II multicenter study by the Nordic Lymphoma Group. Blood 2008;112:2687-2693. Eskelund CW, Kolstad A, Jerkeman M, et al. 15-year follow-up of the Second Nordic Mantle Cell Lymphoma trial (MCL2): prolonged remissions without survival plateau. Br J Haematol 2016;175:410-418. LyMA regimen: RDHA (rituximab, dexamethasone, cytarabine) + platinum (cisplatin, oxalilatin or carbopatin) x 4 cycles followed by RCHOP for non-PET CR Sarkozy C, Thieblemont C, Oberic L, et al. Long-term follow-up of rituximab maintenance in young patients with mantle-cell lymphoma included in the LYMA trial: A LYSA study. J Clin Oncol 2024;42:769-773. Tessoulin B, Chiron D, Thieblemont C, et al. Oxalilatin before autologous transplantation in combination with high-dose cytarabine and rituximab provides longer disease control than cisplatin or carbopatin in patients with mantle-cell lymphoma: results from the LyMA prospective trial. Bone Marrow Transplant 2021;56:1700-1709. Rituximab, bendamustine followed by rituximab, high-dose cytarabine Merryman R, Edwin N, Redd R, et al. Rituximab/bendamustine and rituximab/cytarabine induction therapy for transplant-eligible mantle cell lymphoma. Blood Adv 2020;45:858-867. RBAC500 (rituximab, bendamustine, cytarabine) Tisi MC, Moia R, Patti C, et al. Long-term follow-up of rituximab plus bendamustine and cytarabine in older patients with newly diagnosed MCL. Blood Adv 2023;7:3916-3924. Bega G, Olivieri J, Riva M, et al. Rituximab and Bendamustine (BR) Compared with Rituximab, Bendamustine, and Cytarabine (R-BAC) in Previously Untreated Elderly Patients with Mantle Cell Lymphoma. Cancers (Basel) 2021;13:6089.

Less aggressive therapy

Acalabrutinib (continuous) + bendamustine + rituximab

Wang M, Salek D, Belada D, et al. Acalabrutinib plus bendamustine-rituximab in untreated mantle cell lymphoma. J Clin Oncol 2025;43:2276-2284.

Acalebrutinib + rituximab

Jain P, Ok CY, Fetooh A, et al. Alabrutinib with rituximab as first-line therapy for older patients with mantle cell lymphoma—A phase II clinical trial [abstract]. Hematol Oncol 2023;41:150-151.

Bendamustine + rituximab

Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet 2013;381:1203-1210.

Flinn IW, van der Jagt R, Kahl BS, et al. Open-label, randomized, nonferinity of study and condamise-rituximab or R-CHOP/R-CVP in first-line treatment of advanced indolent NHL or MCL: the BRIGHT study. Blood 2014;123:2944:2952.

CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) + rituximab

Lenz G, Dreyling M, Hoster E, et al. Immunochemotherapy with rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone significantly improves response and time to treatment failure, but not long-term outcome in patients with previously untreated mantle cell lymphoma. results of a prospective randomized trial of the German Low Grade Lymphoma Study Group (GLSG). J Clin Oncol 2005;23:1844-1992.

Kluin-Nelemans HC, Hoster E, Hermine O, et al. Treatment of older patients with mantle-cell lymphoma. N Eng J Med 2012;367:520-531.

Ibrutinib + rituximab

Lewis DJ, Jerkeman M, Sorrell L, et al. Ibrutinib and rituximab versus immunochemotherapy in patients with previously untreated mantle cell lymphoma (ENRICH): A randomised, open-label, phase 2/3 superiority trial. Lancet 2025;406:1953-1968.

Lenalidomide + rituximab

Yamshon S, Chen GZ, Gibbin C, et al. Nine-year follow-up of lenalidomide plus rituximab as initial treatment for mantle cell lymphoma. Blood Adv 2023;7:6579-6588.

VR-CAP (bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone)

Robak T., Jin J. Pylypenko H., et al. Frontline bortezomib, vitumaxib, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) versus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in transplantation-ineligible patients with newly diagnosed mantle cell lymphoma: final overall survival results of a randomised, open-label, phase 3 study. Lancet Oncol 2018;19:1449-1458.

Induction Therapy for classical TP53 mutated MCL Zanubrutinib, obinutuzumab, and venetoclax

Induction Therapy for classical TP53 mutated MCL

Zanubrutinib, obinutuzumab, and venetoclax

Kumar A, Soumerai J, Abramson JS, et al. Zanubrutinib, obinutuzumab, and venetoclax for first-line treatment of mantle cell lymphoma with a TP53 mutation. Blood 2025;145:497-507.

Continued

NCCN

National Cancer Network®

NCCN Guidelines Version 1.2026

Mantle Cell Lymphoma

NCCN Guidelines Index Table of Contents Discussion

SUGGESTED TREATMENT REGIMENS REFERENCES

First-line Consolidation High-dose therapy with autologous stem cell rescue Fenske TS, Wang XV, Till BG, et al. Lack of Benefit of Autologous Hematopoetic Cell Transplantation (auto-HCT) in Mantle Cell Lymphoma (MCL) Patients (pts) in First Complete Remission (CR) with Undetectable Minimal Residual Disease (uMRD): Initial Report from the ECOG-ACRIN EA4151 Phase 3 Randomized Trial [abstract]. Blood 2024;144:Abstract LBA-6. Maintenance with rituximab $\pm$ ibritinib and HDTASCR or aggressive induction therapy Dreyling, M Doordujin J, Gine E, et al. I. Brutbinib combined with immunochemotherapy with or without autologous stem-cell transplantation versus immunochemotherapy and autologous stem-cell transplantation in previously untreated patients with mantle cell lymphoma (TRIANGLE): a three-arm, randomised, open label, phase 3 superiority of the European Mantle Cell Lymphoma Network. Lancet 2024;403:2293-2306. Le Gouill S, Thieblement O, Cberic L, et al. Rituximab after autologous stem cell transplantation in mantle cell lymphoma. N Engl J Med 2017;377:1250-1260. Itienle cell lymphoma and after aggressive therapy Rituximab��ance after less aggressive therapy Sarkozy C, Thieblement C, Oberic L, et al. Long-term follow-up of rituximab maintenance in young patients with mantle-cell lymphoma included in the LYMA trial: ALYSA study. J Clin Oncol 2024;42:769-773. KUN-Nelemans HC, Hoster E, Hermine O, et al. Treatment of older patients with mantle cell lymphoma (MCL): Long-term follow-up of the randomized European MCL Elderly Trial. J Clin Oncol 2020;38:248-256. Rummel MJ, Lerchemmüller C, Hensel M, et al. Two years rituximab maintenance vs. observation after first line treatment with bendamustine plus rituximab (B-R) in patients with dalenström's macroglobulinemia (MW): Results of a prospective, randomized, multicenter phase 3 study (the StIL NHLa, WERLE) TANTAIN trial [apapal] of the 2024;42:769-256.

Second-line and Subsequent Therapy Acalabritinii Wang M, Rule S, Zinzani PL, et al. Durable response with single-agent acalabrutinib in patients with relapsed or refractory mantle cell lymphoma. Leukemia 2019;33:2762-2766. Bendamustine Robinson KS, Williams ME, van der Jagt RH, et al. Phase II multicenter study of bendamustine plus rituximab in denentidol bent B-cell and mantle cell non-Hodgkin's Lymphoma. J Clin Oncol 2008;26:4473-4479. Lymphoma. J Clin Oncol 2008;26:4473-4479. Burrum M, Kaiser U, Balser C, et al. Bendamustine plus rituximab versus fludarabine plus rituximab for patients with relapsed indolent and mantle-cell lymphomas: a multicentre, randomised, open-label, non-inferiority phase 3 trial. Lancet Oncol 2016;17:57-66.

Bendamustine

Robinson KS, Williams ME, van der Jagt RH, et al. Phase II multicenter study of bendamunisme plus rituximab in potenti med indolent B-cell and mantle cell Non-Hodgkin's Lymphoma. J Clin Oncol 2008;26:4473-4479. Rummel M. Kaiser U, Baiser C, et al. Bendamustine plus rituximab versus fludarabine plus rituximab for patients with relapsed indolent and mantle-cell lymphomas: a multicentre, randomised, open-label, non-inferiority phase 3 trial. Lancet Oncol 2016;17:57-66.

Bortezomib ± rituximab

Goy A, Bernstein SH, Kahl BS, et al. Bortezomib in patients with relapsed or refractory mantle cell lymphoma: updated time-to-event analyses of the multicenter phase 2 PINNACLE study. Ann Oncol 2009;20:520-525.

Baiocchi RA, Alinari L, Lustberg ME, et al. Phase 2 trial of rituximab and bortezomib in patients with relapsed or refractory mantle cell and follicular lymphoma. Cancer 2011;117:2442-2451. (Dax (dexamethasone, cytarabine) + platinum (carboplatin, cisplatin, or oxaliplatin) + rituximab

Mey UJ, Olropp KS, Flieger D, et al. Dexamethasone, high-dose cytarabine, and cisplatin combination with rimuotam as salvage treatment for with relapsed or refractory aggressive non-Hodgkin's lymphoma. Cancer Invest 2006;24:593-600.

Lignon J, Sibon D, Madelaine I, et al. Rituximab, dexamethasone, cytarabine, and oxaliplatin (R-DHAX) is effective and valamethase of relrefar respiration and red/refract. Lymphoma. Clin Lymphoma Myeloma Leuk 2010;10:262-269.

Rigacci L, Fabri A, Puccini B, et al. Oxalilatin-based chemotherapy (dexamethasone, high-relapsed or exalpiatin) +/- rituimina (t) +/- rituimina (t) +/- rituimina (t) +/- rituimina (t) +/- rituimina (t) +/- rituimina (t) +/- rituimina (t) +/- rituimina (t) +/- rituimina (t) +/- rituimina (t) +/- rituimina (t) +/- rituimina (t) +/- rituimina (t) +/- rituimina (t) +/- rituimina (t) +/- rituimina (t) +/- rituimina (t) +/- rituimina (t) +/- rituimina (t) +/- rituimina (t) +/- rituimina (t) +/- ritui

GenOx (gemcitabine, oxaliplatin) + rituximab

Obrador-Hevia A, Serra-Sitjar M. Rodríguez J, et al. Efficacy of the GemOx-R regimen leads to the identification of Oxaliplin as a highly effective drug against Mantle Cell Lymphoma. Br J Haematol 2016;174:899-910.

Broduez J, Gutierrez A, Palacios A, et al. Rituximab, gemicatubine and oxalipatin: an effective regimen in patients with refractory and relapsing mantle cell lymphoma. Leuk Lymphoma 2007;48:2172-2178.

Ibrutinibit và rituximab

Wang MLur, BlA KA, Martin P, et al. Long-term follow-up of MCL patients treated with single-agent ibrutinib: updated fabetin and efficacy results. Blood 2015;126:739-745.

Rule J, Surczak W, Jerkeman M, et al. Ibrutinib versus tensirolimus: 3-year follow-up of patients with previously treated mantle cell lymphoma from the phase 3, international, randomized, open-label RAY study. Leukemia 2018:32:1799-1803.

Wang ML, Lee H, Chuang H, et al. Ibrutinib in combination with rituximab in relapsed or refractory mantle cell lymphoma: a single-centre, open-label, phase 2 trial. Lancet Oncol 2016;7:48-56.

Ibrutinib + venetoclast

Wang M, Jurczak W, Trneny M, et al. Ibrutinib plus venetoclax in relapsed or refractory mantle cell lymphoma (SYMPATICO) a multicentre, randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol 2025;26:200-213.

Lenalidomide + rituximab

Wang M, Fayard - Wertag, B-Aterbant, N et al. Lenalidomide in combination with rituximab for patients with relapsed or refractory mantle cell lymphoma: a phase 1/2 clinical trial. Lancet Oncol 2012;13:716-723.

RBAC500 (0 rituximab, bendamustine, cytarabine)

Meculloch R, Lewis D, Crobsbie N, et al. (Ibrutinib for mantle cell lymphoma at first relapse: a United Kingdom real-world analysis of outcomes in 211 patients. Br J Haematol 2021;193:290-298.

Venetocax & rituximab

Davidms MS, Roberts AW, Kenke VP, et al. Long-term follow-up of patients with relapsed or refractory non-Hodgkin lymphoma treated with venetoclas in a phase 1; first-in-human study. Clin Cancer Res 2021;27:4690-4695.

Davids M, von Keudell G, Portell G, et al. Revised dose ramp-up to mitigate the risk of tumor lysis syndrome when initiating venetoclast in patients with mantle cell lymphoma. J Clin Oncol 2018;36:3525-3527.

Sawalha Y, Goyal S, Switchenko JM, et al. A multicenter analysis of the outcomes with venetoclax in patients with mantle cell lymphoma. Blood Adv 2023;7:2983-2993.

Zanubrutinin

Song Y, Zhou K, Zou D, et al. Treatment of patients with relapsed or refractory mantle-cell lymphoma with a binar, a selective inhibitor of Bruton's tyrosine kinase. Clin Cancer Res 2020;26:42:4216-4224.

Tam CS, Opat, S. Simpson D, et al. Zanubrutinib for the treatment of relapsed or refractory mantle cell lymphoma. H 2021;5:2577:2585.

Brexucalcagene atoleucel

Wang M, Munoz J, Goy A, et al. Three-year follow-up of KTE-X19 in patients with relapsed/refractory mantle cell lymphoma, including high-risk subgroups, in the ZUMA-2 study. J Clin Oncol 2023;41:555-567.

Lisocabtagene maraleucel

Wang M, Siddiq T, Gordon LI, et al. Lisocabtagene maraleucel in relapsed/refractory mantle cell lymphoma: primary analysis of the mantle cell lymphoma cohort from TRANSCEND NHL 001, a phase I multicenter seamless design study. J Clin Oncol 2024;42:1146-1157.

Pirtobrutinib

Wang ML, Jurczak W, Zinzani PL, et al. Pirtobrutinib in covalent Bruton tyrosine kinase inhibitor pretreated mantle-cell lymphoma. J Clin Oncol 2023;41:3988-3997.

Glofitamab

Phillips T, Carlo-Stella C, Morschhauser F, et al. Glofitamab monotherapy in patients with heavily pretreated relapsed/refractory (R/R) mantle cell lymphoma (MCL): Updated analysis from a phase I/Il study [abstract]. J Clin Oncol 2024;42:Abstract 7008.

Mosunetuzumab + polatuzumab vedotin

Budde LE, Kamdar M, Assouline S, et al. Fixed-duration outpatient subcutaneous mosunetuzumab + polatuzumab shows robust efficacy in a phase II study of relapsed/refractory post-BTKi mantle cell lymphoma [abstract]. Hematological Oncology 2025;43:e50_70093.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Diffuse Large B-Cell Lymphoma

NCCN Guidelines Index Table of Contents Discussion

ADDITIONAL DIAGNOSTIC TESTING$^{a,b}$

ESSENTIAL:

* Adequate immunophenotyping to establish diagnosis and germinal center B-cell (GCB) versus non-GCB origin$^{c}$

$\bullet$ IHC panel: CD3, CD20, CD10, CD21, BCL2, BCL6, IRF/M4/MYC, MYC with or without

$\bullet$ Flow cytometry with peripheral blood and/or biopsy specimen: kappa/lambda, CD3, CD5, CD19, CD10, CD20, CD45,

* FISH for MYC; FISH for BCL2, BCL6 rearrangements if MYC positive

USEFUL UNDER CERTAIN CIRCUMSTANCES:

* Additional IHC studies to establish lymphoma subtype

$\bullet$ IHC panel: cyclin D1, kappa/lambda, CD5, CD30, CD45, CD138, anaplastic lymphoma kinase (ALK), human herpesvirus-8 (HHV8), SOX11, Ki-67

$\bullet$ Epstein-Barr virus (EBV)-encoded RNA (EBER) in situ hybridization (EBER-ISH)

* FISH for IRF4/MUM1 rearrangements$^{d}$

$\bullet$ MGPT with lymphoma panel$^{b}$

SUBTYPES

![DLBCL, not otherwise specified (DLBCL-NOS)e(includes germinal center [GC] and non-GC)●FL3B (ICC)/FLBCL (WHO5)● Intravascular LBCLWorkup● DLBCL associated with chronic inflammation● Fibrin-associated LBCL(BCEL-2)●EBV-positive DLBCL, NOS● T-cell/histiocyte-rich LBCL● LBCL with IRF4/MUM1 rearrangement●HGBL with MYC and BCL6 rearrangements (ICC)BCEL-10● Primary cutaneous DLBCL, leg type●ALK-positive LBCLBCEL-B 1 of 2●Mediastinal gray zone lymphoma (MGZL)BCEL-B 2 of 2●Primary mediastinal large B-cell lymphoma (PMBLPMBL-1●HGBLHGBL-1●HGBL,NOS● LBCL with 11q aberration [ICC]/HGBL with 11q aberrations [WHO5]BURK-1●DLBCL arising from FL or MZLHTBCEL-1●Primary DLBCL of the CNS (See NCCN Guidelines for CNS·DLBCL arising from CLL (Richter transformation) (See NCCN Guidelines for CLL/SLL\n](1/parseimages/figurea372b19b3a314bfd915194fa47eac30c_0_17.png) a Special Considerations for Adolescent and Young Adult (AYA) Patients with B-Cell Lymphomas (NHODG-B 4 of 5).

b See BCEL-A 1 of 3 for a minimal list of accepted genes that should be included in the MGPT lymphoma panel for DLBCL.

c Typical immunophenotype: CD20+, CD45+, CD3-; additional markers are used for subclassification.

d LBCL with IRF4/MUM1 rearrangement are usually DLBCL but occasionally are purely FL grade 3b (ICC/FLBCL [WHO5]) and often DLBCL with FL grade 3b. Patients typically present with Waldeyer's ring involvement and are often children/young adults. These lymphomas are locally aggressive but respond well to chemotherapy ± RT. They do not have a BCL2 rearrangement and should not be treated as low-grade FL.

e GC (or follicle center) phenotype is not equivalent to FL and can occur in DLBCL and BL. Morphology is required to establish diagnosis.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Diffuse Large B-Cell Lymphoma

NCCN Guidelines Index Table of Contents Discussion

WORKUP

ESSENTIAL:

* Physical exam: attention to node-bearing areas, including Waldeyer's ring, and to size of liver and spleen

$\bullet$ Performance status

* B symptoms

$\bullet$ CBC with differential

$\cdot$ LDH

* Comprehensive metabolic panel

$\bullet$ Uric acid

$\bullet$ PET/CT scan (preferred) or C/A/P CT with contrast of diagnostic quality

* Calculation of International Prognostic Index (IPI) (BCEL-A 2 of 3)

$\bullet$ Hepatitis B testing$^{f}$

$\bullet$ Echocardiogram or MUGA scan if anthracycline or anthracenedione-based regimen is indicated

* Pregnancy testing in patients of childbearing age (if therapy planned)

![First-LIne Therapy(BCEL-3\n](1/parseimages/figure77e27f66a92047258ee1237907d7cd08_0_18.png)

USEFUL IN SELECTED CASES:

* Head CT/MRI with contrast or neck CT/MRI with contrast

* HIV testing

$\bullet$ Hepatitis C testing

$\bullet$ Beta-2-microglobulin

$\bullet$ Lumbar puncture for patients at risk for CNS involvement; see BCEL-A 3 of 3

$\bullet$ Adequate bone marrow biopsy (>1.6 cm) ± aspirate; bone marrow biopsy is not necessary if PET/CT scan demonstrates bone disease. Bone marrow biopsy with a negative PET/CT scan may reveal discordant lymphoma

a negative PET/CT scan may reveal discordant lymphoma

$\bullet$ Discuss fertility preservation$^{9}$

f Hepatitis B testing is indicated because of the risk of reactivation with immunotherapy + chemotherapy. Tests include HBsAg and core antibody for a patient with no risk factors. For patients with risk factors or previous history of hepatitis B, add e-antigen (NHODG-B). If positive, check viral load and consider consult with gastroenterologist.

$^{9}$ Fertility preservation options include: sperm banking, IVF, or ovarian tissue or oocyte cryopreservation.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Diffuse Large B-Cell Lymphoma

NCCN Guidelines Index Table of Contents Discussion

STAGE

FIRST-LINE THERAPYP

![Stage I, II\n(excluding stage\nII with extensive mesenteric\ndisease$^{h}$) i, j, k, l\n\nNonbulky\n(<7.5 cm)$^{l}$\n\nSmlPI 0-1 $\rightarrow$ RCHOP x 3 cycles\nInterim restaging with\nPET/CT\nBCEL-4\nStage I, II\n(excluding stage\nII with extensive mesenteric\ndisease or Stage III, IV\nBulky\n(≥7.5 cm)$^{l}$\n\nSmlPI 0-1 $\rightarrow$ RCHOP x 3-4 cycles\nInterim restaging with\nPET/CT$^{o}$\n\nBCEL-5\nStep 11 with extensive disease$^{h}$\n(或) I, i, k, m, n, o\n\nFirst-line therapy\nSee Suggested Regimens (BCEL-C)\nInterim restaging with PET/\nCT$^{q}$ or CT after 2-4 cycles\nBCEL-6\nStage III, IV i, k, m, n, o\n](1/parseimages/figure20dad9db391f41a1b9b57e5064b31a1c_0_6.png) ![Stage II with extensive mesenteric disease$^{h}$ or Stage III, IV $^{i,k,m,n,o}$\n\nFirst-line therapy See Suggested Regimens (BCEL-C) CT$^{q}$ or CT after 2-4 cycles BCEL-6\n\nStage III, IV $^{i,k,m,n,o}$\n](1/parseimages/figurec70a04446121477ab8381c99571d149b_0_7.png) $^{1}$ Includes multifocal disease and bulky disease that is not amenable to RT.

i In testicular lymphoma, after completion of chemoimmunotherapy, scrotal RT should be given. See Principles of Radiation Therapy (NHODG-D).

$^{j}$ In patients who are not candidates for chemoimmunotherapy, ISRT is recommended.

k See BCEL-C for regimens used in patients with poor left ventricular function, patients who are very frail, and patients >80 years of age with comorbidities. There are limited data for treatment of early-stage disease with these regimens; however, short-course chemoimmunotherapy + RT for stage I-II disease is practiced at NCCN Member Institutions.

$^{1}$ Some studies have used 10 cm as the cutoff for bulky disease.

m Prognostic Model to Assess the Risk of CNS Disease (BCEL-A 3 of 3).

n Patients with systemic disease with concurrent CNS disease; see BCEL-C.

° In selected cases, RT to initially bulky sites of disease may be beneficial (category 2B).

* P Recommendations are for HIV-negative lymphoma only. For HIV-positive DLBCL, see HIVLYM-2.

$^{9}$ PET/CT scan at interim restaging can lead to increased false positives and should be carefully considered in select cases. If PET/CT scan performed and positive, rebiopsy before changing course of treatment. In selected cases, PET is necessary when disease is occult on CT scan (eg, bone only disease).

Note: All recommendations are category 2A unless otherwise indicated.

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Diffuse Large B-Cell Lymphoma

NCCN Guidelines Index Table of Contents Discussion

![STAGE I (smIPI 0-1; Non-bulky; <7.5 cm)\n\nEnd-OF-TREATMENT RESPONSE\n\nFOLLOW-UP\n\nClinicalH&P and labs, every 3-6 mo for 5 y and then annually or as clinically indicated Imaging$^{w}$\n\nRelapse<12 mo\n\nRelapse<12 mo\n\nRestage with PET/CT after 3 cycles of RCHOP $k^{f}$|PET positive [5-PS 4]$^{f}$|S|RP $^{f}$|S|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|T|\n](1/parseimages/figure2fab0deea9fc486486831d46251503d3_0_4.png) i In testicular lymphoma, after completion of chemoimmunotherapy, scrotal RT should be given. See Principles of Radiation Therapy (NHODG-D).

$^{k}$ See BCEL-C for regimens used in patients with poor left ventricular function, patients who are very frail, and patients >80 years of age with comorbidities. There are limited data for treatment of early-stage disease with these regimens; however, short-course chemoimmunotherapy + RT for stage I-II disease is practiced at NCCN Member Institutions.

$^{1}$ Lugano Response Criteria for Non-Hodgkin Lymphoma (NHODG-C).

$^{s}$ PET/CT scan should be interpreted via the PET 5-PS (NHODG-C 3 of 3).

$^{t}$ Principles of Radiation Therapy (NHODG-D).

$^{u}$ Repeat biopsy should be strongly considered if PET-positive prior to additional therapy. If biopsy negative, follow PET-negative pathway. In cases where biopsy cannot be done or is unsafe, clinical judgment should be used.

$\bullet$ The optimum timing of end-of-treatment PET/CT is unknown; however, waiting a minimum of 8 weeks after RT to repeat PET/CT scan is suggested. False positives may occur due to post-treatment changes. If end-of treatment PET is positive, consider repeat biopsy or if biopsy not feasible, consider circulating tumor DNA (ctDNA) for MRD (ctDNA-MRD) assessment (category 2B), using the detection limit of <1 part per million, prior to additional therapy. If biopsy and/or ctDNA-MRD- negative, follow PET-negative pathway.

W Surveillance imaging at 12 mo has treatment implications. Surveillance imaging is used for monitoring asymptomatic patients. When a site of disease can only be visualized on PET/CT scan (eg, bone), it is appropriate to proceed with PET/CT scans for surveillance.

Note: All recommendations are category 2A unless otherwise indicated.

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Diffuse Large B-Cell Lymphoma

NCCN Guidelines Index Table of Contents Discussion

![STAGE I-II (smIPI 0-1; BULKY; ≥7.5 CM)\n(EXCLUDING STAGE II WITH EXTENSIVE MESENTERIC DISEASEh)RESTAGING AND ADDITIONAL THERAPY\n\nRestage with PET/CT after 3-4 cycles of RCHOP $^{e}$, $^{f}$ (PET positive [5-PS 4])$^{g}$\n\n$^{f}$ (PET negative [5-PS 1-3])$^{g}$\n\n$^{f}$ (PET negative [5-PS 1-3])$^{g}$\n\n$^{f}$ (PET response$^{f}$, $^{g}$) $^{f}$ (PET positive [5-PS 1-3])$^{g}$\n\n$^{f}$ (PET response$^{f}$, $^{g}$) $^{f}$ (PET negative [5-PS 1-3])$^{g}$\n\n$^{f}$ (PET negative [5-PS 1-3])$^{g}$ (PET negative [5-PS 1-3])$^{g}$ (PET negative [5-PS 1-3])$^{g}$ (PET negative [5-PS 1-3])$^{g}$ (PET negative [5-PS 1-3])$^{g}$ (PET negative [5-PS 1-3])$^{g}$ (PET negative [5-PS 1-3])$^{g}$ (PET negative [5-PS 1-3])$^{g}$ (PET negative [5-PS 1-3])$^{g}$ (PET negative [5-PS 1-3])$^{g}$ (PET negative [5-PS 1-3])$^{g}$ (PET negative [5-PS 1-3])$^{g}$ (PET negative [5-PS 1-3])$^{g}$ (PET negative [5-PS 1-3])$^{g}$ (PET negative [5-PS 1-3])$^{g}$ (PET negative [5-PS 1-3])$^{g}$ (PET negative [5-PS 1-3])$^{g}$ (PET negative [5-PS 1-3])$^{g}$ (PET negative [5-PS 1-3])$^{g}$ (PET negative [5-PS 1-3])$^{g}$ (\n](1/parseimages/figureb35733c3689049b19446c80d9cfea6d9_0_4.png) $^{1}$ Includes multifocal disease and bulky disease that is not amenable to RT.

i In testicular lymphoma, after completion of chemoimmunotherapy, scrotal RT should be given. See Principles of Radiation Therapy (NHODG-D).

k See BCEL-C for regimens used in patients with poor left ventricular function, patients who are very frail, and patients >80 years of age with comorbidities. There are limited data for treatment of early-stage disease with these regimens; however, short-course chemoimmunotherapy + RT for stage I–II disease is practiced at NCCN Member Institutions.

* Lugano Response Criteria for Non-Hodgkin Lymphoma (NHODG-C).

s PET/CT scan should be interpreted via the PET 5-PS (NHODG-C 3 of 3).

† Principles of Radiation Therapy (NHODG-D).

Note: All recommendations are category 2A unless otherwise indicated.

V The optimum timing of end-of-treatment PET/CT is unknown; however, waiting a minimum of 8 weeks after RT to repeat PET/CT scan is suggested. False positives may occur due to post-treatment changes. If end-of treatment PET is positive, consider repeat biopsy or if biopsy not feasible, consider ctDNA-MRD assessment (category 2B), using a test with a detection limit of <1 part per million, prior to additional therapy. If biopsy and/or ctDNA-MRD-negative, follow PET-negative pathway.

w Surveillance imaging at 12 mo has treatment implications. Surveillance imaging is used for monitoring asymptomatic patients. When a site of disease can only be visualized on PET/CT scan (eg, bone), it is appropriate to proceed with PET/CT scans for surveillance.

$\bullet$ Patients in first remission may be candidates for consolidation trials including HDT/ASCR.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Diffuse Large B-Cell Lymphoma

NCCN Guidelines Index Table of Contents Discussion

![STAGE I-II WITH EXTENSIVE MESENTERIC DISEASE$^{1}$ OR STAGE III-IV DISEASE RESTAGING AND ADDITIONAL THERAPY\n\nFOLLOW-UP\nEND-OF-TREATMENT RESPONSE\n\nComplete response$^{1}$ (PET negative [5-PS 1-3]$^{s}$ or partial response$^{1}$ (PET positive [5-PS 4a/5])$^{s}$\n\nContinue first-line therapy$^{1}$ (TET positive [5-PS 4a/5])$^{s}$\n\nAt end of treatment, repeat all positive studies$^{1}$, aa\n\nComplete response$^{1}$ (PET negative [5-PS 4a/5])$^{s}$\n\nComplete response$^{1}$ (PET negative [5-PS 4a/5])$^{s}$\n\nAt end of treatment, repeat all positive studies$^{1}$, aa\n\nComplete response$^{1}$ (PET negative [5-PS 4a/5])$^{s}$\n\nComplete response$^{1}$ (PET negative [5-PS 4a/5])$^{s}$\n\nAt end of treatment, repeat all positive studies$^{1}$, aa\n\nComplete response$^{1}$ (PET negative [5-PS 4a/5])$^{s}$\n\nComplete response$^{1}$ (PET negative [5-PS 4a/5])$^{s}$\n\nAt end of treatment, repeat all positive studies$^{1}$, aa\n\nComplete response$^{1}$ (PET negative [5-PS 4a/5])$^{s}$\n\nComplete response$^{1}$ (PET negative [5-PS 4a/5])$^{s}$\n\nComplete response$^{1}$ (PET negative [5-PS 4a/5])$^{s}$\n\nComplete response$^{1}$ (PET negative [5-PS 4a/5])$^{s}$\n\nComplete response$^{1}$ (PET negative [5-PS 4a/5])$^{s}$\n\nComplete response$^{1}$ (PET negative [5-PS 4a/5])$^{s}$\n\nComplete response$^{1}$ (PET negative [5-PS 4a/5])$^{s}$\n\nComplete response$^{1}$ (PET negative [5-PS 4a/5])$^{s}$\n\nComplete response$^{1}$ (PET negative [5-PS 4a/5])$^{s}$\n\nComplete response$^{1}$ (PET negative [5-PS 4a/5])$^{s}$\n\nComplete response$^{1}$ (PET negative [5-PS 4a/5])$^{s}$\n\nComplete response$^{1}$ (PET negative [5-PS 4a/5])$^{s}$\n\nComplete response$^{1}$ (PET negative [5-PS 4a/5])$^{s}$\n\nComplete response$^{1}$ (PET negative [5-PS 4a/5])$^{s}$\n\nComplete response$^{1}$ (PET negative [5-PS 4a/5])$^{s}$\n\nComplete response$^{1}$ (PET negative [5-PS 4a/5])$^{s}$\n\nComplete response$^{1}$ (PET negative [5-PS 4a/5])$^{s}$\n\nComplete response$^{1}$ (PET negative [5-PS 4a/5])$^{s}$\n\nComplete response$^{1}$ (PET negative [\n](1/parseimages/figure3b40573d410f4687a85f9505140a061e_0_4.png) h Includes multifocal disease and bulky disease that is not amenable to RT.

r `Lugano Response Criteria` for Non-Hodgkin Lymphoma (NHODG-C).

s PET/CT scan should be interpreted via the PET 5-PS (NHODG-C 3 of 3).

† Principles of Radiation Therapy (NHODG-D).

$^{w}$ Surveillance imaging at 12 mo has treatment implications. Surveillance imaging is used for monitoring asymptomatic patients. When a site of disease can only be visualized on PET/CT scan (eg, bone), it is appropriate to proceed with PET/CT scans for surveillance.

$^{5}$ See BCEL-C for regimens used in patients with poor left ventricular function, patients who are very frail, and patients >80 years of age with comorbidities.

$^{2}$ In selected cases, PET is necessary when disease is occult on CT scan (eg, bone only disease). PET/CT scan at interim restaging can lead to increased false positives and should be carefully considered in select cases. If PET/CT scan performed and positive, rebiopsy before changing course of treatment.

aa If end-of treatment PET is positive, consider repeat biopsy or if biopsy not feasible, consider ctDNA-MRD assessment (category 2B), using a test with a detection limit of <1 part per million, prior to additional therapy. If biopsy and/or ctDNA-MRD-negative, follow PET-negative pathway.

$^{bb}$ In cases where PET/CT needs to be used, a 5-PS = 4 response can reflect post-treatment inflammation as well as active disease. If there is uncertainty regarding interpretation of the response, consider brief interval restaging to clarify post-treatment inflammation response.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Diffuse Large B-Cell Lymphoma

NCCN Guidelines Index Table of Contents Discussion

RELAPSE/ REFRACTORY DISEASE

ADDITIONAL THERAPY

RESPONSE ASSESSMENT

![NCCN 授权医脉通提供NCCN指南全文下载。wmlsyy于2025/12/23,21:20在医脉通平台下载,仅供个人使用,严禁分发。2025 美国国家综合癌症网络版权所有。\n\nNCCN Guidelines Index\nTable of Contents\n#NCCN Configuration\nRELAPSE/REFRACTORY DISEASE\nADDITIONAL THERAPY\nRESPONSE ASSESSMENT\nRelapsed disease<12 mo or Primary refractory diseasecc\nClinical trial or Second-line therapy; see Suggested Regimens (BCEL-C 2 of 7) or Palliative ISRTt or Best supportive care (See NCCN Guidelines for Palliative Care)\n{12 mo or Primary refractory diseasecc}\n](1/parseimages/figure9b0d424a03a740ba8f779f74808d5ce1_0_7.png) $^{f}$ Lugano Response Criteria for Non-Hodgkin Lymphoma (NHODG-C).

$^{†}$ Principles of Radiation Therapy (NHODG-D).

cc Management of localized refractory disease is uncertain. RT ± chemoimmunotherapy followed by HDT/ASCR may be an option for some patients.

dd When using holding therapy (prepheresis), potential complications of the holding therapy regimen on the collection of T-cells should be considered. Delay bendamustine until after CAR-T leukapheresis. If holding or bridging (postpheresis) therapy results in CR or very good PR, proceeding with HDT/ASCR is an appropriate alternative.

ee Repeat biopsy should be strongly considered if PET-positive prior to additional therapy, because PET positivity may represent post-treatment inflammation. If biopsy negative, follow CR pathway.

ff In patients who do not have access to CAR T-cell therapy or bispecific antibodies, optional consolidation with HDT/ASCR can be considered if CR is achieved after 2L therapy regimens (BCEL-C 3 of 7 - Intention to Proceed to Transplant). Additional RT can be given before or after transplant to sites of previous positive disease.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Diffuse Large B-Cell Lymphoma

NCCN Guidelines Index Table of Contents Discussion

![RELAPSE/REFRACTORY DISEASE\n\nADDITIONAL THERAPY\n\nRESPONSE ASSESSMENT\n\nConsolidation/ADDITIONAL THERAPY\n\nDILEPSTRAY\n\nComplete response\n\nCAR T-cell therapy (BCEL-C 2 of 7) or HDT/ASCR ± ISRT$^{t}$,hh or Allogeneic HCT in selected cases$^{ii}$ ± ISRT$^{t}$,hh\n\n{Controlention to proceed to transplant} → Second-line therapy; see Suggested Regimens (BCEL-C 3 of 7) or BDT/ASCR ± ISRT$^{t}$,hh or CAR T-cell therapy (BCEL-C 2 of 7) or HDT/ASCR ± ISRT$^{t}$,hh or CAR T-cell therapy (BCEL-C 2 of 7) or BDT/ASCR ± ISRT$^{t}$,hh or CAR T-cell therapy (BCEL-C 3 of 7) or BDT/ASCR ± ISRT$^{t}$,hh or CBR T-cell therapy (BCEL-C 2 of 7) or BDT/ASCR ± ISRT$^{t}$,hh or CBR T-cell therapy (BCEL-C 3 of 7) or BDT/ASCR ± ISRT$^{t}$,hh or CBR T-cell therapy (BCEL-C 3 of 7) or BDT/ASCR ± ISRT$^{t}$,hh or CBR T-cell therapy (BCEL-C 3 of 7) or BDT/ASCR ± ISRT$^{t}$,hh or CBR T-cell therapy (BCEL-C 3 of 7) or BDT/ASCR ± ISRT$^{t}$,hh or CBR T-cell therapy (BCEL-C 3 of 7) or BDT/ASCR ± ISRT$^{t}$,hh or CBR T-cell therapy (BCEL-C 3 of 7) or BDT/ASCR ± ISRT$^{t}$,hh or CBR T-cell therapy (BCEL-C 3 of 7) or BDT/ASCR ± ISRT$^{t}$,hh or CBR T-cell therapy (BCEL-C 3 of 7) or BDT/ASCR ± ISRT$^{t}$,hh or CBR T-cell therapy (BCEL-C 3 of 7) or BDT/ASCR ± ISRT$^{t}$,hh or CBR T-cell therapy (BCEL-C 3 of 7) or BDT/ASCR ± ISRT$^{t}$,hh or CBR T-cell therapy (BCEL-C 3 of 7) or BDT/ASCR ± ISRT$^{t}$,hh or CBR T-cell therapy (BCEL-C 3 of 7) or BDT/ASCR ± ISRT$^{t}$,hh or CBR T-cell therapy (BCEL-C 3 of 7) or BDT/ASCR ± ISRT$^{t}$,hh or CBR T-cell therapy (BCEL-C 3 of 7) or BDT/ASCR ± ISRT$^{t}$,hh or CBR T-cell therapy (BCEL-C 3 of 7) or BDT/ASCR ± ISRT$^{t}$,hh or CBR T-cell therapy (BCEL-C 3 of 7) or BDT/ASCR ± ISRT$^\n](1/parseimages/figurec092d81fa5a14a38bdf1e906fe345b9e_0_4.png) * Lugano Response Criteria for Non-Hodgkin Lymphoma (NHODG-C).

† Principles of Radiation Therapy (NHODG-D).

$^{99}$ Some NCCN Member Institutions require a complete metabolic response in order to proceed to HDT/ASCR.

hh Additional RT can be given before or after transplant to sites of previous positive disease.

$^{ii}$ Selected cases include mobilization failures and persistent bone marrow involvement.

jj Repeat biopsy should be strongly considered if PET-positive prior to additional therapy, because PET positivity may represent post-treatment inflammation. If biopsy negative, follow CR pathway.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Diffuse Large B-Cell Lymphoma

NCCN Guidelines Index Table of Contents Discussion

![FOLLOW-UP\n\nFOLLOW-UP\n\nFollow-up after treatment for relapsed/refractory disease\n\nClinical H&P and labs, every 3-6 mo for 5 y and then annually or as clinically indicated\n\nImagingW\n\nC/A/P CT scan with contrast no more often than every 6 mo for 2 y after completion of treatment, then only as clinically indicated\n\nPartial response,klk or Relapse\n\n|F座\n|F座\n|F座\n|F座\n|F座\n|F座\n|F座\n|F座\n|F座\n|F座\n|F座\n|F座\n|F座\n|F座\n|F座\n|F座\n|F座\n|F座\n|F座\n|F座\n|F座\n|F座\n|F座\n|F座\n|F座\n|F座\n|F座\n|F座\n|F座\n|F座\n|F座\n|F座\n|F座\n|F座\n|F座\n|F座\n|F座\n|F座\n|F\n](1/parseimages/figure8b86e8af35684327933206496bb221dc_0_4.png) * Lugano Response Criteria for Non-Hodgkin Lymphoma (NHODG-C).

† Principles of Radiation Therapy (NHODG-D).

w Surveillance imaging is used for monitoring asymptomatic patients. When a site of disease can only be visualized on PET/CT scan (eg, bone), it is appropriate to proceed with PET/CT scans for surveillance.

hh Additional RT can be given before or after transplant to sites of previous positive disease.

ii Selected cases include mobilization failures and persistent bone marrow involvement.

kk Repeat biopsy should be strongly considered if PET-positive prior to additional therapy, because PET positivity may represent post-treatment inflammation.

$^{11}$ Patients who progress after three successive regimens are unlikely to derive additional benefit from currently utilized combination chemotherapy regimens, except for patients with a long disease-free interval.

$^{mm}$ If not a candidate for T-cell mediated therapy or clinical trial.

$^{nn}$ Patients achieving high-quality CR/PR following alternative second-line therapy may benefit from an allogeneic HCT.

Note: All recommendations are category 2A unless otherwise indicated.

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Diffuse Large B-Cell Lymphoma

NCCN Guidelines Index Table of Contents Discussion

PRIMARY CUTANEOUS DIFFUSE LARGE B-CELL LYMPHOMA, LEG TYPE$^{00}$

![STAGEPP\n\nINITIAL THERAPYqq,rr,ss\n\nClinical\nH&P and labs, every 3-6 mo for 5 y and then annually or as clinically indicated Imaging\nC/A/P CT scan with contrast no more often than every 6 mo for 2 y after completion of treatment, then only as clinically indicated\n\nRelompire regional, T1-2 → Local ISRTt,uu or Clinical trial\n\nPR or NR or Progressive disease\n\nPola-R-CHPtt + local ISRTt or or Local ISRTt,uu or or Clinical trial\n\nPola-R-CHPtt (if not previously received) or or Mar or 6 mo for 2 y after completion of treatment, then only as clinically indicated\n\nPR or NR or Progressive disease\n\nPola-R-CHPtt (if not previously received) or Mar or 7 y after completion of treatment, then only as clinically indicated\n\nAPR or NR or Progressive disease\n\nSPRCTTt\n(60)\nPola-R-CHPtt\n(60)\nPola-R-CHPtt\n(60)\nPola-R-CHPtt\n(60)\nPola-R-CHPtt\n(60)\nPola-R-CHPtt\n(60)\nPola-R-CHPtt\n(60)\nPola-R-CHPtt\n(60)\nPola-R-CHPtt\n(60)\nPola-R-CHPtt\n(60)\nPola-R-CHPtt\n(60)\nPola-R-CHPtt\n(60)\nPola-R-CHPtt\n(60)\nPola-R-CHPtt\n(60)\nPola-R-CHPtt\n(60)\nPola-R-CHPtt\n(60)\nPola-R-CHPtt\n(60)\nPola-R-CHPtt\n(60)\nPola-R-CHPtt\n(60)\nPola-R-CHPtt\n\n](1/parseimages/figure546c3052368c40f29afa6a8a67fa4f73_0_5.png) † Principles of Radiation Therapy (NHODG-D).

$^{00}$ Expert hematopathologist review is essential to confirm the diagnosis of primary cutaneous DLBCL, leg type.

PP For TNM Classification of Cutaneous Lymphoma other than MF/SS, see NCCN Guidelines for Cutaneous Lymphoma.

* ㊹Consider prophylaxis for tumor lysis syndrome (NHODG-B) and see monoclonal antibody and viral reactivation (NHODG-B).

* "An FDA-approved biosimilar is an appropriate substitute for any recommended systemic biologic therapy in the NCCN Guidelines. Rituximab and hyaluronidase human injection for subcutaneous use may be substituted for rituximab after patients have received the first full dose of rituximab by intravenous infusion.

SS These patients are at higher risk for CNS involvement (BCEL-A 3 of 3); consider CNS prophylaxis according to institutional standards.

$^{tt}$ For patients who cannot tolerate anthracyclines, see BCEL-C for regimens for patients with poor left ventricular function.

uu For patients not able to tolerate chemoimmunotherapy.

$\blacktriangledown$ PET/CT (strongly preferred) or C/A/P CT with contrast at the end of treatment to assess response. It can be repeated if there is clinical suspicion of progressive disease.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Diffuse Large B-Cell Lymphoma

NCCN Guidelines Index Table of Contents Discussion

CLINICAL UTILITY OF GENOMIC ALTERATIONS IN DLBCLª

|GENE|CLINICAL ASSOCIATION| |---|---| |ACTB, BCL2,$^{b}$ BCL6, CARD11, CD79B, CREBBP, EZH2, KMT2D, MYC,$^{c}$ MYD88, MEF2B, SOCS1|Diagnostic significance| |BTK, CARD11, CD79B, MYD88|Associated with non-GCB DLBCL| |NOTCH2|BN2 molecular subclassification| |EZH2, SMARCB1|Treatment significance (EZH2 inhibitors)| |PLCG2|Richter transformation; DLBCL arising from BTKi treated CLL/SLL| |$TP53^{c}$|Mutations are frequent in DLBCL associated with chronic inflammation; TP53 mutations in conjunction with MYC rearrangement are associated with worse prognosis| |ID3, TCF3, SMARCA4, CCND3|Mutations are more frequent in BL| |B2M, CREBBP, EZH2, MYD88 L265P, SOCS1, TNFRSF14|Mutations favor other aggressive B-cell lymphoma subtypes other than BL| |KMT2D, TP53|Mutations are more frequent in dark zone gene expression signature + LBCL with MYC and BCL2 or BCL6 rearrangements (double-hit lymphomas)| |JAK/STAT, MAPK/ERK, NOTCH1 or NOTCH2|Mutations are frequent in plasmablastic lymphoma| |MYD88, CD79B, PDL1, PDL2|Mutations are frequent in intravascular LBCL, primary cutaneous DLBCL, leg type, primary LBCL of immune-privileged sites| |IL4R, ITPKB, NFKBIE, SOCS1, STAT6, XPO1|Mutations are characteristic of PMBL| |CD79B, CREBBP, KMT2D, MYD88, PIM1|Often mutated in DLBCL, NOS, but not altered in PMBL| |ATM, BIRC3, NSD2, UBR5|Mutations support the diagnosis of MCL|

ª This table provides a minimal list of accepted genes that should be included in the MGPT lymphoma panel for DLBCL.

$^{e}$ BCL2 mutations imply the presence of IGH::BCL2, thereby favoring entities other than BL.

$^{c}$ Blastoid MCL may harbor secondary MYC rearrangement or TP53 mutations.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Diffuse Large B-Cell Lymphoma

NCCN Guidelines Index Table of Contents Discussion

|INTERNATIONAL PROGNOSTIC $INDEX^{a}$|| |---|---| |ALL PATIENTS:|INTERNATIONAL INDEX, ALL PATIENTS:| |• Age >60 years|• Low 0 or 1| |• Serum LDH > normal|• Low-intermediate 2| |• Performance status 2-4|• High-intermediate 3| |• Stage III or IV|• High 4 or 5| |• Extranodal involvement >1 site||

|AGE-ADJUSTED INTERNATIONAL PROGNOSTIC $INDEX^{a}$|| |---|---| |PATIENTS ≤60 YEARS:|INTERNATIONAL INDEX, PATIENTS ≤60 YEARS:| |• Stage III or IV|• Low| |• Serum LDH > normal|• Low-intermediate| |• Performance status 2-4|• High-intermediate| ||• High|

|STAGE-MODIFIED INTERNATIONAL PROGNOSTIC INDEX (smIPI)$^{b}$|| |---|---| |STAGE I OR II PATIENTS:|INTERNATIONAL INDEX, STAGE I OR II PATIENTS:| |• Age >60 years|• Low 0 or 1| |• Serum LDH > normal|• High 2-4| |• Performance status 2-4|| |• Stage II or IIE||

|NCCN-IP1c|NCCN-IP1c|NCCN-IP1c|NCCN-IP1c| |---|---|---|---| |||RISK GROUP|RISK GROUP| |Age, years|Age, years||| |>40 to ≤60|1|• Low|0-1| |>60 to <75|2|• Low-intermediate|2-3| |≥75|3|• High-intermediate|4-5| |LDH, normalized|LDH, normalized|• High|≥6| |>1 to ≤3|1||| |>3|2||| |Ann Arbor stage III-IV|1||| |Extranodal disease*|1|*Disease in bone marrow, CNS, liver/GI tract, or lung.|| |Performance status ≥2|1|||

ª The International Non-Hodgkin's Lymphoma Prognostic Factors Project. A predictive model for aggressive non-Hodgkin's lymphoma. N Engl J Med 1993;329:987-994.

b Miller TP, Dahlberg S, Cassady JR. Chemotherapy alone compared with chemotherapy plus radiotherapy for localized intermediate- and high-grade non-Hodgkin's lymphoma. N Engl J Med 1998;339:21-26.

c This research was originally published in Blood. Zhou Z, Sehn LH, Rademaker AW, et al. An enhanced International Prognostic Index (NCCN-IPI) for patients with diffuse large B-cell lymphoma treated in the rituximab era. Blood 2014;123:837-842. © The American Society of Hematology

Note: All recommendations are category 2A unless otherwise indicated.

Back to Workup (BCEL-2)

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Diffuse Large B-Cell Lymphoma

NCCN Guidelines Index Table of Contents Discussion

|PROGNOSTIC MODEL TO ASSESS THE RISK OF CNS DISEASE$^{d}$||| |---|---|---| |RISK FACTORS|RISK GROUPS|RISK GROUPS| |• Age >60 years|• Low risk|0–1| |• Serum LDH > normal|• Intermediate-risk|2–3| |• Performance status >1|• High-risk|4–6 or kidney or adrenal gland involvement| |• Stage III or IV||| |• Extranodal involvement >1 site||| |• Kidney or adrenal gland involvement|||

* Additional indications for CNS prophylaxis independent of CNS risk score

$\bullet$ Testicular lymphoma

$\bullet$ Primary cutaneous DLBCL, leg type

$\bullet$ Stage IE DLBCL of the breast

$\bullet$ Kidney or adrenal gland involvement

* Role of CNS prophylaxis remains controversial but can be considered in patients with high-risk factors based on the aforementioned criteria. If CNS prophylaxis is used, options include:

* Systemic high-dose methotrexate (3-3.5 g/m$^{2}$ for 2-4 cycles) during or after the course of treatment and/or

$\bullet$ IT methotrexate and/or cytarabine (4-8 doses) during or after the course of treatment

d Schmitz N, Zeynalova S, Nickelsen M, et al. CNS International Prognostic Index: A risk model for CNS relapse in patients with diffuse large B-cell lymphoma treated with R-CHOP. J Clin Oncol 2016;34:3150-3156.

e Wilson M, Eyre T, Kirkwood A, et al. Timing of high-dose methotrexate CNS prophylaxis in DLBCL: A multicenter international analysis of 1384 patients. Blood 2022;139:2499–2511.

Note: All recommendations are category 2A unless otherwise indicated.

Back to Workup (BCEL-2)

BCEL-A 3 OF 3

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Diffuse Large B-Cell Lymphoma

NCCN Guidelines Index Table of Contents Discussion

|ALK-POSITIVE LARGE B-CELL LYMPHOMAS (ALK+ LBCL)a||| |---|---|---| |Definition|• ALK-positive LBCL is a mature aggressive B-cell lymphoma characterized by large cells with plasmablastic differentiation and cytoplasmic expression of ALK, and lacking CD20 expression. • Cytoplasmic ALK expression helps differentiate this entity from other aggressive CD20-negative LBCL with plasmacytic differentiation such as plasmablastic lymphoma, primary effusion lymphoma (PEL), and HHV8-positive DLBCL. • EBV and HHV8 are negative in ALK-positive LBCL, and there is no association with immune deficiency. • Cy�ogenetic/FISH analysis most commonly demonstrates the t(2;17)(p23;q23), denoting the CLTC (clathrin heavy chain):ALK fusion.|| |Clinical presentation|• The median age at diagnosis is approximately 40 years and there is a strong male predominance. • Most patients present with rapidly progressive disease at advanced stage, and both nodal and extranodal involvement are common.|| |Treatment|Initial therapy • Clinical trial is recommended, if available • Consolidative ISRT is preferred for localized $disease^{b}$ • These are most often CD20 negative and rituximab is not necessary. • While the optimal systemic treatment approach is not established, the following induction regimens have been used: • DA-EPOCH • CHOEP • CHOP may be associated with a suboptimal outcome. CHOP can be considered for patients with early-stage disease receiving combined modality therapy. • Mini-CHOP may be considered for patients who are frail or older • Potentially toxic regimens; performance status and comorbidities should be considered: ◇ HyperCVAD ◇ CODOX-M alternating with IVAC||

ª Castillo JJ, et al. Leuk Lymphoma 2021;62:2845-2853; WHO Classification of Tumours Editorial Board. Haematolymphoid tumours. (WHO classification of tumours series, 5th ed; vol 11). Lyon (France): International Agency for Research on Cancer; 2024; Campo E, et al. Blood 2022;140:1229-1253; Soumerai JD, et al. N Blood 2022;140:1822-1826. ᵇ Principles of Radiation Therapy (NHODG-D).

Note: All recommendations are category 2A unless otherwise indicated.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Diffuse Large B-Cell Lymphoma

NCCN Guidelines Index Table of Contents Discussion

|MEDIASTINAL GRAY ZONE LYMPHOMA (MGZL)$^{a}$ (overlapping features between PMBL and CHL)|| |---|---| |Clinical presentation$^{b}$|Present with large anterior mediastinal mass with or without supraclavicular lymph nodes. More common in males, presenting between 20-40 y| |Morphology|Expert hematopathology review is essential. Diagnosis should not be made on a core needle biopsy. Large pleomorphic cells in a diffusely fibrous stroma. Typically larger and more pleomorphic than in PMBL, sometimes resembling lacunar or Hodgkin-like cells. Necrosis without neutrophilic infiltrate is frequent.| |Immunophenotype|Atypical immunophenotype, often showing transitional features between PMBL and CHL. Typical immunophenotype: CD45+, PAX5+, BOB.1+, OCT-2+, CD15+, CD20+, CD30+, and CD79a+; CD10- and ALK-; BCL6 is variably expressed and EBV is usually negative.If the morphology more closely resembles PMBL: CD20 dim/-; CD30+ and CD15+ would be suggestive of gray zone lymphoma.If the morphology more closely resembles CHL: Strong uniform CD20+ (and/or other B-cell markers) and CD15- would be suggestive of MGZL.| |Prognosis and Treatment|A worse prognosis than either CHL or PMBL has been suggested. While there is no consensus on the treatment, aggressive LBCL regimens are preferred.If the tumor cells are CD20+, the addition of rituximal to chemotherapy should be considered.CData suggest that the use of anthracycline-based chemioimmunotherapy as recommended for DLBCL (BCEL-C)$^{d}$ is helpful.If localized disease, then consolidative ISRT is preferred.|

a Pilichowska M, et al. Blood Adv 2017;1:2600-2609; Wilson WH, et al. Blood 2014;124:1563-1569; WHO Classification of Tumours Editorial Board. Haematolymphoid tumours. (WHO classification of tumours series, 5th ed; vol 11). Lyon (France): International Agency for Research on Cancer; 2024; Campo E, et al. Blood 2022;140:1229-1253; Quintanilla-Martinez L, et al. J Hematop 2009;2:211-236. b Clinical and genomic data indicate that most non-mediastinal gray-zone lymphomas are distinct from MGZL; thus, patients with extra-mediastinal disease should be diagnosed as having DLBCL-NOS.

c An FDA-approved biosimilar is an appropriate substitute for any recommended systemic biologic therapy in the NCCN Guidelines. Rituximab and hyaluronidase human injection for subcutaneous use may be substituted for rituximab after patients have received the first full dose of rituximab by intravenous infusion. d Polatuzumab-R-CHP is not recommended for mediastinal gray zone lymphoma.

Note: All recommendations are category 2A unless otherwise indicated.

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Diffuse Large B-Cell Lymphoma

NCCN Guidelines Index Table of Contents Discussion

SUGGESTED TREATMENT REGIMENSa,b

|FIRST-LINE THERAPY|FIRST-LINE THERAPY|FIRST-LINE THERAPY|FIRST-LINE THERAPY| |---|---|---|---| |Stage I-II (excluding stage II with extensive mesenteric disease)|Stage II (with extensive mesenteric disease) or Stage III-IV|Patients with Poor Left Ventricular $Function^{e,f,g}$ (all stages)|Patients Who are Very Frail and Patients >80 Years of Age with Comorbidities$^{f,g}$ (all stages)| |• CHOP + Rituximab^{c}$ • Pola-R-CHP (CHP [Cyclophosphamide/ Doxorubicin/Prednisone] + Polatuzumab vedotin-piq + Rituximab) (smIPI >1)$^{d}$ (category 1)|Preferred • CHOP + Rituximab^{c} (category 1) • Pola-R-CHP (IPI ≥2)$^{d}$ (category 1) Other recommended • Dose-adjusted EPOCH (Etoposide/Prednisone/Vincristine/ Cyclophosphamide/Doxorubicin) + Rituximab|Other recommended (in alphabetical order by category) • D-EPOCH^{h}$ + Rituximab • CDOP (Cyclophosphamide/Liposomal Doxorubicin/Vincristine/Prednisone) + Rituximab • CEOP (Cyclophosphamide/Etoposide/Vincristine/Prednisone) + Rituximab • GCVP (Gemcitabine/Cyclophosphamide/Vincristine/Prednisone) + Rituximab|Other recommended (in alphabetical order by category) • CDOP + Rituximab • Mini-CHOP + Rituximab • GCVP + Rituximab|

|CONCURRENT PRESENTATION WITH CNS DISEASE$^{1}$| |---| |• Parenchymal: systemic high-dose Methotrexate (≥3 g/m² given with anthracycline-based chemoimmunotherapy cycle that has been supported by growth factors). Different schedules have been used for the integration of high-dose Methotrexate with anthracycline-based chemoimmunotherapy; however, the Panel prefers day 15 of a 21-day cycle. • Leptomeningeal: IT Cytarabine/Methotrexate/Hydrocortisone, consider Ommaya reservoir placement. Systemic high-dose Methotrexate (3-3.5 g/m²) can be given in combination with anthracycline-based chemoimmunotherapy or as consolidation after anthracycline-based chemoimmunotherapy + IT Cytarabine/Methotrexate/Hydrocortisone • Consider consolidation with HDT/ASCR|

Consider prophylaxis for tumor lysis syndrome (NHODG-B) See monoclonal antibody and viral reactivation (NHODG-B)

Footnotes Second-line Therapy on BCEL-C 2 of 7 and BCEL-C 3 of 7

Note: All recommendations are category 2A unless otherwise indicated.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Diffuse Large B-Cell Lymphoma

NCCN Guidelines Index Table of Contents Discussion

SUGGESTED TREATMENT REGIMENSª,b

|SECOND-LINE THERAPY^{e,j,k} (relapsed disease <12 mo or primary refractory disease)|| |---|---| |Candidates for CAR T-Cell Therapy|Non-Candidates for CAR T-Cell Therapy| |CAR T-cell therapy^{l} ▲ Axicabtagene ciloleucel (CD19-directed) (category 1) ▲ Lisocabtagene maraleucel (CD19-directed) (category 1) Holding Therapy (prepheresis) Options DHA + platinum (Carboplatin, Cisplatin, or Oxaliplatin) ± Rituximab • GDP (Gemcitabine/Dexamethasone/Carboplatin or Cisplatin) ± Rituximab • GEMOX ± Rituximab • ICE (Ifosfamide/Carboplatin/Etoposide) ± Rituximab • Polatuzumab vedotin-piiq + Rituximab • ISRT (can be used as monotherapy or sequentially with systemic therapy) (NHODG-D 3 of 4) Bridging Therapy (postpheresis) Options (≥1 cycles as needed until CAR T-cell product is available) • DHA + platinum (Carboplatin, Cisplatin, or Oxaliplatin) ± Rituximab • GDP (Gemcitabine/Dexamethasone/Carboplatin or Cisplatin) ± Rituximab • GEMOX ± Rituximab • ICE (Ifosfamide/Carboplatin/Etoposide) ± Rituximab • Polatuzumab vedotin-piiq ± Rituximab ± Bendamustine^{m} ▲ Bisrot (can be used as monotherapy or sequentially with systemic therapy) (NHODG-D 3 of 4)|Preferred (in alphabetical order) • GEMOX^{n} + Epcoritamab-bysp^{o} ▲ GEMOX^{n} + Glofitamab-gxbm^{o} ▲ GEMOX^{n} + Polatuzumab vedotin-piiq + Rituximab • Lenalidomide + Tafasitamab-cxix^{p} (excluding primary refractory disease) • Polatuzumab vedotin-piiq ± Bendamustine^{m} ± Rituximab • Mosunetuzumab-axgb^{n,0} + Polatuzumab vedotin-piiq ▲ Other recommended (in alphabetical order) • CEOP ± Rituximab • DHA (Dexamethasone/Cytarabine) + platinum (Carboplatin, Cisplatin, or Oxaliplatin) ± Rituximab • ESHAP (Etoposide/Methylprednisolone/Cytarabine/Cisplatin) ± Rituximab • GDP ± Rituximab • GEMOX ± Rituximab (if unable to receive Epcoritamab-bysp, Glofitamab-gxbm, or Polatuzumab vedotin-piiq ▲ ICE ± Rituximab Useful in certain circumstances • Brentuximab vedotin • Ibrutinib^{n} (non-GCB DLBCL) • Lenalidomide ± Rituximab (non-GCB DLBCL)|

Footnotes

First-line Therapy on BCEL-C 1 of 7 Second-line Therapy (relapsed disease >12 mo) on BCEL-C 3 of 7

Third-line Therapy on BCEL-C 4 of 7

Note: All recommendations are category 2A unless otherwise indicated.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Diffuse Large B-Cell Lymphoma

NCCN Guidelines Index Table of Contents Discussion

SUGGESTED TREATMENT REGIMENSª,b

|SECOND-LINE THERAPY^{e,j,k}(relapsed disease >12 mo)|| |---|---| |Intention to Proceed to Transplant|No Intention to Proceed to Transplant| |Preferred (in alphabetical order)DHA + platinum (Carboplatin, Cisplatin, or Oxaliplatin) ± RituximabGDP ± RituximabICE ± RituximabOther recommended (in alphabetical order)ESHAP ± RituximabGEMOX ± Rituximab|Preferred (in alphabetical order)CAR T-cell therapy (CD19-directed) (with pre/postpheresis therapy as needed;BCEL-C 2 of 7) (if eligible)Lisocabtagene maraleucelGEMOX + Epcoritamab-bysp°GEMOX + Glofitamab-gxbm0GEMOX + Polatuzumab vedotin-piiq + RituximabLenalidomide + Tafasitamab-cxixPPolatuzumab vedotin-piiq ± BendamustineM ± RituximabMosunetuzumab-axgb^{n,0} + Polatuzumab vedotin-piiqOther recommended (in alphabetical order)CEOP ± RituximabGDP ± RituximabGEMOX ± Rituximab (if unable to receive epcoritamab-bysp, glofitamab-gxbm, or polatuzumab vedotin-piiq)RituximabUseful in certain circumstancesBrentuximab vedotin lbrutinib^{n} (non-GCB DLBCL)Lenalidomide ± Rituximab (non-GCB DLBCL)|

Footnotes

First-line Therapy on BCEL-C 1 of 7 Second-line Therapy (relapsed disease <12 mo or primary refractory disease) on BCEL-C 2 of 7 Third-line Therapy on BCEL-C 4 of 7

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 1.2026

Diffuse Large B-Cell Lymphoma

NCCN Guidelines Index Table of Contents Discussion

Note: All recommendations are category 2A unless otherwise indicated.

BCEL-C 4 OF 7

SUGGESTED TREATMENT REGIMENSa,b

Consider prophylaxis for tumor lysis syndrome (NHODG-B)

See monoclonal antibody and viral reactivation (NHODG-B)

THIRD-LINE AND SUBSEQUENT THERAPY

Second-line therapy regimens (BCEL-C 2 of 7 and BCEL-C 3 of 7) that were not previously given can also be used as options for third-line and subsequent therapy

Preferred

• T-cell mediated therapyo

CAR T-cell therapyl,p,q (preferred)

(in alphabetical order)

◊ Axicabtagene ciloleucel (CD19-directed)

◊ Lisocabtagene maraleucel (CD19-directed)

◊ Tisagenlecleucel (CD19-directed)

Bispecific antibody therapy (including patients with disease

progression after transplant or CAR T-cell therapy) (in alphabetical

order)

◊ Epcoritamab-byspn

◊ Glofitamab-gxbmn

Other recommended

• Lenalidomide + Brentuximab vedotin + Rituximab

• Loncastuximab tesirine-lpylp

• Selinexor (including patients with disease progression after transplant or CAR T-cell therapy)

Footnotes First-line Therapy on BCEL-C 1 of 7 Second-line Therapy on BCEL-C 2 of 7 and BCEL-C 3 of 7

NCCN Guidelines Version 1.2026

Diffuse Large B-Cell Lymphoma

NCCN Guidelines Index Table of Contents Discussion

a See references for regimens on BCEL-C 6 of 7 and BCEL-C 7 of 7.b An FDA-approved biosimilar is an appropriate substitute for any recommended systemic biologic therapy in the NCCN Guidelines. Rituximab and hyaluronidase

human injection for subcutaneous use may be substituted for rituximab after patients have received the first full dose of rituximab by intravenous infusion.

c In RCHOP-21, may consider increasing dose of rituximab to 500 mg/m2 in patients assigned male at birth >60 y.d Patients with a known history of histologic transformation of indolent lymphoma were not included in the POLARIX study.e Inclusion of any anthracycline or anthracenedione in patients with impaired cardiac functioning should have more frequent cardiac monitoring.f There are limited published data regarding the use of these regimens; however, they are used at NCCN Member Institutions for the first-line treatment of DLBCL for

patients with poor left ventricular function, patients who are very frail, and patients >80 years of age with comorbidities.

g There are limited data for treatment of early-stage disease with these regimens; however, short-course chemoimmunotherapy + RT for stage I–II disease is practiced at NCCN Member Institutions.

h If upward dose adjustment is necessary, doxorubicin should be maintained at base dose and not increased.i Concurrent high-dose methotrexate with dose-adjusted EPOCH can result in unacceptable toxicities.j If additional anthracycline is administered after a full course of therapy, careful cardiac monitoring is essential. Dexrazoxane may be added as a cardioprotectant.k Rituximab should be included in second-line therapy if there is relapse after a reasonable remission (>6 mo); however; rituximab can be omitted in patients with

primary refractory disease.

l NCCN Guidelines for Management of CAR T-Cell and Lymphocyte Engager-Related Toxicities.m In patients intended to receive CAR T-cell therapy or CD3 x CD20 bispecific antibody therapy, bendamustine should be used with caution. Delay bendamustine until after CAR-T leukapheresis.

n Refer to package insert for full prescribing information, dose modifications, and monitoring for adverse reactions: https://www.accessdata.fda.gov/scripts/cder/daf/

index.cfm.

o In the setting of CD20-negative lymphomas, the efficacy of CD3 x CD20 bispecific antibody therapy is poor. If clinically feasible, repeat biopsy to confirm antigen

expression prior to the initiation of T-cell mediated therapy.

p It is unknown if tafasitamab-cxix or loncastuximab tesirine-lpyl or if any other CD19–directed therapy would have a negative impact on the efficacy of subsequent antiCD19 CAR T-cell therapy. If clinically feasible, repeat biopsy to confirm antigen expression prior to the initiation of CD19-directed CAR T-cell therapy.

q In selected circumstances, an alternate CAR T-cell therapy can be used upon disease progression.

SUGGESTED TREATMENT REGIMENS FOOTNOTES

Note: All recommendations are category 2A unless otherwise indicated.

BCEL-C 5 OF 7

NCCN

National Concomprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Diffuse Large B-Cell Lymphoma

NCCN Guidelines Index Table of Contents Discussion

SUGGESTED TREATMENT REGENS REFERENCES

First-line Therapy CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) + rituximab with RT Miller TP, Dahlberg S, Cassady JR, et al. Chemotherapy alone compared with chemotherapy plus radiotherapy for localized intermediate- and high-grade non-Hodgkin's lymphoma. N Engl J Med 1998;339:21-26. Horning SJ, Weller E, Kim K, et al. Chemotherapy with or without radiotherapy in limited-stage diffuse aggressive non-Hodgkin's lymphoma: Eastern Cooperative Oncology Group Study 1484. J Clin Oncol 2004;22:3032-3038. Persky DO, Unger JM, Spier CM, et al. Phase II study of rituximab plus three cycles of CHOP and involved-field radiotherapy for patients with limited-stage aggressive B-cell lymphoma: Southwest Oncology Group Study 0014. J Clin Oncol 2008;26:2258-2263. CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) + rituximab Coiffier B, Thieblemont C, Van Den Neste E, et al. Long-term outcome of patients in the LNH-98.5 trial, the first randomized study comparing rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: a study by the Groupe d'Etudes des Lymphomes de l'Adulte. Blood 2010;116:2040-2045. Feugier P, Van Hoof A, Sebban C, et al. Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: a study by the Groupe d'Etudes des Lymphomes de l'Adulte. J Clin Oncol 2005;23:411-4126. Pfreundschuh M, Trumper L, Osterborg A, et al. CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MinT) Group. Lancet Oncol 2006;7:379-391. Poeschel V, Held G, Ziepert M, et al. Four versus six cycles of CHOP chemotherapy in combination with six applications of rituximab in patients with aggressive B-cell lymphoma with favourable prognosis (FLYER): a randomised, phase 3, non-inferiority trial. Lancet 2019;394:2271-2281. Persky DO, Li H, Stephens DM, et al. Positron emission tomography-directed therapy for patients with limited-stage diffuse large B-cell lymphoma: Results of Intergroup National Clinical Trials Network Study 1.001. J Clin Oncol 2020;38:3003-3011. Pola-R-CHP (polatuzumab vedotin-pilq, rituximab, cyclophosphamide, doxorubicin, prednisone) Morschhauser F, Salles G, Sehn LH, et al. Five-year outcomes of the POLARIX study comparing Pola-R-CHP and R-CHOP in patients with diffuse large b-cell lymphoma. J Clin Oncol 2025;43:3698-3705. Dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) + rituximab Purroy N, Bergua J, Gallur L, et al. Long-term follow-up of dose-adjusted EPOCH plus rituximab (DA-EPOCH-R) in untreated patients with poor prognosis large B-cell lymphoma. A phase II study conducted by the Spanish PETHEMA Group. Br J Haematol 2015;169:188-198. Wilson WH, Dunleavy K, Pittaluga S, et al. Phase II study of dose-adjusted EPOCH and rituximab in untreated diffuse large B-cell lymphoma with analysis of germinal center and post-germinal center biomarkers. J Clin Oncol 2008;26:2717-2724. Wilson WH, Jung SH, Porcu P, et al. A Cancer and Leukemia Group B multi-center study of DA-EPOCH-rituximab in untreated diffuse large B-cell lymphoma with analysis of outcome by molecular subtype. Haematologica 2012;97:758-765.

First-line Therapy for Patients with Poor Left Ventricular Function CDOP (cyclophosphamide, liposomal doxorubicin, vincristine, prednisone) + rituximab Martino R, Perea G, Caballero MD, et al. Cyclophosphamide, pegylated liposomal doxorubicin (Caelyx), vincristine and prednisone (CCOP) in elderly patients with diffuse large B-cell lymphoma: Results from a prospective phase II study. Haematologica 2002;87:822-827. Zaja F, Tomadini V, Zaccaria A, et al. CHOP-rituximab with pegylated liposomal doxorubicin for the treatment of elderly patients with diffuse large B-cell lymphoma. Leuk Lymphoma 2006; 47:274:2180. RCEOP (rituximab, cyclophosphamide, etoposide, vincristine, prednisone) Moccia AA, Schaff K, Freeman C, et al. Long-term outcomes of R-CEOP show curative potential in patients with DLBCL and a contraindication to anthracyclines. Blood Adv 2021;5:1483:1489. RGCPV (rituximab, gemictabine, cyclophosphamide, vincristine, prednisone)

2024;99:216-222. Second-line and Subsequent Therapy Polatuzumab vedotin ± bendamustine ± rituximab

Morschhauser F, Flinn IW, Advani R, et al. Polatuzumab vedotin or pinatuzumab vedotin plus rituximab in patients with relapsed or refractory non-Hodgkin lymphoma: final results from a phase 2 randomised study (ROMULUS). Lancet Haematol 2019;6:e254-e265. Sehn LH, Herrera AF, Flowers CR, et al. Polatuzumab vedotin or refractory diffuse large B-cell lymphoma. J Clin Oncol 2020;38:155-165.

Budde LE, Olszewski AJ, Assouline S, et al. Mosunetuzumab with polatuzumab vedotin in relapsed or refractory aggressive large B cell lymphoma: a phase 1b/2 trial. Nat Med 2024;30:229-239.

Brentuximab vedotin

Jacobsen ED, Sharman JP, Oki Y, et al. Brentuximab vedotin demonstrates objective responses in a phase 2 study of relapsed/refractory DLBCL with variable CD30 expression. Blood 2015;125:1394-1402.

CEPP (cyclophosphamide, etoposide, prednisone, procarbazine) ± rituximab

Chao NJ, Rosenberg SA, and Horning SJ. CEPP(B): An effective and well-tolerated regimen in poor-risk, aggressive non-Hodgkin's lymphoma. Blood 1990;76:1293-1298.

DHAP (dexamethasone, cisplatin, cytarabine) ± rituximab

Mey UJ, Orlopp KS, Flieger D, et al. Dexamethasone, high-dose cytarabine, and cisplatin in combination with rituximab as salvage treatment for patients with relapsed or refractory aggressive non-Hodgkin's lymphoma. Cancer Invest 2006;24:593-600.

Gisselbrecht C, Schmitz N, Mounier N, et al. Rituximab maintenance therapy after autologous stem-cell transplantation in patients with relapsed CD20+ diffuse large B-cell lymphoma: Final analysis of the collaborative trial in relapsed aggressive lymphoma. J Clin Oncol 2012;30:4462-4469.

Continued

Note: All recommendations are category 2A unless otherwise indicated.

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NCCN National Congresso NCCN Cancer Network®

NCCN Guidelines Version 1.2026 Diffuse Large B-Cell Lymphoma

NCCN Guidelines Index Table of Contents Discussion

SUGGESTED TREATMENT REGIMENS REFERENCES

Second-line and Subsequent Therapy (continued)

DHAX (dexamethosa, cytarabine, oxaliatin) ± rituximab

Lignon J, Sibon D, Madelaine I, et al. Rituximab, dexamethasone, cytarabine, and oxaliplatin (R-DHAX) is an effective and safe salvage regimen in relapsed/refractory B-cell non-Hodgkin lymphoma. Clin Vymphoma Myeloma Leuk 20;10:262-269.

Rigacci L, Fabbri A, Puccini B, et al. Oxaliplatin-based chemotherapy (dexamethasone, high-dose cylarabine, and oxaliplatin) +/- rituximab is an effective salvage regimen in patients with relapsed or refractory lymphoma. Cancer 2010:116:4573-4579.

ESHAP (etoposide, methylprednisolone, cytarabine, cisplatin) ± rituximab

Velasquez WS, McLaughlin P. Tucker S, et al. ESHAP - an effective chemotherapy regimen in refractory and relapsing lymphoma: a 4-year follow-up study. J Clin Oncol 1994;12:1169-1176.

Martin A, Conde E, Arnan M, et al. R-ESHAP as salvage therapy for patients with relapsed or refractory diffuse large B-cell lymphoma: the influence of prior exposure to rituximab on outcome. A GEL/TAMO study. Haematologica 2008;93:1829-1836.

GDP (gemcitabine, dexamethasome, carboplatin) or cisputin) at rituximab

Crump M, Kuruvilla J, Couban S, et al. Randomized comparison of gemitabine, dexamethasone, and cisplatin versus dexamethasone, cytarabine, and cisplatin methothery before autologous stem-cell transplantation for relapsed and refractory aggressive lymphomas: NCIC-CTG LY.12. J Clin Oncol 2014;32:340:3496.

Gopal AK, Press OW, Stustov AR, et al. Efficacy and safety of gemictabine, carboplatin, dexamethasone, and rituximab in patients with relapsed/refractory lymphoma: a prospective multi-center phase II study by the Puget Sound Oncology Consortium. Leuk Lymphoma 2010:51:1523-1529. GemOX (gemicitabine, axelipatin) ± rituximab

Corazzelli G, Capobianco G, Arcamone M, et al. Long-term results of gemictabine plus oxaliplatin with and without rituximab as salvage treatment for transplant-ineligible patients with refractory/relapsing B-cell lymphoma. Cancer Chemother Pharmacol 2009:64:907-916.

Mounier N, El Gnaoui T, Tilly H, et al. Rituximab plus gemicitabine and oxalilatin in patients with refractory/relapsed diffuse large B-cell lymphoma who are not candidates for high-dose therapy. A phase II Lymphoma Study Association trial. Haematologica 2013;98:1726-1731.

GEMOX + Polatuzumab vedotin + Rituximab

Matasar M. Li Z-M. Vassilakopoulos TP. et al. Polatuzumab vedotin, rituximab, gemicitandine a oxilatin (POLA-R-GEMOX) for relapsed/refractory (R/R) diffuse large b-cell lymphoma (DLBCL): Results from the randomized phase III polargo trial [abstract]. EHA; 2025:Abstract S101.

Ibrutinib

Wilson WH, Young RM, Schmitz R, et al. Targeting B cell receptor signaling with ibrutinib in diffuse large B cell lymphoma. Nat Med 2015;21:922-926.

ICE (ifosfamide, carboplatin, etoposide) ± rituximab

Kewaramani T, Zelenetz AD, Nimer SD, et al. Rituximab and ICE (RICE) as second-line therapy prior to autologous stem cell transplantation for relapsed or primary refractory diffuse large B-cell lymphoma. Blood 2004;103:3684-3688.

Lenalidomide ± rituximab

Wang M, Fowler N, Wagner-Bartak N, et al. Oral lenalidomide with rituximab in relapsed or refractory diffuse large cell, follicular, and transformed lymphoma: a phase II clinical trial. Leukemia 2013;27:1902-1909.

Czuczman MS, Trneny M, Davies A, et al. A phase 2/3 multicenter, randomized, open-label study to compare the efficacy and safety of lenalidomide versus investigator's choice in patients with relapsed or refractory diffuse large B-cell lymphoma. Clin Cancer Res 2017;23:4127-4137.

Tafasamab + lenalidomide

Duell J, Abrisqueta P, Andre M, et al. Tafasitamab for patients with relapsed or refractory diffuse large B-cell lymphoma: final 5-year efficacy and safety findings in the phase II L-MIND study. Haematologica 2024;109:553-852.

SUGGESTED TREATMENT REGIMENS REFERENCES

Third-line and Subsequent Therapy

Brentuximab vedotin + lenalidomide + rituximab

Bartlett NL, Hahn U, Kim WS, et al. Brentuximab vedotin combination for relapsed diffuse large B-cell lymphoma. J Clin Oncol 2025;43:1061-1072.

Loncastuximab tesirine

Caimi PF, Ai WZ, Alderuccio JP, et al. Loncastuximab tesirine in relapsed/refractory diffuse large B-cell lymphoma: long-term efficacy and safety from the phase II LUTIS-1107S: 1184:1184.

Selinexor

Kalakonda N, Maerevoet M, Cavallo F, et al. Selinexor in patients with relapsed or refractory diffuse large B-cell lymphoma (SADAL): a single-arm, multinational, multicentre, open-label, phase 2 trial. Lancet Haematol 2020;7:e511-e522.

T-Celled Therapy

CAR T-Cell Therapy

Axicabtagene ciloleucel

Neelapu SS, Jacobson CA, Ghobadi A, et al. Five-year follow-up of ZUMA-1 supports the curative potential of axacbagene cileoculin in refractory large B-cell lymphoma. Blood 2023;141:2307-2315.

Locke FL, Miklos DB, Jacobson CA, et al. Axicabtagene ciloleucel as second-line therapy for large B-cell lymphoma. N Engl J Med 2023;386:640-654.

Lisocabtagene maralecute

Abramson JS, Solomon SR, Arnason JE, et al. Lisocabtagene maraleucel as second-line therapy for large B-cell lymphoma: primary analysis of phase 3 TRANSFORM study. Blood 2023;141:1675-1684.

Hoda D, Sehgal A, Riedell PA, et al. Lisocabtagene maraleucel (liso-cel) as second-line therapy for R/R large B-cell lymphoma in patients not intended for hematopoietic stem cell transplantation (HSCT): Final analysis of the phase 2 P.LLOT study. Transplantation and Cellular Therapy 2024;30:30:52:02.

Abramson JS, Palomba ML, Gordon LI, et al. Lisocabtagene maraleucel for patients with relapsed or

Incentratory large B-cell lymphoma (TRANSCEND NHL 001): a multicentre seamless design study. Lancet 2020;396:839-852.

Tisagenlecleucel

Schuster SJ, Tam CS, Borchmann P, et al. Long-term clinical outcomes of tisagenleucleucel in patients with relapse or refractory aggressive B-cell lymphomas (JULIET): a multicentre, open-label, single-arm, phase 2 study. Lancet Oncol 2021;22:1403-1415.

Bispecific Antibody therapy

Epcoritamab-byso

Thieblemont C, Phillips T, Ghesquieres H, et al. Epcoritamab, a novel, subcutaneous CD3xD20 bispecific T-cell-engaging antibody, in relapsed or refractory large B-cell lymphoma: Dose expansion in a phase I/II trial. J Clin Oncol 2023;41:2238-2247.

T-cell-engaging antibody, in relapsed or refractory large B-cell lymphoma: Dose expansion in a phase I/II

The biemonton C, Phillips T, Ghesquieres H, et al. Epcoritamab, a novel, subcutaneous CD3xD20 bispecific T-cell-engaging antibody, in relapsed or refractory large B-cell lymphoma: Dose expansion in a phase I/II trial. J Clin Oncol 2023;41:2238-2247.

leads to deep and durable responses in relapsed or refractory large B-cell lymphoma [abstract]. Blood 2024;144:Abstract 4480.

Epcoritamab-bysp + GemOx

Brody JD, Jørgensen J, Belada D, et al. Epcoritamab plus GemOx in transplant ineligible relapsed/ refractory DLBCL: Results from the EPCORE NHL-2 trial. Blood 2025;145:1621-1631.

Glofitamab-gxbm

Dickinson MJ, Carlo-Stella C, Morschhauser F, et al. Glofitamab for relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med 2022;387:2220-2231.

Dickinson MJ, Carlo-Stella C, Morschhauser F, et al. Fixed-duration glofitamab monotherapy continues to a abbanan and abbanan and abbanan and abbanan and abbanan and abbanan and abbanan and abbanan and abbanan and abbanan and abbanan and abbanan and abbanan and abbanan and abbanan and abbanan and abbanan and abbanan and abbanan and abbanan and abbanan and abbanan and abbanan and abbanan and abbanan and abbanan and abbanan and abbanan and abbanan and abbanan and abbanan and abbanan and abbanan an

Glofamab-gxbm + GemOx

Abramson JS, Ku M, Hertzberg M, et al. Glofitamab plus gemcitabine and oxaliplatin (GemOx) versus rituximab-GemOx for relapsed or refractory diffuse large B-cell lymphoma (STARGLO): a global phase 3, randomised, open-label trial. Lancet 2024;404:1940-1954.

Note: All recommendations are category 2A unless otherwise indicated.

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Primary Mediastinal Large B-Cell Lymphoma

NCCN Guidelines Index Table of Contents Discussion

![FIRST-LINE THERAPY a,b\n\nOptimal first-line therapy for PMBL c is more controversial than other subtypes. Most commonly used treatment options are listed below.\n\nDose-adjusted EPOCH + rituximab (DA-EPOCH-R) x 6 cycles\n\nRCHOP-14 x 4-6 cycles\n\nRCHOP-21 x 6 cycles\n\nRestage with PET/CT\n\npartial response d (PET positive bPSy) e, d\n\nPartio response d (PET positive bPSy) e, d\n\nPartio response d (PET positive bPSy) e, d\n\nNo response or Progressive disease d (PET positive bPSy) e, d\n\nPartio response d (PET positive bPSy) e, d\n\nPartio response d (PET positive bPSy) e, d\n\nPartio response d (PET positive bPSy) e, d\n\nPartio response d (PET positive bPSy) e, d\n\nPartio response d (PET positive bPSy) e, d\n\nPartio response d (PET positive bPSy) e, d\n\nPartio response d (PET positive bPSy) e, d\n\nPartio response d (PET positive bPSy) e, d\n\nPartio response d (PET positive bPSy) e, d\n\nPartio response d (PET positive bPSy) e, d\n\nPartio response d (PET positive bPSy) e, d\n\nPartio response d (PET positive bPSy) e, d\n\nPartio response d (PET positive bPSy) e, d\n\nPartio response d (PET positive bPSy) e, d\n\nPartio response d (PET positive bPSy) e, d\n\nPartio response d (PET positive bPSy) e, d\n\nPartio response d (PET positive bPSy) e, d\n\nPartio response d (PET positive bPSy) e, d\n\nPartio response d (PET positive bPSy) e, d\n\nPartio response d (PET positive bPSy) e, d\n\nPartio response d (PET positive bPSy) e, \n](1/parseimages/figurefc914fb4f9264d67b96ea9789dc6fc10_0_4.png) a Consider prophylaxis for tumor lysis syndrome (NHODG-B) and see monoclonal antibody and viral reactivation (NHODG-B).

b An FDA-approved biosimilar is an appropriate substitute for any recommended systemic biologic therapy in the NCCN Guidelines. Rituximab and hyaluronidase human injection for subcutaneous use may be substituted for rituximab after patients have received the first full dose of rituximab by intravenous infusion.

c PMBL can be defined as a clinical entity presenting with primary site of disease in the anterior mediastinum with or without other sites and has histology of DLBCL. Clinical pathologic correlation is required to establish diagnosis. PMBL overlaps with MGZL that have intermediate features between Hodgkin lymphoma and PMBL and have unique diagnostic characteristics. See Mediastinal Gray Zone Lymphoma (BCEL-B 2 of 2). See Special Considerations for Adolescent and Young Adult (AYA) Patients with B-Cell Lymphomas (NHODG-B 4 of 5).

d Lugano Response Criteria for Non-Hodgkin Lymphoma (NHODG-C).

e PET/CT scan should be interpreted via the PET 5-PS (NHODG-C 3 of 3).

Note: All recommendations are category 2A unless otherwise indicated.

f Persistent PET/CT positive masses at end of treatment after DA-EPOCH-R (5-PS 4 and on visual inspection demonstrate minimal uptake above liver) can be observed (with follow-up scans) without biopsy.

$^{g}$ Principles of Radiation Therapy (NHODG-D).

h Residual mediastinal masses are common. PET/CT scan is essential post-treatment. Biopsy of PET/CT scan positive mass is recommended if additional systemic treatment is contemplated.

$^{1}$ Surveillance imaging is used for monitoring asymptomatic patients. When a site of disease can only be visualized on PET/CT scan (eg, bone), it is appropriate to proceed with PET/CT scans for surveillance.

j Responses with BV have been seen in patients with a low level of CD30 positivity and any level of CD30 positivity is acceptable for the use of BV-based regimens.

NCCN Guidelines Version 1.2026

Primary Mediastinal Large B-Cell Lymphoma

NCCN Guidelines Index Table of Contents Discussion

Note: All recommendations are category 2A unless otherwise indicated.

PMBL-A

Dose-adjusted EPOCH-rituximab

Dunleavy K, Pittaluga S, Maeda LS, et al. Dose-adjusted EPOCH-rituximab therapy in primary mediastinal B-cell lymphoma. N Engl J Med 2013;368:1408-1416.

RCHOP-14 x 6 cycles

Camus V, Rossi C, Sesques P, et al. Outcomes after first-line immunochemotherapy for primary mediastinal B-cell lymphoma: a LYSA study. Blood Adv 2021;5:3862-

3872.

RCHOP-14 followed by ICE

Bantilan KS, Luttwak E, Moskowitz CH, et al. Sequential R-CHOP/(R)-ICE and dose-adjusted EPOCH-R are both appropriate frontline treatments for newly diagnosed primary mediastinal B-cell lymphoma: Results of a retrospective analysis [abstract]. Blood 2024;144: Abstract 4485.

Pembrolizumab

Armand P, Rodig S, Melnichenko V, et al. Pembrolizumab in relapsed or refractory primary mediastinal large B-cell lymphoma. J Clin Oncol 2019;37:3291-3299.

Nivolumab + brentuximab vedotin

Zinzani P, Santoro A, Gritti G, et al. Nivolumab combined with brentuximab vedotin for relapsed/refractory primary mediastinal large b-cell lymphoma: efficacy and safety from the phase II Checkmate 436 study. J Clin Oncol 2019;37:3081-3089.

REFERENCES

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Histologic Transformation of

Indolent Lymphomas to DLBCL

NCCN Guidelines Index Table of Contents Discussion

HISTOLOGIC TRANSFORMATION OF INDOLENT LYMPHOMAS TO DLBCL

![Histologic transformation after minimal or no prior therapy^{a,b,c}^{a,b,c} DLBCL or HGBL with MYC and BCL6 rearrangements^{f}^{f}^{a,b,c} Chemoimmunotherapy (anthracycline-based regimens preferred unless contraindicated) (See BCEL-C, first-line therapy) ± ISRT$^{g,h}^{a}$ $I_{ISRT}^{g,h}^{g}$ $PET/CT$ → Response to Therapy to Therapy (HTBCEL-2)\n](1/parseimages/figure3ca61ddc23e84850acfc2c4fad5e4fea_0_5.png) Histologic transformation after multiple lines of prior therapies$^{d,e}$

HTBCEL-3

a Perform FISH for BCL2 rearrangement [t(14;18)], and MYC rearrangements [t(8;14) or variants, t(8;22), t(2;8)].

b ISRT alone or one course of single-agent therapy including rituximab.

c MGPT may be useful for treatment selection.

d This includes $\ge 2$ of chemoimmunotherapy regimens for indolent lymphomas prior to histologic transformation. For example, prior treatment with BR and RCHOP.

e Perform FISH for BCL6 and MYC rearrangements.

f Campo E, Jaffe ES, Cook JR, et al. The International Consensus Classification of Mature Lymphoid Neoplasms: A report from the Clinical Advisory Committee. Blood 2022;140:1229-1253; WHO Classification of Tumours Editorial Board. Haematolymphoid tumours. (WHO classification of tumours series, 5th ed; vol 11). Lyon (France): International Agency for Research on Cancer; 2024.

g Principles of Radiation Therapy (NHODG-D).

h Consider ISRT for localized presentations, bulky disease, and/or limited osseous disease.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Histologic Transformation of

Indolent Lymphomas to DLBCL

NCCN Guidelines Index Table of Contents Discussion

HISTOLOGIC TRANSFORMATION OF INDOLENT LYMPHOMAS TO DLBCL (AFTER MINIMAL OR NO PRIOR THERAPY)

RESPONSE TO THERAPY

![CR\n(PET negative [5-PS 1-3])$^{i,j}$\n\nActive surveillance$^{k}$ or Clinical trial\n\nRelapsed disease$^{j}$\n\nRepeat biopsy$^{l}$\n\nHistologic Transformation\n(HTBCEL-3)\n](1/parseimages/figurea93251ca700f42f2804756bd61389946_0_6.png) ![PR (PET positive [5-PS 4])$^{i,j}$ or NR or progressive disease (PET positive [5-PS 5])$^{i}$\n\nCAR T-cell therapy (HTBCEL-A) with or without pre/post pheresis therapy (if eligible)\n\nIf not eligible, see HTBCEL-A for suggested systemic therapy regimens\n\nResponse Assessment and Additional Therapy (HTBCEL-3)\n\n(HTBCEL-3)\n](1/parseimages/figure6cd9196a40a2411aa1a7a6e55ac8afcc_0_7.png) $^{i}$ Lugano Response Criteria for Non-Hodgkin Lymphoma (NHODG-C). PET/CT scan should be interpreted via the PET 5-PS.

If transformation is coexisting with extensive FL, consider maintenance (see FOLL-5, Optional Extended Therapy).

k Follow-up includes diagnostic tests and imaging using the same modalities performed during workup as clinically indicated. Imaging should be performed whenever there are clinical indications. For surveillance imaging, see [Discussion](#) for consensus imaging recommendations.

$^{1}$ Repeat biopsy should be strongly considered if PET-positive prior to additional therapy because PET positivity may represent post-treatment inflammation. If biopsy negative, follow CR pathway. Patients with a durable response for transformed disease may recur with the original indolent lymphoma. In that case, the management should be as per FOLL-5 or NMZL-4.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Histologic Transformation of

Indolent Lymphomas to DLBCL

NCCN Guidelines Index Table of Contents Discussion

HISTOLOGIC TRANSFORMATION OF INDOLENT LYMPHOMAS TO DLBCL (AFTER MULTIPLE LINES OF PRIOR THERAPIES)$^{d}$

![Histologic transformation of Indolent Lymphomas to DLBCL\n\n### Histologic transformation after multiple lines of prior $therapies^{d}$\n\n#### Clinical trial or See HTBCEL-A for suggested systemic therapy regimens (Selection of regimen must be highly individualized taking into account prior treatment history) ± $ISRT^{9}$ or $ISRT^{9}$ or $ISRT^{9}$ or $ISRT^{9}$ or $ISRT^{9}$ or $ISRT^{9}$ for localized residual and/or residual FDG-avid disease not previously irradiated (See NCCN Guidelines for Palliative Care)\n\n############################################################################################################################################################################################################################################################################################\n](1/parseimages/figure298303523d0b4d9b926d60c90fe97471_0_5.png) d This includes ≥2 of chemoimmunotherapy regimens for indolent lymphomas prior to histologic transformation. For example, prior treatment with BR and RCHOP.

$^{g}$ Principles of Radiation Therapy (NHODG-D).

h Consider ISRT for localized presentations, bulky disease, and/or limited osseous disease.

i Lugano Response Criteria for Non-Hodgkin Lymphoma (NHODG-C). PET/CT scan should be interpreted via the PET 5-PS.

m If proceeding to transplant, consider additional systemic therapy not previously given ± ISRT to induce CR prior to transplant.

$^{n}$ Data on transplant after treatment with CAR T-cell (CD19-directed) are not available. HDT/ASCR is not recommended CAR T-cell (CD19-directed) therapy.

Allogeneic HCT could be considered but remains investigational.

$\circ$ Selected cases include mobilization failures and persistent bone marrow involvement.

P Patients should have received at least one anthracycline-based regimen, unless contraindicated.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Histologic Transformation of

Indolent Lymphomas to DLBCL

NCCN Guidelines Index Table of Contents Discussion

SUGGESTED TREATMENT REGIMENSª

|SYSTEMIC THERAPY REGIMENS|| |---|---| |Intention to proceed to transplant|PreferredCHOP + Rituximab (if not previously given)If previously treated with anthracycline-based regimen (in alphabetical order)DHA + platinum (Carboplatin, Cisplatin, or Oxaliplatin) ± RituximabGDPICE ± Rituximab| |No intention to proceed to transplant|PreferredCHOP + Rituximab (if not previously given)If previously treated with anthracycline-based regimen (in alphabetical order)Polatuzumab vedotin-piiq ± Bendamustinec ± RituximabLenalidomide + Tafasitamab-cixd|

T-CELL MEDIATED THERAPY

$\bullet$ CAR T-cell therapyd,e,f,g (in alphabetical order)

$\bullet$ Bispecific antibody therapy$^{h}$ (only after at least two lines of systemic therapy; including patients with disease progression after transplant or CAR T-cell therapy)

$\bullet$ Lisocabtagene maraleucel (CD-19 directed)

$\bullet$ Tisagenlecleucel (CD-19 directed)

$\bullet$ Eporitamab-bysp

$\bullet$ Glofitamab-gxbm

Consider prophylaxis for tumor lysis syndrome (NHODG-B) See monoclonal antibody and viral reactivation (NHODG-B)

Note: All recommendations are category 2A unless otherwise indicated.

References on BCEL-C 5 of 7

Footnotes

HTBCEL-A 1 OF 2

NCCN Guidelines Version 1.2026 Histologic Transformation of

Indolent Lymphomas to DLBCL

NCCN Guidelines Index Table of Contents Discussion

Note: All recommendations are category 2A unless otherwise indicated.

HTBCEL-A 2 OF 2

FOOTNOTES

SUGGESTED TREATMENT REGIMENS

a An FDA-approved biosimilar is an appropriate substitute for any recommended systemic biologic therapy in the NCCN Guidelines. Rituximab and hyaluronidase

human injection for subcutaneous use may be substituted for rituximab after patients have received the first full dose of rituximab by intravenous infusion.

b Inclusion of any anthracycline in patients with impaired cardiac functioning should have more frequent cardiac monitoring.c In patients intended to receive CAR T-cell therapy or CD3 x CD20 bispecific antibody therapy, bendamustine should be used with caution. Delay bendamustine until after CAR-T leukapheresis.

d It is unknown if tafasitamab, loncastuximab tesirine, or any other CD19–directed therapy would have a negative impact on the efficacy of subsequent CAR T-cell

(CD19-directed) therapy. If clinically feasible, repeat biopsy to confirm antigen expression prior to the initiation of CD19-directed CAR T-cell therapy.

e NCCN Guidelines for Management of CAR T-Cell and Lymphocyte Engager-Related Toxicities.f Patients should have received at least one anthracycline-based regimen, unless contraindicated.g In selected circumstances, an alternate CAR T-cell therapy can be used upon disease progression.h Refer to package insert for full prescribing information, dose modifications, and monitoring for adverse reactions: https://www.accessdata.fda.gov/scripts/cder/daf/

index.cfm. In the setting of CD20-negative lymphomas, the efficacy of CD3 x CD20 bispecific antibody therapy is poor. If clinically feasible, repeat biopsy to confirm antigen expression prior to the initiation of T-cell mediated therapy.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

High-Grade B-Cell Lymphomas (HGBL)a

NCCN Guidelines Index Table of Contents Discussion

|Classification|HGBL with MYC and BCL2 rearrangements with or without BCL6 rearrangements (ICC) DLBCL/HGBL with MYC and BCL2 rearrangements (WHO5)$^{b}$|HGBL with MYC and BCL6 rearrangements (ICC)$^{b}$|HGBL-NOS (ICC and WHO5)$^{c}$| |---|---|---|---| |Treatment $options^{d,e}$|Clinical trial is recommended. • Consolidative ISRT is preferred for localized disease.$^{f}$ While the optimal treatment approach is not established, the following induction regimens have been used: • DA-EPOCH + Rituximab • CHOP + Rituximab may be associated with a suboptimal outcome. Could be considered for patients with low risk disease (IPI <2). • Mini-CHOP + Rituximab may be considered for patients who are frail or older • Potentially toxic regimens; performance status and comorbidities should be considered: ◇ HyperCVAD + Rituximab ◇ CDOX-M alternating with IVAC + Rituximab • Relapsed/refractory disease, see <12 months (BCEL-7) or >12 months (BCEL-8).|• Manage as DLBCL (BCEL-1). • HGBL with BCL6 and MYC rearrangements appear to have outcomes equivalent to DLBCL NOS; however many of these patients were managed with DA-EPOCH + Rituximab. Therefore, the optimal chemotherapy regimen remains uncertain.|• Clinical trial is recommended. • Consider consolidative ISRT for early-stage disease.$^{f}$ • While the optimal treatment approach is not established, the following induction regimens have been used: • DA-EPOCH + Rituximab • Pola-R-CHP (category 2B) • CHOP + Rituximab • Mini-CHOP + Rituximab may be considered for patients who are frail or older • Potentially toxic regimens; performance status and comorbidities should be considered ◇ HyperCVAD + Rituximab ◇ CODOX-M alternating with IVAC + Rituximab • Relapsed/refractory disease, see <12 months (BCEL-7) or >12 months (BCEL-8).|

a TdT expression has prognostic implications but doesn't change therapy.

b LBCL with MYC and BCL2 or BCL6 rearrangements as detected by FISH or are known as "double-hit" lymphomas. If all three rearrangements present, they are referred to as "triple-hit" lymphomas. The vast majority are GCB-like lymphomas. Patients often present with poor prognostic variables, such as elevated LDH, bone marrow and CNS involvement, and a high IPI score.

c HGBL-NOS includes cases that appear blastoid or cases intermediate between DLBCL and BL, but which lack MYC and BCL2 with or without BCL6 rearrangement. This category excludes HGBL with MYC and BCL2 with or without BCL6 rearrangement or clear DLBCL. Patients often present with poor prognostic parameters, such as elevated LDH, bone marrow and CNS involvement, and a high IPI score.

d An FDA-approved biosimilar is an appropriate substitute for any recommended systemic biologic therapy in the NCCN Guidelines. Rituximab and hyaluronidase human injection for subcutaneous use may be substituted for rituximab after patients have received the first full dose of rituximab by intravenous infusion.

e Special Considerations for Adolescent and Young Adult (AYA) Patients with B-Cell Lymphomas (NHODG-B 4 of 5).

f Principles of Radiation Therapy (NHODG-D).

References on HGBL-A

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 1.2026

High-Grade B-Cell Lymphomas (HGBL)a

NCCN Guidelines Index Table of Contents Discussion

Note: All recommendations are category 2A unless otherwise indicated.

HGBL-A

Campo E, Jaffe ES, Cook JR, et al. The International Consensus Classification of Mature Lymphoid Neoplasms: A report from the Clinical Advisory Committee. Blood 2022;140:1229-1253; WHO Classification of Tumours Editorial Board. Haematolymphoid tumours. (WHO classification of tumours series, 5th ed; vol 11). Lyon

(France): International Agency for Research on Cancer; 2024.

Petrich A, Gandhi M, Jovanovic B, et al. Impact of induction regimen and stem cell transplantation on outcomes in double-hit lymphoma: a multicenter retrospective

analysis. Blood 2014;124:2354-2361.

Dunleavy K, Fanale MA, Abramson JS, et al. Dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) in untreated aggressive diffuse large B-cell lymphoma with MYC rearrangement: a prospective, multicentre, single-arm phase 2 study. Lancet Haematol 2018;5:e609-e617.

Johnson NA, Slack GW, Savage KJ, et al. Concurrent expression of MYC and BCL2 in diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide,

doxorubicin, vincristine, and prednisone. J Clin Oncol 2012;30:3452-3459.

Green TM, Young KH, Visco C, et al. Immunohistochemical double-hit score is a strong predictor of outcome in patients with diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol 2012;30:3460-3467.

REFERENCES

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Burkitt Lymphoma

NCCN Guidelines Index Table of Contents Discussion

ADDITIONAL DIAGNOSTIC TESTING$^{a,b,c}$

ESSENTIAL:

$\bullet$ Adequate immunophenotyping to establish diagnosisd,e

$\bullet$ IHC panel: CD45, CD20, CD3, CD5, CD10, Ki-67, BCL2, BCL6, TdT with or without

$\bullet$ Flow cytometry with peripheral blood and/or biopsy specimen: kappa/lambda, CD45, CD20, CD3, CD5, CD9, CD19, CD10, TdT

* FISH: t(8;14) or variants; MYC, BCL2; BCL6 rearrangement

USEFUL UNDER CERTAIN CIRCUMSTANCES

$\bullet$ EBER-ISH

$\bullet$ Consider chromosomal microarray to evaluate for 11q aberrations if otherwise resembles BL but FISH for MYC, MYC::IGH, MYC::IGL, and MYC::IGK are negative for LBCL with 11q aberration (ICC)/HGBL with 11q aberrations (WHO5)

WORKUP

ESSENTIAL:

$\bullet$ Physical exam: attention to node-bearing areas, including Waldeyer's ring, and to size of liver and spleen

* Performance status

$\bullet$ B symptoms

$\bullet$ CBC with differential

$\bullet$ LDH

Comprehensive metabolic panel

$\bullet$ Uric acid

$\bullet$ PET/CT scan (preferred; initiation of therapy should not be delayed for PET/CT scan) or C/A/P CT with contrast of diagnostic quality; pretreatment imaging is essential$^{f}$

$\bullet$ Lumbar puncture

* Flow cytometry of cerebrospinal fluid

* HIV testing (if positive, see HIVLYM-1)

$\bullet$ Hepatitis B testing$^{9}$

$\bullet$ Echocardiogram or MUGA scan if anthracycline-based regimen is indicated

$\bullet$ Pregnancy testing in patients of childbearing age (if therapy planned)

USEFUL IN SELECTED CASES:

* Unilateral or bilateral bone marrow biopsy ± aspirate

$\bullet$ Hepatitis C testing

* Neck CT with contrast

$\bullet$ Brain MRI with and without contrast

$\bullet$ Discuss fertility preservation$^{h}$

a Special Considerations for Adolescent and Young Adult (AYA)Patients with B-Cell Lymphomas (NHODG-B 4 of 5).

b For treatment of double- or triple-hit tumors, see HGBL-1. In other cases where it is not possible to distinguish between BL and high-grade lymphoma, therapy per this guideline may be appropriate.

$^{c}$ This disease is complex and curable; it is preferred that treatment occur at centers with expertise in the management of the disease.

d Typical immunophenotype: slg+, CD10+, CD20+, TdT-, Ki-67+ (≥95%), BCL2-, BCL6+.

e If flow cytometry initially performed, IHC for selected markers (BCL2 and Ki-67) can supplement the flow results.

f If obtaining PET scan is delayed due to logistics, a C/A/P CT scan should be obtained.

$^{9}$ Hepat�by T testing is indicated because of the risk of reactivation with immunotherapy + chemotherapy. Tests include HBsAg and core antibody for a patient with no risk factors. For patients with risk factors or previous history of hepatitis B, add e-antigen (NHODG-B). If positive, check viral load and consider consult with gastroenterologist.

h Fertility preservation options include: sperm banking, IVF, or ovarian tissue or oocyte cryopreservation.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Burkitt Lymphoma

NCCN Guidelines Index Table of Contents Discussion

![RISK ASSESSMENT\n\nINDUCTION THERAPY\n\nINITIAL RESPONSE\n\nRELAPSE\n\nLow risk\nNormal LDH and Stage I (Single extra-abdominal mass <10 cm) or Completely resected abdominal lesion\n\nClinical trial or $N_{\text{Regimens}}^{i}$\n\nComplete $n_{\text{J}}^{i}$\n\n$C_{\text{A}}^{i}$\n\n$C_{\text{A}}^{i}$\n\n$C_{\text{A}}^{i}$\n\n$C_{\text{A}}^{i}$\n\n$C_{\text{A}}^{i}$\n\n$C_{\text{A}}^{i}$\n\n$C_{\text{A}}^{i}$\n\n$C_{\text{A}}^{i}$\n\n$C_{\text{A}}^{i}$\n\n$C_{\text{A}}^{i}$\n\n$C_{\text{A}}^{i}$\n\n$C_{\text{A}}^{i}$\n\n$C_{\text{A}}^{i}$\n\n$C_{\text{A}}^{i}$\n\n$C_{\text{A}}^{i}$\n\n$C_{\text{A}}^{i}$\n\n$C_{\text{A}}^{i}$\n\n$C_{\text{A}}^{i}$\n\n$C_{\text{A}}^{i}$\n\n$C_{\text{A}}^{i}$\n\n$C_{\text{A}}^{i}$\n\n$C_{\text{A}}^{i}$\n\n$C_{\text{A}}^{i}$\n\n$C_{\text{A}}^{i}$\n\n$C_{\text{A}}^{i}$\n\n$C_{\text{A}}^{i}$\n\n$C_{\text{A}}^{i}$\n\n$C_{\text{A}}\n](1/parseimages/figure6e2c6f64bfdb4105976698a1edd505a6_0_4.png) $^{i}$ All regimens for BL include CNS prophylaxis/therapy.

J Lugano Response Criteria for Non-Hodgkin Lymphoma (NHODG-C).

$^{k}$ Relapse after 1 y is uncommon; therefore, follow-up should be individualized according to patient characteristics.

$^{1}$ If there is no clinical trial available, some NCCN Member Institutions use non-cross-resistant second-line therapy regimens listed on [BURK-A] in selected cases.

$^{m}$ Principles of Radiation Therapy (NHODG-D).

Note: All recommendations are category 2A unless otherwise indicated.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Burkitt Lymphoma

NCCN Guidelines Index Table of Contents Discussion

![SECOND-LINE THERAPY\nRESPONSE ASSESSMENT\n\nCONSOLIDATION/ADDITION THERAPY\n\nConsolidation/ADDITIONAL THERAPY\n\nComplete response\n\nConsider HDT/ASCR ± ISRT$^{m}$ or Consider allogeneic HCT in selected cases$^{n}$ ± ISRT$^{m}$\n\n$^{n}$ Consider allogeneic HCT in selected cases$^{n}$ ± ISRT$^{m}$\n\nDisease relapse >6 to 18 mo after appropriate first-line therapy\n\n$^{n}$ Conse Second-line therapy$^{i}$ or $^{(BURK-A)}$ or $^{(BURK-A)}$ or $^{(NCCN Guidelines for Palliative Care)}$\n\n### Clinical trial or $^{(C)O}$ or $^{(A)O}$ or $^{(BURK-A)}$ or $^{(BURK-A)}$ or $^{(C)O}$ or $^{(A)O}$ or $^{(BURK-A)}$ or $^{(C)O}$ or $^{(A)O}$ or $^{(A)O}$ or $^{(A)O}$ or $^{(A)O}$ or $^{(A)O}$ or $^{(A)O}$ or $^{(A)O}$ or $^{(A)O}$ or $^{(A)O}$ or $^{(A)O}$ or $^{(A)O}$ or $^{(A)O}$ or $^{(A)O}$ or $^{(A)O}$ or $^{(A)O}$ or $^{(A)O}$ or $^{(A)O}$ or $^{(A)O}$ or $^{(A)O}$ or $^{(A)O}$ or $^{(A)O}$ or $^{(A)O}$ or $^{(A)O}$ or $^{(A)O}$ or $^{(A)O}$ or $^{(A)O}$ or $^{(A)O}$ or $^{(A)O}$ or $^{(A)O}$ or $^{(A)O}$ or $^{(A)O}$ or $^{(A)O}$ or $^{(A)O}$ or $^{(A)O}$ or $^{(A)O}$ or $^{(A)O}$ or $^{(A)O}$ or $^{(\n](1/parseimages/figure570065063d5647d9aa7204da7f70d557_0_4.png) $^{1}$ All regimens for BL include CNS prophylaxis/therapy.

J Lugano Response Criteria for Non-Hodgkin Lymphoma (NHODG-C).

$^{1}$ If there is no clinical trial available, some NCCN Member Institutions use non-cross-resistant second-line therapy regimens listed on [BURK-A] in selected cases.

$^{m}$ Principles of Radiation Therapy (NHODG-D).

$^{n}$ Selected cases include mobilization failures and persistent bone marrow involvement.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Burkitt Lymphoma

NCCN Guidelines Index Table of Contents Discussion

SUGGESTED TREATMENT REGIMENSa,b,c

CHOP is not an adequate therapy.

|AGE|RISK|INDUCTION THERAPY (Regimens are listed in alphabetical order)| |---|---|---| |<60 y|Low Risk|CODOX-M (original or modified) (Cyclophosphamide/Vincristine/Doxorubicin with intrathecal [IT] Methotrexate and Cytarabine followed by high-dose systemic Methotrexate) + Rituximab (3 cycles)DA-EPOCH + RR (Etoposide/Prednisone/Vincristine/Cyclophosphamide/Doxorubicin) + Rituximab on day 1 and 5 x 2 cycles followed by PET $scan^{d}$:CR (PET-negative) after 2 cycles: DA-EPOCH-RR (Rituximab day 1 and 5) x 1 cycle (total of 3 cycles)PR (PET-positive) after 2 cycles: DA-EPOCH-R (Rituximab day 1 only) x 4 cycles (total of 6 cycles) + IT MethotrexateHyperCVAD (Cyclophosphamide/Vincristine/Doxorubicin/Dexamethasone) alternating with Cytarabine/high-dose Methotrexate + Rituximab (regimen includes IT therapy)| |<60 y|High Risk|Patients presenting with symptomatic CNS disease:Initiate treatment with the portion of the systemic therapy that contains CNS-penetrating drugsCDOOX-M (original or modified) alternating with IVC (Ifosfamide/Etoposide/High-Dose Cytarabine) + IT Methotrexate+Rituximab HyperCVAD alternating with Cytarabine/high-dose Methotrexate + Rituximab + Rituximab for 6 cycles + IT Methotrexatee (for patients not able to tolerate aggressive therapy)| |≥60 y|Low Risk|DA-EPOCH + RR (Rituximab day 1 and 5) x 2 cycles followed by PET $scan^{d}$:CR (PET-negative) after 2 cycles: DA-EPOCH-RR (Rituximab day 1 and 5) x 1 cycle (total of 3 cycles)PR (PET-positive) after 2 cycles: DA-EPOCH-RR (Rituximab day 1 only) x 4 cycles (total of 6 cycles) + IT Methotrexate| |≥60 y|High Risk|Dose-adjusted EPOCH + Rituximab$^{d}$ for 6 cycles + intensive IT Methotrexatee (for patients presenting with symptomatic CNS disease)|

Prophylaxis for tumor lysis syndrome is mandatory (NHODG-B) See monoclonal antibody and viral reactivation (NHODG-B)

a See references for regimens on BURK-A 3 of 3.

c All regimens for BL include CNS prophylaxis/therapy.

d Data included patients with leptomeningeal CNS disease; patients with parenchymal CNS disease were excluded in the clinical trials of this regimen.

e Patients with active CSF involvement as determined by flow cytometry and/or cytology received treatment with methotrexate intrathecally twice for at least 4 weeks, then weekly for 6 weeks, and then monthly for 6 months. Intravenous methotrexate was not permitted (Roschewski M, et al. J Clin Oncol 2020;38:2519-2529).

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 1.2026 Burkitt Lymphoma

NCCN Guidelines Index Table of Contents Discussion

SECOND-LINE THERAPY

• Patients with disease relapse >6 to 18 months after appropriate first-line therapy should be treated with alternate regimens. While no definitive second-line therapies exist, there are limited data for the following regimens:

Other recommended (in alphabetical order)

• DA-EPOCH + Rituximabd for 6 cycles (if not previously given) + intensive IT methotrexate (for patients presenting with symptomatic CNS disease)

• ICE (Ifosfamide/Carboplatin/Etoposide) + Rituximab; IT methotrexate if have not received previously

• IVAC (Ifosfamide/Cytarabine/Etoposide) + Rituximab; IT methotrexate if have not received previously

Useful in certain circumstances (in alphabetical order)

• High-dose Cytarabine + Rituximab

• GDP + Rituximab

• Glofitamab-gxbmf + Polatuzumab vedotin-piiq as a bridge to transplant in candidates for allogeneic HCT

Note: All recommendations are category 2A unless otherwise indicated.

BURK-A 2 OF 3

a See references for regimens on BURK-A 3 of 3.b An FDA-approved biosimilar is an appropriate substitute for any recommended systemic biologic therapy in the NCCN Guidelines. Rituximab and hyaluronidase

human injection for subcutaneous use may be substituted for rituximab after patients have received the first full dose of rituximab by intravenous infusion.

c All regimens for BL include CNS prophylaxis/therapy.d Data included patients with leptomeningeal CNS disease; patients with parenchymal CNS disease were excluded in the clinical trials of this regimen.f Refer to package insert for full prescribing information, dose modifications, and monitoring for adverse reactions: https://www.accessdata.fda.gov/scripts/cder/daf/index.

cfm. In the setting of CD20-negative lymphomas, the efficacy of CD3 x CD20 bispecific antibody therapy is poor. If clinically feasible, repeat biopsy to confirm antigen expression prior to the initiation of T-cell mediated therapy.

SUGGESTED TREATMENT REGIMENSa,b,c

Prophylaxis for tumor lysis syndrome is mandatory (NHODG-B)

See monoclonal antibody and viral

reactivation (NHODG-B)

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Burkitt Lymphoma

NCCN Guidelines Index Table of Contents Discussion

SUGGESTED TREATMENT REGIMENS REFERENCES

Induction Therapy

Low- and High-Risk Combination Regimens

CODOX-M (original or modified) (cyclophosphamide, doxorubicin, vincristine with intrathecal methotrexate and cytarabine followed by high-dose systemic methotrexate) with (for high-risk) or without (for low-risk) alternating IVAC (ifosfamide, cytarabine, etoposide, and intrathecal methotrexate ± rituximab)

LaCasce A, Howard O, Lib S, et al. Modified magrath regimens for adults with Burkitt and Burkitt-like lymphoma: preserved efficacy with decreased toxicity. Leuk Lymphoma 2004;45:761-767.

Mead GM, Sydes MR, Walewski J, et al. An international evaluation of CODOX-M and CODOX-M alternating with IVAC in adult Burkitt's lymphoma: results of United Kingdom Lymphoma Group LY06 study. Ann Oncol 2002;13:1264-1274.

Barnes JA, Lacasac AS, Feng Y, et al. Evaluation of the addition of rituximab to CDOX-M/IVAC for Burkitt's lymphoma: a retrospective analysis. Ann Oncol 2011;22:1859-1864.

Evens AM, Carson KR, Kolesar J, et al. A multicenter phase II study incorporating high-dose rituximab and liposomal doxorubicin into the CODOX-M/IVAC regimen for untreated Burkitt's lymphoma. Ann Oncol 2013;24:3076-3081.

Phillips EH, Burton C, Kirkwood AA, et al. Favourable outcomes for high-risk Burkitt lymphoma patients (IPI 3-5) treated with rituximab plus CODOX-M/IVAC: Results of a phase 2 UK NCRI trial. EJHaem 2020;1:133-141.

Dose-adjusted EPOCH plus rituximab (regimen includes IT methotrexate)

Dunleavy K, Pittaluga S, Shovlin M, et al. Low-intensity therapy in adults with Burkitt's lymphoma. N Engl J Med 2013;369:1915-1925.

Roschewski M, Dunleavy K, Abramson JS, et al. Multicenter study of risk-adapted therapy with dose-adjusted EPOCH-R in adults with untreated Burkitt lymphoma. J Clin Oncol 2020;38:2519-2529.

HyperCVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) alternating with high-dose methotrexate and cytarabine + rituximab

Thomas DA, FaderI S, O'Brien S, et al. Chemoimmunotherapy with hyper-CVAD plus rituximab for the treatment of adult Burkitt and Burkitt-type lymphoma or acute lymphoblastic leukemia. Cancer 2006;106:1569-1580.

Samra B, Khoury JD, Morita K, et al. Long-term outcome of hyper-CVAD-R for Burkitt leukemia/lymphoma and high-grade B-cell lymphoma: focus on CNS relapse. Blood Adv 2021;5:3913-3918.

Second-line Therapy

Glofitamab + Polatuzumab vedotin

Prica A, Roschewski M, Beale P, et al. Glofitamab with polatuzumab vedotin in refractory Burkitt's lymphoma. N Engl J Med 2025;392:1760-1762.

RICE (rituximab, ifosfamide, carboplatin, etoposide)

Griffin TC, Weitzman S, Weinstein H, et al. A study of rituximab and ifosfamide, carboplatin, and etoposide chemotherapy in children with recurrent/refractory B-cell (CD20+) non-Hodgkin lymphoma and mature B-cell acute lymphoblastic leukemia: A report from the Children's Oncology Group. Pediatr Blood Cancer 2009;52:177-181.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 1.2026 HIV-Related B-Cell Lymphomas

NCCN Guidelines Index Table of Contents Discussion

Note: All recommendations are category 2A unless otherwise indicated.

HIVLYM-1

ESSENTIAL:

• Adequate immunophenotyping to establish diagnosis and

subclassification (eg, DLBCL, BL, plasmablastic lymphoma, PEL)

IHC panel: CD45, CD20, CD3, CD10, BCL2, BCL6,

Ki-67, CD138, kappa/lambda, HHV8 latency-associated nuclear

antigen (LANA),a CD30 for PEL,

with or without

Flow cytometry with peripheral blood and/or biopsy specimen:

kappa/lambda, CD45, CD3, CD5, CD19, CD10, CD20

• FISH for MYC; FISH for BCL2, BCL6 rearrangements if MYC positive

• EBER-ISH

a HHV8 can also be detected by polymerase chain reaction (PCR).

Workup

(HIVLYM-2)

ADDITIONAL DIAGNOSTIC TESTING

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

HIV-Related B-Cell Lymphomas

NCCN Guidelines Index Table of Contents Discussion

WORKUP

ESSENTIAL

* Physical exam: attention to node-bearing areas, including Waldeyer's ring, and to size of liver and spleen

* Performance status

* B symptoms

$\bullet$ CBC with differential

$\bullet$ LDH

* Comprehensive metabolic panel

* Uric acid, phosphate

* PET/CT scan (preferred) or C/A/P CT with contrast of diagnostic quality

$\bullet$ CD4 count

* HIV viral load

$\bullet$ Hepatitis B testing$^{b}$

$\bullet$ Hepatitis C testing$^{c}$

* Echocardiogram or MUGA scan if anthracycline or anthracenedione-based regimen is indicated

* Pregnancy testing in patients of childbearing age (if therapy planned)

USEFUL IN SELECTED CASES:

* Upper GI/barium enema/endoscopy

$\bullet$ Adequate bone marrow biopsy (>1.6 cm) ± aspirate; bone marrow biopsy is not necessary if PET/CT scan demonstrates bone disease

$\bullet$ Lumbar puncture, except for PEL

$\bullet$ Neck CT with contrast

* Plain bone radiographs and bone scan

* Brain MRI with and without contrast, or head CT with contrast

* Beta-2-microglobulin

* EBV polymerase chain reaction (PCR)

$\bullet$ SPEP with SIFE and/or quantitative lg levels

$\bullet$ Discuss fertility preservation$^{d}$

c Hepatitis C antibody and if positive, viral load and consult with hepatologist.

d Fertility preservation options include: sperm banking, IVF, or ovarian tissue or oocyte cryopreservation..

Note: All recommendations are category 2A unless otherwise indicated.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

HIV-Related B-Cell Lymphomas

NCCN Guidelines Index Table of Contents Discussion

TREATMENT

Antiretroviral therapy (ART) can be administered safely with chemotherapy, but consultation with an HIV specialist or pharmacist is important to optimize compatibility. With continued development of new ARTs, effective alternatives are often available to patients when the existing ARTs are expected to affect metabolism of or share toxicities with chemotherapy. In general, avoidance of zidovudine, cobicistat, and ritonavir is strongly recommended. Concurrent ART is associated with higher CR rates (Barta S, et al. Blood 2013;122:3251-3262). Patients with HIV-related DLBCL receiving ART are suitable candidates for CAR T-cell therapies with appropriate supportive care measures for HIV control. For principles of concurrent HIV management and supportive care, see the NCCN Guidelines for Cancer in People with HIV. e

![BL\n\n- First-line therapy - See Suggested Treatment Regimens (HIVLYM-A)$^{e}$\n- If CD4 <50, maximize supportive care and monitor closely for cytopenias and infections (BURK-3)\n- Granulocyte colony-stimulating factor (G-CSF) for all patients\n](1/parseimages/figure6e928945cf954891b7d1278ba04f0f90_0_6.png) ![* Initiate ART, if not already receiving\n* Even with poorly controlled HIV and/or marginal performance status, consider high-dose methotrexatef\n* For select patients with good performance status on ART, see the NCCN Guidelines for CNS - Primary CNS Lymphoma\n* Consider RT alone as initial treatment for patients who are not candidates for systemic therapy at presentation, then reassess eligibility for systemic therapy after RT\n* Best supportive care (See NCCN Guidelines for Palliative Care)\n](1/parseimages/figuree1c53137439c427f8aaab37ad0d0fcc8_0_7.png) e In the NCCN Guidelines for Cancer in People with HIV, see the Principles of HIV Management While Undergoing Cancer Therapy; Principles of Systemic Therapy and Drug-Drug Interactions; and Principles of Supportive Care. f Gupta N, et al. Neuro Oncol 2017;19:99-108.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

HIV-Related B-Cell Lymphomas

NCCN Guidelines Index Table of Contents Discussion

TREATMENT

ART can be administered safely with chemotherapy, but consultation with an HIV specialist or pharmacist is important to optimize compatibility. With continued development of new ARTs, effective alternatives are often available to patients when the existing ARTs are expected to affect metabolism of or share toxicities with chemotherapy. In general, avoidance of zidovudine, cobicistat, and ritonavir is strongly recommended. Concurrent ART is associated with higher CR rates (Barta S, et al. Blood 2013;122:3251-3262). Patients with HIV-related DLBCL receiving ART are suitable candidates for CAR T-cell therapies with appropriate supportive care measures for HIV control. For principles of concurrent HIV management and supportive care, see the NCCN Guidelines for Cancer in People with HIV.

![$\bullet$ DLBCL\n$\bullet$ HHV8-positive DLBCL, NOS\n$\bullet$ PEL\n$\bullet$ First-line therapy - See Suggested Treatment Regimens (HIVLYM-A)$^{e}$ $\rightarrow$ For relapse, see\n$\bullet$ G-CSF for all patients\n$\bullet$ IT therapy as per BCEL-A 3 of 3\n$\bullet$ Bortezomib/ICE ± Rituximab (category 2B)\n$\bullet$ If CD20-, rituximab is not indicated\n$\bullet$ If CD4 <50, maximize supportive care and monitor closely for cytopenias and infections while administering lymphoma therapy\n](1/parseimages/figureb97da737c68c44c0bc861e93a9b54994_0_6.png) ![Plasmablastic lymphoma$^{9}$\n\n- For relapse, Se\n- Consider HDT/ASCR in first complete remission in select patients with high-risk disease$^{10}$\n\n- Consider consolidation with ISRT in patients with localized disease\n- See BCEL-C second-line therapy (without rituximab)\n](1/parseimages/figure31ce966fa083453e82b0700516fbb5b5_0_7.png) e In the NCCN Guidelines for Cancer in People with HIV, see the Principles of HIV Management While Undergoing Cancer Therapy; Principles of Systemic Therapy and Drug-Drug Interactions; and Principles of Supportive Care.

$^{9}$ Management can also apply to HIV-negative plasmablastic lymphoma.

h High-risk features include an age-adjusted IPI higher than 2, presence of MYC gene rearrangement, or TP53 gene deletion. Note that patients negative for HIV with plasmablastic lymphoma are generally considered to have higher risk disease. Optimization of HIV control with ART is important.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 1.2026 HIV-Related B-Cell Lymphomas

NCCN Guidelines Index Table of Contents Discussion

Note: All recommendations are category 2A unless otherwise indicated.

HIVLYM-A 1 OF 2

SUGGESTED TREATMENT REGIMENSa

BURKITT LYMPHOMA - FIRST-LINE THERAPYb

Preferred

• CODOX-M alternating with IVAC (modified) + Rituximabc

• DA-EPOCH + Rituximabd

Other recommended

• HyperCVAD alternating with Cytarabinec/High-dose Methotrexate + Rituximab

a See references for regimens on HIVLYM-A 2 of 2. b An FDA-approved biosimilar is an appropriate substitute for any recommended systemic biologic therapy in the NCCN Guidelines. Rituximab and hyaluronidase

human injection for subcutaneous use may be substituted for rituximab after patients have received the first full dose of rituximab by intravenous infusion.

c Patients presenting with high-risk and symptomatic CNS disease should be started with the portion of the systemic therapy that contains CNS-penetrating drugs.d Dunleavy K, Pittaluga S, Shovlin M, et al. Engl J Med 2013;369:1915-1925. Roschewski M, Dunleavy K, Abramson JS, et al. J Clin Oncol 2020;38:2519-2529. For dosing, see BURK-A 1 of 3.

DLBCL, HHV8-POSITIVE DLBCL, NOS, PEL - FIRST-LINE THERAPYb

• If CD20-, rituximab is not indicated

Preferred

• EPOCH with dose adjustment (HIVLYM-B) + Rituximab

Other recommended

• CHOP + Rituximab

PLASMABLASTIC LYMPHOMA - FIRST-LINE THERAPY

Preferred

• EPOCH with dose adjustment (HIVLYM-B)

• EPOCH with dose adjustment (HIVLYM-B) + Daratumumab

Other recommended

• CODOX-M alternating with IVAC (modified)

• HyperCVAD

Prophylaxis for tumor lysis syndrome (NHODG-B)

Prophylaxis for tumor lysis syndrome is mandatory for BL

See monoclonal antibody and viral reactivation (NHODG-B)

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 HIV-Related B-Cell Lymphomas

NCCN Guidelines Index Table of Contents Discussion

SUGGESTED TREATMENT REGIMENS REFERENCES

CODOX-M/IVAC (cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate alternating with ifosfamide, etoposide, high-dose cytarabine) ± rituximab

Wang ES, Straus DJ, Teruya-Feldstein J, et al. Intensive chemotherapy with cyclophosphamide, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, and high-dose cytarabine (CODOX-M/IVAC) for human immunodeficiency virus-associated Burkitt lymphoma. Cancer 2003;98:1196-1205.

Barnes JA, LaCasce AS, Feng Y, et al. Evaluation of the addition of rituximab to CDOX-M/IVAC for Burkitt's lymphoma: A retrospective analysis. Ann Oncol 2011; 22:1859-1864.

Noy A, Lee JY, Cesarman E, et al. AMC 048: modified CODOX-M/IVAC-rituximab is safe and effective for HIV-associated Burkitt lymphoma. Blood 2015;126:160-166.

Dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin)

Little RF, Pittaluga S, Grant N, et al. Highly effective treatment of acquired immunodeficiency syndrome-related lymphoma with dose-adjusted EPOCH: impact of antiretroviral therapy suspension and tumor biology. Blood 2003;101:4653-4659.

Roschewski M, Dunleavy K, Abramson JS, et al. Multicenter study of risk-adapted therapy with dose-adjusted EPOCH-R in adults with untreated Burkitt lymphoma. J Clin Oncol 2020;38:2519-2529.

EPOCH + daratumumab

Noy A, Barta SK, Kwon D, et al. Daratumumab with dose-adjusted EPOCH is feasible in newly diagnosed plasmablastic lymphoma: AIDS malignancy consortium 105 [abstract]. Blood 2024;144:Abstract 870.

EPOCH + rituximab

Barta SK, Lee JY, Kaplan LD, et al. Pooled analysis of AIDS malignancy consortium trials evaluating rituximab plus CHOP or infusional EPOCH chemotherapy in HIV-associated non-Hodgkin lymphoma. Cancer 2012;118:3977-3983.

Bayraktar UD, Ramos JC, Petrich A, et al. Outcome of patients with relapsed/refractory acquired immune deficiency syndrome-related lymphoma diagnosed 1999-2008 and treated with curative intent in the AIDS Malignancy Consortium. Leuk Lymphoma 2012;53:2383-2389.

Dunleavy K, Pittaluga S, Shovlin M, et al. Low-intensity therapy in adults with Burkitt's lymphoma. N Engl J Med 2013;369:1915-1925.

Ramos J, Sparano J, Rudek M, et al. Safety and preliminary efficacy of vorinostat with R-EPOCH in high-risk HIV-associated non-Hodgkin's lymphoma (AMC-075). Clin Lymphoma Myeloma Leuk 2018;18:180-190.

Sparano JA, Lee JY, Kaplan LD et al. Rituximab plus concurrent infusional EPOCH chemotherapy is highly effective in HIV-associated B-cell non-Hodgkin lymphoma. Blood 2010;115:3008-3016.

Note: All recommendations are category 2A unless otherwise indicated.

HyperCVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate and cytarabine) ± rituximab

Cortes J, Thomas D, Rios A, et al. Hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone and highly active antiretroviral therapy for patients with acquired immunodeficiency syndrome-related Burkitt lymphoma/leukemia. Cancer 2002;94:1492-1499.

Thomas DA, Faderl S, O'Brien S, et al. Chemoimmunotherapy with hyper-CVAD plus rituximab for the treatment of adult Burkitt and Burkitt-type lymphoma or acute lymphoblastic leukemia. Cancer 2006;106:1569-1580.

Samra B, Khoury JD, Morita K, et al. Long-term outcome of hyper-CVAD-R for Burkitt leukemia/lymphoma and high-grade B-cell lymphoma: focus on CNS relapse. Blood Advances 2021;5:3913-3918.

CHOP + rituximab

Boue F, Gabarre J, Gisselbrecht C, et al. Phase II trial of CHOP plus rituximab in patients with HIV-associated non-Hodgkin's lymphoma. J Clin Oncol 2006;24:4123-4128.

virus-associated diffuse large B-cell lymphoma: results of a phase II trial. Br J Haematol

Reid EG, Looney D, Maldarelli F, et al. Safety and efficacy of an oncolytic viral strategy

Bortezomib/ICE (ifosfamide, carboplatin, etoposide) ± rituximab

Reid EG, Looney D, Maldarelli F, et al. Safety and efficacy of an oncolytic viral strategy using bortezomib with ICE/R in relapsed/refractory HIV-positive lymphomas. Blood Adv 2018;2:3618-3626.

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 HIV-Related B-Cell Lymphomas

NCCN Guidelines Index Table of Contents Discussion

RECOMMENDATIONS FOR EPOCH ± RITUXIMAB DOSE ADJUSTMENTS FOR NON-BURKITT LYMPHOMAS$^{1}$

EPOCH ± Rituximab dosing recommendations for cycle 1:

$\bullet$ Lituximab (if CD20-positive) 375 mg/m$^{2}$ IV on Day 1

$\bullet$ Etoposide 50 mg/m$^{2}$/day continuous IV infusion for 4 days (96 hours)

$\bullet$ Doxorubicin 10 mg/m$^{2}$/day continuous IV infusion for 4 days (96 hours)

$\bullet$ Vincristine 0.4 mg/m$^{2}$/day continuous IV infusion for 4 days (96 hours)

* Day 5 cyclophosphamide dosing

$\bullet$ If baseline CD4 count is >200 cells/mm$^{3}$, start cyclophosphamide at 750 mg/m$^{2}$

$\bullet$ If baseline CD4 count is 50–200 cells/mm$^{3}$, start cyclophosphamide at 375 mg/m$^{2}$

$\bullet$ For baseline CD4 counts <50 cells/mm$^{3}$, cycle 1 doses of cyclophosphamide above 187.5 mg/m$^{2}$ have not been published

* Prednisone 60 mg/m$^{2}$/day for 5 days

Event CPOCH Dose Modifications for Subsequent Cycles Based on Cyptenias (Non-Burkitt Lymphomas)$^{1}$

|Event|Action| |---|---| |ANC nadir on any cycle <500/mm³ on 2 nonconsecutive days at least 3 days apart and/or platelet nadir <25,000/mm³ in the previous cycle|Reduce cyclophosphamide dose by 187 mg/m²| |ANC nadir <500/mm³ x ≥ 3 days or platelets <25,000/mm³ x ≥ 3 days, AND patient was receiving no cyclophosphamide in the previous cycle|Reduce doxorubicin and etoposide by 25% of the full dose| |ANC nadir ≥500/mm³ AND platelet nadir ≥50,000/mm³ in the previous cycle|Increase cyclophosphamide dose by 187 mg/m² each cycle to a maximum dose of 750 mg/m²|

$^{1}$ For R-EPOCH dosing for non-Burkitt lymphomas, see Ramos J, Sparano J, Rudek M, et al. Safety and preliminary efficacy of vorinostat with R-EPOCH in high-risk HIV-associated non-Hodgkin's lymphoma (AMC-075). Clin Lymphoma Myeloma Leuk 2018;18:180-190. This is an ongoing clinical trial and the utility of adding vorinostat to R-EPOCH has not yet been established.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Lymphoblastic Lymphoma

NCCN Guidelines Index Table of Contents Discussion

ADDITIONAL DIAGNOSTIC TESTING$^{a,b,c}$

ESSENTIAL:

* Adequate immunophenotyping to establish $diagnosis^{d}$ $\blacktriangleright$ IHC panel: CD45, CD19, CD20, CD79a, CD3, CD2, CD5, CD7, Td7, TdT, CD1a, CD10, cyclin D1, myeloperoxidase, lysozyme, CD34, CD4, CD8 with or without

$\bullet$ Flow cytometry with peripheral blood and/or biopsy specimen: kappa/lambda/lambda, CD45, CD3, CD5, CD4, CD7, CD8, CD19, CD20, CD10, TdT, CD13, CD33, CD34, CD1a, cytoplasmic CD3, CD22, myeloperoxidase

$\bullet$ Flow cytometry with peripheral blood and/or biopsy specimen: kappa/lambda, CD45, CD3, CD5, CD4, CD7, CD8, CD19, CD20, CD10, TdT, CD13, CD33, CD34, CD1a, cytoplasmic CD3, CD22, myeloperoxidase

* FISH: MYC; t(9;22); t(8;14) and variants; or PCR for BCR::ABL1

USEFUL UNDER CERTAIN CIRCUMSTANCES:

* Additional immunohistochemical studies to establish lymphoma subtype

$\blacktriangleright$ IHC panel: CD22, CD4, CD8, cyclin D1

$\bullet$ Molecular analysis to detect: Ig gene rearrangements

$\bullet$ FISH: Ph-like

WORKUP

ESSENTIAL:

* Physical exam: attention to node-bearing areas, including Waldeyer's ring, and to size of liver and spleen

* Performance status

* B symptoms

$\bullet$ CBC with differential

$\bullet$ LDH

Comprehensive metabolic panel

* Uric acid, phosphate

C/C/AP CT with contrast of diagnostic quality

$\bullet$ Lumbar puncture

* Flow cytometry of cerebrospinal fluid

$\bullet$ Bilateral or unilateral bone marrow biopsy ± aspirate with flow and cytogenetics

$\bullet$ Hepatitis B testing$^{e}$

* Echocardiogram or MUGA scan if anthracycline or anthracenedione-based regimen is indicated

* Pregnancy testing in patients of childbearing age (if therapy planned)

USEFUL IN SELECTED CASES:

* Beta-2-microglobulin

$\bullet$ Brain MRI with and without contrast

$\bullet$ PET/CT scan$^{f}$

$\bullet$ Discuss fertility preservation$^{9}$

a The LL category comprises two diseases, T-cell LL (T-LBL; 90%) and B-cell LL (B-LL; 10%), which corresponds to T-cell acute lymphoblastic leukemia (T-ALL) and B-cell acute lymphoblastic leukemia (B-ALL), respectively, with presentations in extramedullary sites. See Cytogenetic and Molecular Prognostic Risk Stratification for B-ALL in the NCCN Guidelines for Acute Lymphoblastic Leukemia.

b This disease is complex and curable; it is preferred that treatment occur at centers with expertise in the management of the disease.

c Special Considerations for Adolescent and Young Adult (AYA) Patients with B-Cell Lymphomas (NHODG-B 4 of 5).

d Typical immunophenotype: B-LL: slg-, CD10+/-, CD19+, CD20-/+, TdT+, CD34+, CD79a+. T-LL: slg-, CD10-, CD19/20-, CD3-/+, CD4/8+/+, CD1a+/-, TdT+, CD2+, CD7+ cytoplasmic CD3+, sCD3-/+.

f Initiation of therapy should not be delayed in order to obtain a PET/CT scan.

$^{9}$ Fertility preservation options include: sperm banking, IVF, or ovarian tissue or oocyte cryopreservation.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Post-Transplant Lymphoproliferative Disorders

NCCN Guidelines Index Table of Contents Discussion

ADDITIONAL DIAGNOSTIC TESTINGª

ESSENTIAL:

$\bullet$ Adequate immunophenotyping to establish diagnosis

$\bullet$ IHC panel: CD3, B-cell markers (CD20, CD79a, PAX5), kappa, lambda

$\bullet$ EBV evaluation by EBER-ISH

* Additional immunophenotyping depending on morphology and initial phenotyping:

$\bullet$ IHC panel for cHL: CD15, CD30, CD45, PAX5

$\bullet$ IHC panel for DLBCL/BL: CD10, BCL6, MUM1/IRF4, MYC, TdT, Ki67, BCL2

$\bullet$ IHC panel for plasmacytic/plasmablastic tumors: CD138, MUM1/IRF4, ALK, HHV8

$\bullet$ IHC panel for T-cell lymphoma: CD2, CD5, CD7, CD4, CD8, ALK, TIA-1, granzyme B

$\bullet$ IHC for EBV-LMP1 and EBV-EBNA2 to determine latency status

$\bullet$ Flow cytometry of biopsy specimen to include B and T cell clonality assessment.

$\bullet$ FISH to detect MYC, BCL2, or BCL6 rearrangements

$\bullet$ Molecular analysis to detect: lg gene rearrangements

WORKUP

ESSENTIAL:

$\bullet$ Performance status

* Albumin

History of therapy for transplant

$\bullet$ LDH, electrolytes, BUN, creatinine

$\bullet$ CBC with differential

$\bullet$ Hepatitis B testing$^{b}$

$\bullet$ EBV PCR for cell-free plasma EBV DNA marker$^{c}$

$\bullet$ PET/CT scan and/or C/A/P CT with contrast

* Pregnancy testing in patients of childbearing age (if therapy planned)

USEFUL IN SELECTED CASES:

* Echocardiogram or MUGA scan if anthracycline-based regimen is indicated

$\bullet$ Bone marrow evaluation

* Brain MRI with and without contrast

$\bullet$ Cytomegalovirus (CMV) PCR

$\bullet$ EBV serology for primary versus reactivation

$\bullet$ Hepatitis C testing

$\bullet$ SPEP with SIFE and/or quantitative lg levels

$\bullet$ Discuss fertility preservation$^{d}$

a Special Considerations for Adolescent and Young Adult (AYA) Patients with B-Cell Lymphomas (NHODG-B 4 of 5).

c If EBV-negative, should not be used as response marker.

d Fertility preservation options include: sperm banking, IVF, or ovarian tissue or oocyte cryopreservation.

e Indolent small B-cell lymphomas arising in transplant recipients are not included among PTLDs, with the exception of EBV-positive marginal zone lymphomas in the ICC. Indolent lymphomas arising in transplant recipients are included in the WHO5. EBV-positive mucocutaneous ulcer (WHO5) is an indolent lymphoma.

f In the WHO5, hyperplasia includes follicular hyperplasia, infectious mononucleosis-like hyperplasia (IMH), and plasmacytic hyperplasia (PCH); in the ICC these three types are considered non-destructive.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Post-Transplant Lymphoproliferative Disorders

NCCN Guidelines Index Table of Contents Discussion

![PTLD SUBTYPE\n\nFIRST-LINE THERAPY\n\nINITIAL RESPONSE¹\n\nManage immunosuppression™ and monitor EBV PCR, and graft organ function\n\nNon-destructive lesions (ICC)/ Hyperplasia (WHO5)g\n\nReduction of immunosuppression (RIS)g\n\nPartial response, persistent or progressive disease\n\nRituximab and monitor EBV PCRn\n\nPartial response, persistent or progressive disease\n\nNon-destructive lesions (ICC)/ Hyperplasia (WHO5)g\n\n3 NCCN Guidelines Version 1.2026 Post-Transplant Lymphoproliferative Disorders\n\nFOLLOW-UP/SECOND-LINE THERAPY\n\nManage immunosuppression™ and monitor EBV PCR, and graft organ function\n\nComplete response\n\nManage immunosuppression™ and monitor EBV PCRn and graft organ function\n\nPartial response, persistent or progressive disease\n\nRituximab and monitor EBV PCRn\n\nMonomorphic PTLD → RIS, if possible and/or: → Rituximab alone; or → Chemoimmunotherapy; or → Chemoimmunotherapy; or → Partial response, persistent or progressive disease\n\nNon-destructive lesions (ICC)/ Hyperplasia (WHO5)g\n\nOther than reduction of RIS, there are no established treatments. HDT/ASCR may not be appropriate. → Consider chemotherapy (See NCCN Guidelines for T-Cell Lymphomas)\n\nComplete response\n\nSee appropriate histologic subtype for follow-up\n\nIf RIS was initial therapy, then Rituximab or chemoimmunotherapy; or If rituximab monotherapy was initial therapy, then chemoimmunotherapy; or consider Rituximab for patients with partial response and IPI 0-2° or or If chemoimmunotherapy was initial therapy, see BCEL-7 or Clinical trial or Immunotherapy with EBV-Specific Cytotoxic T-Cell Lymphomas)\n]() $^{9}$ Non-destructive lesions in the ICC Classification are of B-cell type and include PCH, infectious mononucleosis, and florid follicular hyperplasia.

h Treatment is based on the unique histology.

i Response to RIS is variable and patients need to be closely monitored; RIS should be coordinated with the transplant team. RIS: Reduction in calcineurin inhibition (cyclosporin and tacrolimus), discontinuation of antimetabolic agents (azathioprine and mycophenolate mofetil), and for patients who are critically ill all non-glucocorticoid immunosuppression should be discontinued.

$^{1}$ As part of a step-wise approach in patients who are not highly symptomatic or cannot tolerate chemotherapy secondary to comorbidity.

$^{e}$ For concurrent or sequential chemoimmunotherapy, see Suggested Treatment Regimens (PTLD-A).

$^{1}$ Restage in 2 to 4 weeks.

$^{m}$ Re-escalation of immunosuppressive therapy should be individualized, taking into account the extent of initial RIS and the nature of the organ allograft. These decisions should be made in conjunction with the transplant team.

$^{n}$ Monitoring EBV PCR viral load may have utility but frequency and duration of monitoring are undefined.

° Zimmermann H, Koenecke C, Dreyling MH, et al. Modified risk-stratified sequential treatment (subcutaneous rituximab with or without chemotherapy) in B-cell post-transplant lymphoproliferative disorder (PTLD) after solid organ transplantation (SOT): the prospective multicentre phase II PTLD-2 trial. Leukemia 2022;36:2468-2478.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Post-Transplant Lymphoproliferative Disorders

NCCN Guidelines Index Table of Contents Discussion

![PTLD SUBTYPE\n\nFIRST-LINE THERAPY\n\nINITIAL RESPONSE$^{1}$\n\nFOLLOW-UP/SECOND-LINE THERAPY\n\nPolymorphic PTLD (B-cell type) (ICC/ WHO5)\n\nLocalized\n\n$^{1}$R, if possible$^{1}$ and: $^{2}$Rituximab alone or $^{3}$Chemoimmunotherapy$^{2}$Colummunotherapy$^{3}$\n\nComplete response $^{4}$\n\n$^{1}$Protaient response $^{5}$\n\n$^{1}$Protaient response $^{6}$\n\n$^{1}$Protaient response $^{7}$\n\n$^{1}$Protaient response $^{8}$\n\n$^{1}$Protaient response $^{9}$\n\n$^{1}$Protaient response $^{1}$Protaient response $^{1}$Protaient response $^{1}$Protaient response $^{1}$Protaient response $^{1}$Protaient response $^{1}$Protaient response $^{1}$Protaient response $^{1}$Protaient response $^{1}$Protaient response $^{1}$Protaient response $^{1}$Protaient response $^{1}$Protaient response $^{1}$Protaient response $^{1}$Protaient response $^{1}$Protaient response $^{1}$Protaient response $^{1}$Protaient response $^{1}$Protaient response $^{1}$Protaient response $^{1}$Protaient response $^{1}$Protaient response $^{1}$Protaient response $^{1}$Protaient response $^{1}$Protaient response $^{1}$Protaient response $^{1\n](1/parseimages/figure9eaab338c57949aa8b4d602a92ad0f3a_0_4.png) $^{1}$ Response to RIS is variable and patients need to be closely monitored; RIS should be coordinated with the transplant team. RIS: Reduction in calcineurin inhibition (cyclosporin and tacrolimus), discontinuation of antimetabolic agents (azathioprine and mycophenolate mofetil), and for patients who are critically ill all non-glucocorticoid immunosuppression should be discontinued.

* For concurrent or sequential chemoimmunotherapy, see Suggested Treatment Regimens (PTLD-A).

$^{1}$ Restage in 2 to 4 weeks.

$^{n}$ Monitoring EBV PCR viral load may have utility but frequency and duration of monitoring are undefined.

P Principles of Radiation Therapy (NHODG-D).

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 1.2026

Post-Transplant Lymphoproliferative Disorders

NCCN Guidelines Index Table of Contents Discussion

MONOMORPHIC PTLD (B-CELL TYPE) AND POLYMORPHIC PTLD (B-CELL TYPE)Sequential chemoimmunotherapy

• Rituximab 375 mg/m2 weekly x 4 weeksb

Restage with PET/CT scan (in 2–4 weeks)

◊ If PET/CT scan negative (5-PS: 1–3), Rituximab 375 mg/m2 every 3 weeks x 4 cycles

◊ If PET/CT scan positive (5-PS: 4–5), CHOP + Rituximab every 3 weeks + G-CSF x 4 cycles†

Concurrent chemoimmunotherapy

• Pola-R-CHP (≥ IPI 2)

• CHOP + Rituximab

• For patients who are frail who cannot tolerate anthracycline, no specific regimen has been identified but options may includec:CEOP + Rituximab

CVP + Rituximab

GCVP + Rituximab

PRIMARY CNS PTLD (B-CELL TYPE)a

• High-dose Methotrexated + Rituximab

PTLD-A

a An FDA-approved biosimilar is an appropriate substitute for any recommended systemic biologic therapy in the NCCN Guidelines. Rituximab and hyaluronidase

human injection for subcutaneous use may be substituted for rituximab after patients have received the first full dose of rituximab by intravenous infusion.

b Trappe R, Dierickx D, Zimmermann H, et al. Response to rituximab induction is a predictive marker in B-cell post-transplant lymphoproliferative disorder and allows successful stratification into rituximab or R-CHOP consolidation in an international, prospective, multicenter phase II trial. J Clin Oncol 2017;35:536-543.

c There are no published data regarding the use of these regimens; however, they are used at NCCN Member Institutions for the treatment of PTLD.d Patients with PTLD often have renal insufficiency. High-dose methotrexate should be used with caution. Alternate regimens (cytarabine-based) should be considered.

Note: All recommendations are category 2A unless otherwise indicated.

SUGGESTED TREATMENT REGIMENSa (in alphabetical order)

Consider prophylaxis for tumor lysis syndrome (NHODG-B)See monoclonal antibody and viral reactivation (NHODG-B)

† If 5-PS: 5 because of new sites of disease or clear progression, treat as refractory disease.

NCCN Guidelines Version 1.2026 B-Cell Lymphomas

NCCN Guidelines Index Table of Contents Discussion

Note: All recommendations are category 2A unless otherwise indicated.

NHODG-A 1 OF 8 USE OF IMMUNOPHENOTYPING/MOLECULAR ANALYSIS IN DIFFERENTIAL DIAGNOSIS OF MATURE B-CELL AND NK/T-CELL

NEOPLASMSa

(TO BE USED IN CONJUNCTION WITH CLINICAL AND MORPHOLOGIC CORRELATION)

General Principles

• Morphology ± clinical features drive both the choice and the interpretation of special studies.

• Differential diagnosis is based on morphology ± clinical setting.

• Begin with a broad panel appropriate to morphologic diagnosis, limiting panel of antibodies based on the differential diagnosis.

Avoid “shotgun” panels of unnecessary antibodies unless a clinically urgent situation warrants.

• Add antigens in additional panels, based on initial results.

• Follow with molecular analyses as needed.

• Return to clinical picture if immunophenotype + morphology are not specific.

a These are meant to be general guidelines. Interpretation of results should be based on individual circumstances and may vary. Not all tests will be required in every case.

NCCN Guidelines Version 1.2026 B-Cell Lymphomas

NCCN Guidelines Index Table of Contents Discussion

Note: All recommendations are category 2A unless otherwise indicated.

NHODG-A 2 OF 8

a These are meant to be general guidelines. Interpretation of results should be based on individual circumstances and may vary. Not all tests will be required in every

case.

b Some lymphoid neoplasms may lack pan leukocyte (CD45), pan-B, and pan-T antigens. Selection of additional antibodies should be based on the differential diagnosis generated by morphologic and clinical features (eg, plasma cell myeloma, ALK+ DLBCL, plasmablastic lymphoma, anaplastic large cell lymphoma [ALCL], NK-cell

lymphomas).

c Usually 1 pan-B (CD20) and 1 pan-T (CD3) markers are done unless a terminally differentiated B-cell or a specific peripheral T-cell lymphoma (PTCL) is suspected.

B-cell antigens positiveb,c (CD19, CD20, CD79a, PAX5)

• Morphology

Cytology

◊ Small cells

◊ Medium-sized cells

◊ Large cells

Pattern

◊ Diffuse

◊ Nodular, follicular, mantle, marginal

◊ Sinuses

• Clinical

Age (child, adult)

Location

◊ Nodal

◊ Extranodal, specific site

• Immunophenotype

Naïve B cells: CD5, CD23, IgD

GCB cells: CD10, BCL6

Follicular dendritic cells (FDC): CD21, CD23

Post-GCB cells: IRF4/MUM1, CD138

Ig heavy and light chains (surface, cytoplasmic, class switch, light chain type)Oncogene products: BCL2, cyclin D1, MYC, BCL6, ALK

Viruses: EBV, HHV8

Other: CD43, Ki-67, LEF1, SOX11

• Molecular Analysis

BCL2, BCL6, CCND1, MYC, ALK, MYD88, BRAF, IRF4, 11q aberrations, Ig

rearrangement

Initial Morphologic, Clinical, and

Immunophenotypic Analysis (NHODG-A 3 of 8)

USE OF IMMUNOPHENOTYPING/MOLECULAR ANALYSIS IN DIFFERENTIAL DIAGNOSIS OF MATURE B-CELL AND NK/T-CELL

NEOPLASMSa

(TO BE USED IN CONJUNCTION WITH CLINICAL AND MORPHOLOGIC CORRELATION)

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

B-Cell Lymphomas

NCCN Guidelines Index Table of Contents Discussion

USE OF IMMUNOPHENOTYPING/MOLECULAR ANALYSIS IN DIFFERENTIAL DIAGNOSIS OF MATURE B-CELL AND NK/T-CELL NEOPLASMSª

(TO BE USED IN CONJUNCTION WITH CLINICAL AND MORPHOLOGIC CORRELATION) INITIAL MORPHOLOGIC, CLINICAL, AND IMMUNOPHENOTYPIC ANALYSIS

![NCCN 授权医脉通提供NCCN指南全文下载。wmlsyy于2025/12/23,21:20在医脉通平台下载,仅供个人使用,严禁分发。2025 美国国家综合癌症网络版权所有。\n\nNCCN Guidelines Index\nTable of Contents\nNCCN\nAncer\nNetwork®\n#USE OF IMMUNOPHENOTYPING/MOLECULAR ANALYSIS IN DIFFERENTIAL DIAGNOSIS OF MATURE B-CELL AND NK/T-CELL NEOPLASMSa\n(TO BE USED IN CONJUNCTION WITH CLINICAL AND MORPHOLOGIC CORRELATION)INITIAL MORPHOLOGIC, CLINICAL, AND IMMUNOPHENOTYPIC ANALYSIS\n\nSmall cells NHODG-A 4 of 8\nMedium-sized cells NHODG-A 5 of 8\nLarge cells ± anaplastic\nmorphology\nCutaneous localization NHODG-A 8 of 8\nLineage based on immunophenotyped\n(Pan-B and Pan-T antigens)\nor\nSuspected by morphology/\nclinical features\nT-cell neoplasms\nSee NCCN Guidelines for T-Cell Lymphomas\n](1/parseimages/figuref8926675b01e48e0b7196ca09285c05a_0_5.png) a These are meant to be general guidelines. Interpretation of results should be based on individual circumstances and may vary. Not all tests will be required in every case.

d Initial panel will often include additional markers based on morphologic differential diagnosis and clinical features.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

B-Cell Lymphomas

NCCN Guidelines Index Table of Contents Discussion

USE OF IMMUNOPHENOTYPING/MOLECULAR ANALYSIS IN DIFFERENTIAL DIAGNOSIS OF MATURE B-CELL AND NK/T-CELL NEOPLASMSª

(TO BE USED IN CONJUNCTION WITH CLINICAL AND MORPHOLOGIC CORRELATION)

![B-CELL NEOPLASMS\n\nSmall cells\n\nPanel: CD5, CD10, CD21, CD23, cyclin D1, BCL2, BCL6, Ki-67, CD11c, (CD25, CD103)$^{e}$\n\nSmall cells\n\nSmall cells: Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL)Mantle cell lymphoma (MCL)Splenic marginal zone lymphoma (SMZL)Hairy cell leukemia (HCL)Lymphoplasmacytic lymphoma (LPL)Lymphoplasmacytic lymphoma (MCL)Extranodal marginal zone lymphoma (EMZL)Nodal marginal zone lymphoma (NMZL)Policular lymphoma (FL)Pediatric-type follicular lymphoma (PTFL)\n\n$^{e}$and $^{a}$These are meant to be general guidelines. Interpretation of results should be based on individual circumstances and may vary. Not all tests will be required in every case. $^{e}$Flow cytometry on blood or bone marrow done only if HCL is in differential diagnosis by morphology. $^{f}$Rare cases of cyclin D1- and $^{c}$ or $^{f}$CMLS and $^{c}$ or $^{f}$CMLS and $^{c}$ or $^{f}$CMLS and $^{c}$ or $^{f}$CMLS and $^{c}$ or $^{f}$CMLS and $^{c}$ or $^{f}$CMLS and $^{c}$ or $^{f}$CMLS and $^{c}$ or $^{f}$CMLS and $^{c}$ or $^{f}$CMLS and $^{c}$ or $^{f}$CMLS and $^{c}$ or $^{f}$CMLS and $^{c}$ or $^{f}$CMLS and $^{c}$ or $^{f}$CMLS and $^{c}$ or $^{f}$CMLS and $^{c}$ or $^{f}$CMLS and $^{c}$ or $^{f}$CMLS and $^{c}$ or $^{f}$CMLS and $^{c}$ or $^{f}$CMLS and $^{c}$ or $^{f}$CMLS and $^{c}$ or $^{f}$CMLS and $^{c}$ or $^{f}$CMLS and $^{c}$ or $^{f}$CMLS and $^{c}$ or $^{f}$CM\n](1/parseimages/figure8f47437a19bd4bde9634fe67c0851a20_0_5.png) a These are meant to be general guidelines. Interpretation of results should be based on individual circumstances and may vary. Not all tests will be required in every case. e Flow cytometry on blood or bone marrow done only if HCL is in differential diagnosis by morphology. f Rare cases of HCL may be CD10+ or CD5+ and some cases of FL are CD10-. BCL6 is a useful discriminate if needed (rarely). Rare cases of MCL are CD5-. 9 Can be done to confirm if necessary.

h Rare cases of cyclin D1- and t(11;14)-negative MCL have been reported. Consider SOX11 (positive in cyclin D1-negative MCL) and LEF1 (positive in CLL/SLL) IHC. This diagnosis should be made with extreme caution and with expert consultation. $^{1}$ 85% of FL will be BCL2+ or t(14;18)+. $^{2}$ Kappa and lambda light chains; lgG, IgM, and IgA may be helpful. $^{4}$ Splenic diffuse red pulp small B-cell lymphoma (SDRPL) or others.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

B-Cell Lymphomas

NCCN Guidelines Index Table of Contents Discussion

USE OF IMMUNOPHENOTYPING/MOLECULAR ANALYSIS IN DIFFERENTIAL DIAGNOSIS OF MATURE B-CELL AND NK/T-CELL NEOPLASMSª

(TO BE USED IN CONJUNCTION WITH CLINICAL AND MORPHOLOGIC CORRELATION)

![B-CELL NEOPLASMS\n\nDiffuse pattern medium cells ± starry sky pattern$^{1}$\n\nInitial panel: CD5, CD10, cyclin D1, BCL2, BCL6, IRF4/ MUM1, Ki-67m\n\nSee\nWHO Classification of Tumours Editorial Board. Haematolymphoid tumours. (WHO classification of tumours series, 5th ed; vol 11). Lyon (France): International Agency for Research on Cancer; 2024.\nArber DA, Borowitz MJ, Cook JR, et al. The International Consensus Classification of myeloid and lymphoid neoplasms (ed Edition 1); 2025.\nKing RL, Hsi ED, Chan CC, et al. Diagnostic approaches and future directions in Burkitt lymphoma and high-grade B-cell lymphoma Virchows Arch 2023;482:193-205.\n](1/parseimages/figure3469b6014be5472fbad8482171ff3487_0_5.png)

Medium cells

$\bullet$ Burkitt lymphoma (BL)$^{n}$

$\bullet$ MCL, blastoid variant

$\bullet$ High-grade B-cell lymphoma (HGBL), NOS

* HGBL with MYC and BCL2 rearrangements (ICC and WHO-5)

* HGBL with MYC and BCL6 rearrangements (ICC)

* LBCL with 11q aberration [ICC]; HGBL with 11q aberrations [WHO]

ª These are meant to be general guidelines. Interpretation of results should be based on individual circumstances and may vary. Not all tests will be required in every case.

$^{1}$ Starry sky pattern is typically present in BL and frequently in HGBL. If blastoid morphology, exclude LL (usually terminal deoxynucleotidyl transferase+ and often CD34+).

$m$ Ki-67 is a prognostic factor in some lymphomas (eg, mantle cell) and is typically >90% in BL. It is not useful in predicting the presence of MYC rearrangement or in classification.

$^{n}$ Rare MCL may be cyclin D1-. Consider SOX11 IHC.

° Lymphomas resembling BL or HGBL without detectable MYC rearrangement may prompt consideration for LBCL with 11q aberration [ICC]; HGBL with 11q aberrations [WHO]. Chromosomal microarray or FISH may be warranted. Correlation with morphology and clinical features is essential.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

B-Cell Lymphomas

NCCN Guidelines Index Table of Contents Discussion

USE OF IMMUNOPHENOTYPING/MOLECULAR ANALYSIS IN DIFFERENTIAL DIAGNOSIS OF MATURE B-CELL AND NK/T-CELL NEOPLASMSª (TO BE USED IN CONJUNCTION WITH CLINICAL AND MORPHOLOGIC CORRELATION)

B-CELL NEOPLASMS

![Large cells → PanelP: CD5, CD10, BCL6, IRF4/MUM1, Ki-67m CD5- DLBCL, NOS CD5+q CD10+ IRF4/MUM1+ → LBCL with IRF4 rearrangements (Confirm by FISH) CD10+ IRF4/MUM1- → DLBCL, NOS GCB type (BCL6+) CD5- DLBCL\n\nLarge cells: ● Diffuse large B-cell lymphoma (DLBCL), NOS 4GB subtype ● Non-GCB subtype ● PCLBCL of the CNS ● Primary cutaneous DLBCL, leg type ● EBV-positive DLBCL (EBV + DLBCL), NOS ● DLBCL associated with chronic inflammation ● Lymphomatoid granulomatosis ● Primary mediastinal large B-cell lymphoma (PMBL) ● Intravascular LBCL ● ALK-positive LBCL ● Plasmablastic lymphoma ● HHV8+ LBCL, NOS 4GB with IRF4 rearrangement ● HHV8+ LBCL, NOS 4GB with IRF4 rearrangement ● Primary effusion lymphoma (PEL) ● Mediastinal gray zone lymphoma (MGZL) ● MCL, pleomorphic variant ● MCL, pleomorphic variant ● NCCN 2010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010\n](1/parseimages/figure383caa97bc974699b2bfda68b183b0d7_0_6.png) Continued

$\bullet$ Intravascular LBCL

$\bullet$ ALK-positive LBCL

$\bullet$ Plasmablastic lymphoma

$\cdot$ HHV8+ LBCL, NOS

$\bullet$ LBCL with IRF4 rearrangement

* Primary effusion lymphoma (PEL)

$\bullet$ Mediastinal gray zone lymphoma (MGZL)

$\bullet$ MCL, pleomorphic variant

ª These are meant to be general guidelines. Interpretation of results should be based on individual circumstances and may vary. Not all tests will be required in every case.

P CD5 is included to identify pleomorphic MCL; if CD5 is positive, cyclin D1 staining is done to confirm or exclude MCL.

$^{9}$ Consider SOX11 IHC to exclude cyclin D1-negative pleomorphic MCL.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

B-Cell Lymphomas

NCCN Guidelines Index Table of Contents Discussion

USE OF IMMUNOPHENOTYPING/MOLECULAR ANALYSIS IN DIFFERENTIAL DIAGNOSIS OF MATURE B-CELL AND NK/T-CELL NEOPLASMSª (TO BE USED IN CONJUNCTION WITH CLINICAL AND MORPHOLOGIC CORRELATION)

![LARGE CELLS\n(continued)\n\nCD30 - T-cell-rich $\rightarrow$ THRLBCL (May be BCL6+, IRF4/MUM1-)\n\nEBER- Mediastinal $\rightarrow$ PMBL (May be BCL6+, IRF4/MUM1-)\n\nCD30 + + Morphologically borderline with CHL $\uparrow$ CD15- $\rightarrow$ PMBL (May be BCL6, INGCB, NOS\n\nCAD20+ (PAX5+)\n\nEDB+ 3D30 - DLBCL, non-GCB\n\nMediastinal $\rightarrow$ PMBL (May be BCL6+, IRF4/MUM1-)\n\nDCLBCL, non-GCB\n\nMediastinal $\rightarrow$ PMBL (May be BCL6+, IRF4/MUM1-)\n\nMorphologically borderline with CHL $\uparrow$ CD15+ $\rightarrow$ HGBL, NOS\n\nEDB+ 3D30 - EDBCL\n\nEDB+ 3D30 + + Morphologically borderline with CHL $\uparrow$ CD15+ $\rightarrow$ HGBL, NOS\n\nCD20+ (PAX5+)\n\nEDB+ 3D30 + EDBCL\n\nEDB+ 3D30 + EDBCL\n\nEDB+ 3D30 + EDBCL\n\nEDB+ 3D30 + EDBCL\n\nEDB+ 3D30 + EDBCL\n\nEDB+ 3D30 + EDBCL\n\nEDB+ 3D30 + EDBCL\n\nEDB+ 3D30 + EDBCL\n\nEDB+ 3D30 + EDBCL\n\nEDB+ 3D30 + EDBCL\n\nEDB+ 3D30 + EDBCL\n\nEDB+ 3D30 + EDBCL\n\nEDB+ 3D30 + EDBCL\n\nEDB+ 3D30 + EDBCL\n\nEDB+ 3D30 + EDBCL\n\nEDB+ 3D30 + EDBCL\n\nEDB+ 3D30 + EDBCL\n\nEDB+ 3D30 + EDBCL\n\nEDB+ 3D30 + EDBCL\n\nEDB+ 3D30 + EDBCL\n\nEDB+ 3D30 + EDBCL\n\nEDB+ 3D30 + EDBCL\n\nEDB+ 3D30 + EDBCL\n\nEDB+ 3D30 + ED\n](1/parseimages/figure55bc083e026542e38e08c2581eb0ca64_0_5.png) a These are meant to be general guidelines. Interpretation of results should be based on individual circumstances and may vary. Not all tests will be required in every case.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

B-Cell Lymphomas

NCCN Guidelines Index Table of Contents Discussion

USE OF IMMUNOPHENOTYPING/MOLECULAR ANALYSIS IN DIFFERENTIAL DIAGNOSIS OF MATURE B-CELL AND NK/T-CELL NEOPLASMSª (TO BE USED IN CONJUNCTION WITH CLINICAL AND MORPHOLOGIC CORRELATION)

B-CELL NEOPLASMS

![Cutaneous localization\n\n| Panel: CD3, CD5, CD10, r BCL2, BCL6, r IRF4/MUM1, CD21/23 (FDC markers)\n\n| BCL2 - BCL6 - (positive GC) | IRF4/MUM1+/- (FDC + follicular, disrupted) | PCMZL | Small/medium/large cells | Many CD3+ cells | BCL6 - (positive GC) | IRF4/MUM1+/- (FDC + follicular, disrupted) | PCMZL | Small/medium cells | Larger cells in GC) | PCFCL | BCL2 strongly + BCL6+/- BCL6+/- RIF4/MUM1+ (FDC-) | Large round cells | FCD-) | Large round cells | Few CD3+ T cells | BCL6 - (positive GC) | IRF4/MUM1+/- (FDC + follicular, disrupted) | PCMZL | Small/medium cells | BCL2 weakly + BCL6+ | BCL6+ / (FDC±, follicular) | PCFCL | Primary cutaneous follicle center lymphoma (PCFCL) | Primary cutaneous DLBCL, leg type (PC-DLBCL, leg type) | 1. These are meant to be general guidelines. Interpretation of results should be based on individual circumstances and may vary. Not all tests will be required in every case. | These are assessed both in follicles (if present) and in intrafollicular/diffuse areas. CD10+ BCL6 + GCs are present in PCMZL, while both follicular and interfollicular/diffuse areas (tumor cells) are positive for BCL6+/- CD10 in PCFCL | Note: All recommendations are category 2A unless otherwise indicated.\n](1/parseimages/figurefdb1cb7ae6d54e37baa866541a9cf290_0_6.png) ª These are meant to be general guidelines. Interpretation of results should be based on individual circumstances and may vary. Not all tests will be required in every case. $^{a}$ These are assessed both in follicles (if present) and in intrafollicular/diffuse areas. CD10+ BCL6 + GCs are present in PCMZL, while both follicular and interfollicular/diffuse areas (tumor cells) are positive for BCL6+/- CD10 in PCFCL.

Note: All recommendations are category 2A unless otherwise indicated.

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SUPPORTIVE CARE FOR B-CELL LYMPHOMAS

Tumor Lysis Syndrome (TLS)

* Laboratory hallmarks of TLS:

$\bullet$ High potassium

$\bullet$ High uric acid

$\bullet$ High phosphorous

$\bullet$ Low calcium

* Symptoms of TLS:

$\bullet$ Nausea and vomiting, shortness of breath, irregular heartbeat, clouding of urine, lethargy, and/or joint discomfort

* TLS features:

$\bullet$ Consider TLS prophylaxis for patients with the following risk factors:

* Hintologies of BL and LL; occasionally DLBCL

* ◆ Spontaneous TLS

* O elevated white blood cell (WBC) count

* $\triangle$ Bone marrow involvement

* Pre-existing elevated uric acid

$\bullet$ Ineffectiveness/intolerance of allopurinol

* Renal disease or renal involvement by tumor

$\bullet$ Treatment of TLS:

$\bullet$ TLS is best managed if anticipated and treatment is started prior to chemotherapy.

* Centerpiece of treatment includes:

* ñ Rigorous hydration

* Management of hyperuricemia

◇ Frequent monitoring of electrolytes and aggressive correction (essential)

$\bullet$ First-line and at retreatment for hyperuricemia.

◇ Glucose-6-phosphate dehydrogenase (G6PD) testing is required prior to use of rasburicase. Rasburicase is contraindicated in patients with a history consistent with G6PD. In these patients, rasburicase should be substituted with allopurinol.

◇ Low-risk disease:

Allopurinol or febuxostat beginning 2-3 days prior to chemoimmunotherapy and continued for 10-14 days

◇ Intermediate-risk disease: Stage I/II and LDH <2X ULN:

> Allopurinol or febuxostat

Rasburicase if renal dysfunction and uric acid, potassium, and/or phosphate >ULN

$\bullet$ High-risk disease: Stage III/IV and/or LDH ≥2X ULN: Rasburicase

$\bullet$ Rasburicase (doses of 3-6 mg are usually effective).$^{9}$ One dose of rasburicase is frequently adequate. Re-dosing should be individualized and is indicated for patients with any of the following risk factors:

◇ Urgent need to initiate therapy in a high-bulk patient

$\bullet$ Situations where adequate hydration may be difficult or impossible

◇ Acute renal failure

* If TLS is untreated, its progression may cause acute kidney failure, cardiac arrhythmias, seizures, loss of muscle control, and death.

ª There are data to support that fixed-dose rasburicase is very effective in adult patients.

Continued

Note: All recommendations are category 2A unless otherwise indicated.

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SUPPORTIVE CARE FOR B-CELL LYMPHOMAS

For other immunosuppressive situations, see NCCN Guidelines for Prevention and Treatment of Cancer-Related Infections.

Viral Reactivation

Hepatitis B virus (HBV):

$\bullet$ Anti-CD20 mAb-based chemoimmunotherapy is associated with risk of HBV reactivation. Hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (HBcAb) testing for all patients receiving anti-CD20 mAb therapy

$\bullet$ Quantitative hepatitis B viral load by PCR and surface antibody only if one of the screening tests is positive

$\bullet$ Note: Patients receiving IV immunoglobulin (IVIG) may be HBcAb-positive as a consequence of IVIG therapy.

$\bullet$ Prophylactic antiviral therapy with entecavir is recommended for any patient who is HBsAg-positive and receiving anti-lymphoma therapy. If there is active disease (PCR+), it is considered treatment management and not prophylactic therapy. In cases of HBcAb positivity, prophylactic antiviral therapy is preferred; however, if there is a concurrent high-level hepatitis B surface antibody, these patients may be monitored with serial hepatitis B viral load.

$\bullet$ Entecavir is preferred$^{e}$

$\bullet$ Avoid lamivudine due to risks of resistance development.

$\bullet$ Other antivirals including adefovir, telbivudine, and tenofovir are proven active treatments and are acceptable alternatives.

$\bullet$ Monitor hepatitis B viral load with PCR monthly through treatment and every 3 months thereafter.

$\bullet$ If viral load is consistently undetectable, treatment is considered prophylactic.

$\bullet$ If viral load fails to drop or previously undetectable PCR becomes positive, consult hepatologist and discontinue anti-CD20 mAb therapy.

$\bullet$ Maintain prophylaxis up to 12 months after oncologic treatment ends

$\bullet$ Consult with hepatologist for duration of therapy in patient with active HBV.

Hepatitis C virus (HCV):

$\bullet$ New evidence from large epidemiologic studies, molecular biology research, and clinical observation supports an association between HCV and B-cell non-Hodgkin lymphoma (NHL). Recently approved direct-acting antiviral (DAA) agents for chronic carriers of HCV with genotype 1 demonstrated a high rate of sustained viral responses.

$\bullet$ Low-grade B-cell NHL

$\bullet$ According to the American Association for the Study of Liver Diseases, combined therapy with DAA agents should be considered in asymptomatic patients with HCV genotype 1 since this therapy can result in regression of lymphoma.

* Aggressive B-cell NHL

$\bullet$ Patients should be initially treated with chemoimmunotherapy regimens as outlined in these guidelines.

◇ Liver functional tests and serum HCV RNA levels should be closely monitored during and after chemoimmunotherapy for development of hepatotoxicity.

$\bullet$ Antiviral therapy should be considered in patients in complete remission after completion of lymphoma therapy.

John Cunningham virus (JCV) Reactivation:

$\bullet$ Brentuximab vedotin (anti-CD30 antibody-drug conjugate) can cause JCV reactivation and progressive multifocal leukoencephalopathy (PML)

$\bullet$ PML is usually fatal. Clinical indications may include changes in behavior such as confusion, dizziness or loss of balance, difficulty talking or walking, and vision problems.

$\bullet$ Diagnosis made by PCR of cerebrospinal fluid and in some cases brain biopsy.

$\bullet$ No known effective treatment.

Continued

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B-Cell Lymphomas

NCCN Guidelines Index Table of Contents Discussion

SUPPORTIVE CARE FOR B-CELL LYMPHOMAS$^{c}$

Additional Rare Complications of Monoclonal Antibody Therapy

* See NHODG-B 2 of 5 for Monoclonal Antibody Therapy and Viral Reactivation

* Rare complications such as mucocutaneous reactions including paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis can occur. Expert consultation with dermatology is recommended.

* Consider premedication to reduce infusion-related reactions associated with mAbs. Second-generation antihistamines have longer half-lives and are better tolerated.

$\bullet$ Re-challenge with the same mAb is not recommended in patients experiencing rare complications to chosen anti-CD20 mAb (rituximab, obinutuzumab, or ofatumumab). An alternative anti-CD20 mAb (eg, obinutuzumab) could be used for patients with intolerance to rituximab, including those experiencing severe hypersensitivity reactions requiring discontinuation of chosen anti-CD20 mAb, regardless of histology. d It is unclear that the use of alternative anti-CD20 mAb poses the same risk of recurrence.

Rituximab and Obinutuzumab Rapid Infusion

* If no infusion reactions were experienced with prior cycle of rituximab or obinutuzumab, e a rapid infusion over 90 minutes can be used.

Rituximab-Related Neutropenia

$\bullet$ Late-onset neutropenia (weeks to months after last exposure) occurs in up to 20% of patients

$\bullet$ It can be severe, but patients usually do not present with infections and can be initially observed for spontaneous recovery

$\bullet$ A short course of G-CSF is indicated for prolonged neutropenia

$\bullet$ IVIG has been anecdotally successful in patients with neutropenia that is refractory to G-CSF

Obinutuzumab-Related Neutropenia

$\bullet$ Late-onset neutropenia can be seen in up to 20% of patients

$\bullet$ Early-onset neutropenia is a risk with obinutuzumab monotherapy as well as with combination chemotherapy or targeted agents

$\bullet$ Neutropenia is responsive to growth factors

Management of Methotrexate Toxicity

* If a patient receiving high-dose methotrexate experiences delayed elimination due to renal impairment, glucarpidase is strongly recommended when:

$\blacktriangleright$ plasma methotrexate concentrations are two standard deviations above the mean expected plasma concentration as determined by MTXPK.org; or

$\bullet$ plasma methotrexate level is >30 µM at 36 hours, >10 µM at 42 hours, or >5 µM at 48 hours.

$\bullet$ Optimal administration of glucarpidase is within 48 to 60 hours from the start of methotrexate infusion. Leucovorin should be continued for at least 2 days following glucarpidase administration and should be administered at least 2 hours before or 2 hours after the dose of glucarpidase.

c Supportive care measures specific to rituximab include both rituximab as well as rituximab biosimilars.

d Castillo JJ, et al. Br J Haematol 2016;174:645-648; Ghione P, et al. J Clin Oncol 2020;38:Abstract 8062.

e Canales MA, et al. J Clin Oncol 2021;39:Abstract 7545; Ohmachi K, et al. Jpn J Clin Oncol 2018;48:736-742; Sharman JP, et al. Leuk Lymphoma 2019;60:894-903. Zelenetz AD, et al. Blood 2019;133:1964-1976.

Note: All recommendations are category 2A unless otherwise indicated.

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SUPPORTIVE CARE FOR B-CELL LYMPHOMAS

Special Considerations for Adolescent and Young Adult (AYA) Patients with B-Cell Lymphomas

• See NCCN Guidelines for Adolescent and Young Adult (AYA) Oncology for comprehensive initial evaluations and more details on fertility/

fertility preservation and psychosocial assessments in AYA patients.

• The use of dexrazoxane as a cardioprotectant in combination with first-line therapy is not recommended in AYA patients >18 y.

• Consider toxicity of RT, particularly in young females with mediastinal disease.

• Younger AYA patients may be eligible to participate in pediatric clinical trials. See NCCN Guidelines for Pediatric Aggressive Mature B-Cell

Lymphomas.

Immunizations

• See NCCN Guidelines for Survivorship - General Principles of Immunizations.

• COVID-19 vaccination: See CDC for Use of COVID-19 Vaccines in the US.

Anti-Infective Prophylaxis

• Prophylaxis for Pneumocystis Jiroveci Pneumonia (PJP) and Varicella-Zoster Virus (VZV): See NCCN Guidelines for Prevention and

Treatment of Cancer-Related Infections.

• Pemivibart for pre-exposure prophylaxis of COVID-19 for individuals with moderate to severe immunocompromise

Hypogammaglobulinemia

• Patients receiving anti-CD20 mAb and CAR T-cell (CD19–directed) therapy may experience hypogammaglobulinemia. Patients with

recurrent infections may benefit from IVIG replacement.

Continued

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SUPPORTIVE CARE FOR B-CELL LYMPHOMAS

Bone Health: Recommendations for Patients Who Have Received Steroid-Containing Regimensf,g,hi (in addition to standard recommendations for screening)

* Evaluation

$\bullet$ Vitamin D, 25-OH level

$\bullet$ Post-treatment bone mineral density (BMD) evaluation (1 year following therapy)

$\bullet$ Greatest risk in patients with chemotherapy-induced premature menopause

- If osteopenic (T-score between -1.1 and -2.4):

$\bullet$ Use Fracture Risk Assessment Tool (FRAX) to determine if drug therapy is necessary (https://www.sheffield.ac.uk/FRAX/)

- 20% risk for any major osteoporotic fracture or 3% risk for hip fracture are the thresholds where drug therapy is recommended

- If T-score -2 to -2.4 (at any site) or ongoing glucocorticoid exposure repeat BMD every 1-2 years, as long as risk factors persist.$^{1}$

- If T-score -1.5 to -1.9 (at any site) with no risk factors, repeat BMD in 5 years$^{9}$

* Consider diagnosis of avascular necrosis (AVN) in patients who have received corticosteroids presenting with hip pain. See NCCN Guidelines for Survivorship.

* Therapy

$\bullet$ If vitamin D 25-OH is deficient, then replete.

◇ In patients with lymphoma with current elevations in 1,25-dihydroxyvitamin D, deficient 25(OH)D levels should not be aggressively replaced.

$\bullet$ Calcium intake from food (plus supplements if necessary) should be commensurate with National Academy of Medicine recommendations except in cases of lymphoma-induced hypercalciuria/hypercalcemia due to excessive 1,25-dihydroxyvitamin D production.

◇ In patients receiving corticosteroid-containing chemotherapy regimens, adequate calcium intake is of paramount importance since corticosteroids block calcium absorption and increase fracture risk.$^{k}$

$\bullet$ Patients with osteoporotic BMD, with a history of hip or vertebral fractures, or with asymptomatic vertebral compression deformity (as seen on CT scan or other imaging) should be started on therapy as per National Osteoporosis Foundation guidelines; referral to an endocrinologist with expertise in bone health is recommended.

* In appropriate patients with premature menopause, hormone replacement therapy up until the expected time of natural menopause, or raolifene could be considered.

$\bullet$ Bisphosphonates should be used as first-line pharmacologic treatment for osteoporosis.

In patients who cannot tolerate or whose symptoms do not improve with bisphosphonate therapy, denosumab is an effective alternative medication to prevent osteoporotic fractures.

- Teriparatide is contraindicated in patients with a history of RT; also, theoretical concerns in patients with a recent history of cancer exist.

f Crandall CJ, Newberry SJ, Diamant A, et al. Comparative effectiveness of pharmacologic treatments to prevent fractures: an updated systematic review. Ann Intern Med 2014;161:711-723.

$^{9}$ MacLean C, Newberry S, Maglione M, et al. Systematic review: comparative effectiveness of treatments to prevent fractures in men and women with low bone density or osteoporosis. Ann Intern Med 2008;148:197-213.

h Cummings SR, San Martin J, McClung MR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med 2009;361:756-765. [published correction appears in N Engl J Med 2009;361:1914].

i Paccou L, Merlusca I, Henry-Desailly A, et al. Alterations in bone mineral density and bone turnover markers in newly diagnosed adults with lymphoma receiving chemotherapy: a 1-year prospective pilot study. Ann Oncol 2014;25:481-486.

`j` https://www.uptodate.com/contents/screening-for-osteoporosis?source=see_link.

k Van Staa TP, Leufkens HG, Abenhaim L, et al. Use of oral corticosteroids and risk of fractures. J Bone Miner Res 2005;20:1487-1494.

Note: All recommendations are category 2A unless otherwise indicated.

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B-Cell Lymphomas

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LUGANO RESPONSE CRITERIA FOR NON-HODGKIN LYMPHOMA PET should be done with contrast-enhanced diagnostic CT and can be done simultaneously or at separate procedures.

|Response|Site|PET-CT (Metabolic response)|CT (Radiologic response)$^{d}$| |---|---|---|---| |Complete response|Lymph nodes and extralymphatic sites|Score 1, 2, 3ª with or without a residual mass on 5-point scale (5-PS)$^{b,c}$|All of the following: Target nodes/nodal masses must regress to ≤1.5 cm in longest transverse diameter of a lesion (LDi) No extralymphatic sites of disease| |Complete response|Non-measured lesion|Not applicable|Absent| |Complete response|Organ enlargement|Not applicable|Regress to normal| |Complete response|New lesions|None|None| |Complete response|Bone marrow|No evidence of FDG-avid disease in marrow|Normal by morphology; if indeterminate and flow cytometry IHC negative| |Partial response|Lymph nodes and extralymphatic sites|Score 4 or $5^{b}$ with reduced uptake compared with baseline. No new progressive lesions. At interim these findings suggest responding disease. At end of treatment these findings may indicate residual disease.|All of the following: ≥50% decrease in SPD of up to 6 target measurable nodes and extranodal sites When a lesion is too small to measure on CT, assign 5 mm x 5 mm as the default value. When no longer visible, 0x0 mm For a node >5 mm x 5 mm, but smaller than normal, use actual measurement for calculation| |Partial response|Non-measured lesion|Not applicable|Absent/normal, regressed, but no increase| |Partial response|Organ enlargement|Not applicable|Spleen must have regressed by >50% in length beyond normal| |Partial response|New lesions|None|None| |Partial response|Bone marrow|Residual uptake higher than update in normal marrow but reduced compared with baseline (diffuse uptake compatible with reactive changes from chemotherapy allowed). If there are persistent focal changes in the marrow in the content of a nodal response, consider further evaluation with biopsy, or an interval scan.|Not applicable|

Reprinted with permission. © 2014 American Society of Clinical Oncology. All rights reserved. Cheson B, Fisher R, Barrington S, et al. Recommendations for initial evaluation, staging and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol 2014;32:3059-3068.

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LUGANO RESPONSE CRITERIA FOR NON-HODGKIN LYMPHOMA PET should be done with contrast-enhanced diagnostic CT and can be done simultaneously or at separate procedures.

|Response|Site|PET-CT (Metabolic response)|CT (Radiologic response)$^{d}$| |---|---|---|---| |No response or stable disease|Target nodes/ nodal masses, extranodal lesions|Score 4 or $5^{b}$ with no significant change in FDG uptake from baseline at interim or end of treatment. No new or progressive lesions.|<50% decrease from baseline in SPD of up to 6 dominant, measurable nodes and extranodal sites; no criteria for progressive disease are met| |No response or stable disease|Non-measured lesion|Not applicable|No increase consistent with progression| |No response or stable disease|Organ enlargement|Not applicable|No increase consistent with progression| |No response or stable disease|New lesions|None|None| |No response or stable disease|Bone marrow|No change from baseline|Not applicable| |Progressive disease|Individual target nodes/ nodal masses, extranodal lesions|Score 4 or $5^{b}$ with an increase in intensity of uptake from baseline and/or New FDG-avid foci consistent with lymphoma at interim or end-of-treatment $assessment^{e}$|Requires at least one of the following PPD progression: An individual node/lesion must be abnormal with: LDi >1.5 cm and Increase by ≥50% from PPD nadir and An increase in LDi or SDi from nadir 0.5 cm for lesions ≤2 cm 1.0 cm for lesions >2 cm In the setting of splenomegaly, the splenic length must increase by >50% of the extent of its prior increase beyond baseline. If no prior splenomegaly, must increase by at least 2 cm from baseline New or recurrent splenomegaly| |Progressive disease|Non-measured lesion|None|New or clear progression of preexisting nonmeasured lesions| |Progressive disease|New lesions|New FDG-avid foci consistent with lymphoma rather than another etiology (eg, infection, inflammation). If uncertain regarding etiology of new lesions, biopsy or interval scan may be $considered^{e}$|Regrowth of previously resolved lesions A new node >1.5 cm in any axis A new extranodal site >1.0 cm in any axis; if <1 cm in any axis, its presence must be unequivocal and must be attributable to lymphoma Assessable disease of any size unequivocally attributable to lymphoma| |Progressive disease|Bone marrow|New or recurrent FDG-avid foci|New or recurrent involvement|

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LUGANO RESPONSE CRITERIA FOR NON-HODGKIN LYMPHOMA

evaluation, staging and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol 2014;32:3059-3068.

Footnotesa Score 3 in many patients indicates a good prognosis with standard treatment, especially if at the time of an interim scan. However, in trials involving PET where deescalation is investigated, it may be preferable to consider score 3 as an inadequate response (to avoid under-treatment).

b See PET Five-Point Scale (5-PS).c It is recognized that in Waldeyer’s ring or extranodal sites with high physiological uptake or with activation within spleen or marrow, e.g. with chemotherapy or

myeloid colony stimulating factors, uptake may be greater than normal mediastinum and/or liver. In this circumstance, CMR may be inferred if uptake at sites of initial involvement is no greater than surrounding normal tissue even if the tissue has high physiological uptake.

d FDG-avid lymphomas should have response assessed by PET-CT. Diseases that can typically be followed with CT alone include CLL/SLL and marginal zone

lymphomas.

e False-positive PET scans may be observed related to infectious or inflammatory conditions. Biopsy of affected sites remains the gold standard for confirming new or persistent disease at end of therapy.

PET Five-Point Scale (5-PS)

1 No uptake above background

2 Uptake ≤ mediastinum

3 Uptake > mediastinum but ≤ liver

4 Uptake moderately > liver

5 Uptake markedly higher than liver and/or new lesions X New areas of uptake unlikely to be related to lymphoma

SPD – Sum of the product of the perpendicular diameters for multiple lesions

LDi – Longest transverse diameter of a lesion

SDi – Shortest axis perpendicular to the LDi

PPD – Cross product of the LDi and perpendicular diameter

Measured dominant lesions – Up to 6 of the largest dominant nodes, nodal masses and extranodal lesions selected to be clearly measurable in 2 diameters. Nodes should preferably be from disparate regions of the body, and should include, where applicable, mediastinal and retroperitoneal areas. Non-nodal

lesions include those in solid organs, eg, liver, spleen, kidneys, lungs, etc, gastrointestinal involvement, cutaneous lesions of those noted on palpation.

Non-measured lesions – Any disease not selected as measured, dominant disease and truly assessable disease should be considered not measured. These sites include any nodes, nodal masses, and extranodal sites not selected as dominant, measurable or which do not meet the requirements for measurability,

but are still considered abnormal. As well as truly assessable disease which is any site of suspected disease that would be difficult to follow quantitatively with measurement, including pleural effusions, ascites, bone lesions, leptomeningeal disease, abdominal masses and other lesions that cannot be

confirmed and followed by imaging.

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PRINCIPLES OF RADIATION THERAPY

Continued

a See references on NHODG-D 4 of 4.

General Principlesa

• Treatment with photons, electrons, or protons is appropriate depending upon clinical scenario.

• Advanced RT technologies such as intensity-modulated RT (IMRT)/volumetric modulated arc therapy (VMAT),1-4 proton therapy,3,5-9 breathhold10-12 or respiratory gating,13 and/or image-guided therapy12 may offer significant and clinically relevant advantages in specific instances to spare organs at risk (OARs) such as the heart (including coronary arteries and valves), lungs,14,15 kidneys, liver, spinal cord, esophagus,bone marrow, breasts, stomach, muscle/soft tissue, and salivary glands to decrease the risk for late, normal tissue toxicity while still

achieving the primary goal of local tumor control.

• Reducing dose to normal tissues reduces the risk of late complications. Achieving highly conformal dose distributions is especially

important for patients who are being treated with curative intent or who have long life expectancies following therapy.

• For mediastinal and abdominal lymphoma, respiratory motion management such as gating or breath-hold techniques may be advantageous.

Breath-hold techniques have been shown to decrease incidental dose to the heart and lungs in many disease presentations.10-12 Similarly,

for abdominal lymphomas, reduction in radiation exposures to heart, liver, and kidneys may be achieved by motion management

techniques.16

• Since the advantages of these techniques include tightly conformal doses and steep gradients next to normal tissues, target definition and treatment delivery verification require careful monitoring to avoid the risk of tumor geographic miss and subsequent decrease in tumor

control. Image guidance may be required to provide this assurance.

• Randomized studies to test these concepts are unlikely to be done since these techniques are designed to decrease late effects, which take 10+ years to evolve. In light of that, the modalities and techniques that best reduce the doses to the OARs in a clinically meaningful way

without compromising target coverage should be considered.

• Radiation Dose Constraints - Recommendations for normal tissue dose constraints can be found in the Principles of Radiation Therapy

section of the NCCN Guidelines for Hodgkin Lymphoma.

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PRINCIPLES OF RADIATION THERAPYa

Continued

a See references on NHODG-D 4 of 4.

Volumes

• ISRT for nodal disease17

ISRT is the recommended approach for volume definition and treatment planning for NHL. Planning for ISRT requires CT-based treatment

planning and incorporates volume determinations including gross tumor volume (GTV), clinical target volume (CTV), and planning target

volume (PTV). Incorporating other imaging tests such as PET and MRI often enhances treatment volume determination.

The pre-chemotherapy or pre-biopsy GTV provides the basis for determining the CTV. Concerns for questionable subclinical disease and

uncertainties in original imaging accuracy or localization may lead to expansion of the CTV and are determined individually using clinical

judgment. Further, adjacent uninvolved organs (eg, lungs, bone, muscle, kidney) are excluded from the CTV when disease regresses

following chemotherapy.

For early-stage indolent NHL treated with RT alone, larger treatment volumes should be considered to encompass potential microscopic

disease in adjacent lymph nodes or the immediate vicinity. For example, the CTV definition for treating FL with RT alone will be greater than

that used for DLBCL with similar disease distribution, as the latter is treated with combined modality therapy.

Motion of the target caused by respiration as determined by 4D-CT or fluoroscopy (internal target volume [ITV]) should also influence the

final CTV.

The PTV is an additional expansion of the CTV that accounts only for setup variations and potential target motion not previously accounted

for in the CTV (see International Commission on Radiation Units and Measurements [ICRU] definitions). Proton RT planning does not

generally use a PTV, but rather robustness evaluation to ensure coverage of the CTV.

OARs should be outlined for dose-volume analysis and optimizing treatment planning decisions.

The treatment plan can be designed with conventional, 3D conformal, IMRT/VMAT, or proton therapy techniques using clinical treatment

planning considerations of target coverage and normal tissue avoidance.

• ISRT for extranodal disease18

Similar principles as for ISRT nodal sites (see above).

For EMZL, the CTV generally consists of the entire affected organ (eg, stomach, salivary gland, thyroid). Partial organ ISRT may be

appropriate if the disease is well localized on imaging (eg, orbit and breast).

For most NHL subtypes, uninvolved lymph nodes should not be targeted.

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a See references on NHODG-D 4 of 4.b EMZL of stomach - 1.5 Gy fractions often utilized to minimize acute GI toxicity.c Median follow-up 2–3 years. Longer follow-up needed to confirm results.

General Dose Guidelines:

• Definitive RT (1.5–2.0 Gy daily fractions)

FL: 24–30 Gy19,20

Marginal zone lymphoma (MZL)b:

◊ Conventional: 24 Gy (local control >95%)21,22

◊ Dose-adapted: 4 Gy initially (local control 60%–80%); 20–24 Gy sequentially for poor response or relapsed disease. Preferred for orbital MZL to reduce risk of xerophthalmia; supported by prospective studies.23,24,c Strongly consider for parotid MZL to reduce risk of longterm xerostomia. Can be considered for other sites, depending upon patient preference, site-dependent risks of RT, patient age, and

compliance with follow-up. Closer monitoring required given higher risk of local failure.

MCL25:

◊ Primary treatment (without chemoimmunotherapy) - 24–36 Gy

◊ Consolidation after chemoimmunotherapy

– CR - 24–30 Gy

– PR - 24–36 Gy

DLBCL/HGBL/PMBL/MGZL

◊ Primary treatment (without chemoimmunotherapy): 40 Gy

◊ Consolidation after chemoimmunotherapy

– CR (5-PS 1–3) - 20 Gy for DLBCL/HGBL26,27; 30–36 Gy for MGZL/PBL/PMBL

– PR (5-PS 4) - 36–50 Gy

◊ Refractory disease (5-PS 4–5) - 40–55 Gy

◊ In combination with HCT: 20–36 Gy, depending on sites of disease and prior RT exposure28; hypofractionate as appropriate to expedite HCT procedure)

◊ Prophylactic testicular irradiation (25–30 Gy)

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PRINCIPLES OF RADIATION THERAPYa

• Palliative RT

FL/MZL/MCL/SLL: 2 Gy X 2 fractions or 4 Gy X 1 fraction (which may be repeated as needed); doses up to 30 Gy may be appropriate inselect circumstances DLBCL/HGBL/PMBL/MGZL and BL: (higher doses/fraction typically appropriate)◊ 20–30 Gy in 5–10 fractions. Standard hypofractionated palliative treatment schedules such as 20 Gy in 5 fractions and 30 Gy in 10fractions are appropriate depending upon clinical scenario.

HIV-related B-cell lymphomas and PTLD: Treated based on underlying histologic subtype and treatment intent (curative vs. palliative)

• Bridging RT with CAR T-cell Therapy

Localized disease - 20–40 Gy (higher doses and comprehensive coverage preferred if feasible; hypofractionate as appropriate toexpedite CAR T-cell procedure)Extensive disease - 20–30 Gy (hypofractionate as outlined above)

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National Cancer Network®

NCCN Guidelines Version 1.2026 B-Cell Lymphomas

NCCN Guidelines Index Table of Contents Discussion

PRINCIPLES OF RADIATION THERAPY REFERENCES

$^{1}$ Besson N, Pernin V, Zefkili S, et al. Evolution of radiation techniques in the treatment of mediastinal lymphoma: from 3D conformal radiotherapy (3DCRT) to intensity modulated RT (IMRT) using helical tomotherapy (HT): a single-centre experience and review of the literature. Br J Radiol 2016;89:20150409.

RT (IMRT) using helical tomotherapy (HT); a single-centre experience and review of the literature. Br J Radiol 2016;89:20150409.

2. Filippi AR, Ragona R, Piva C, et al. Optimized volumetric modulated arc therapy versus 3D-CRT for early stage mediastinal Hodgkin lymphoma without axillary involvement: A comparison of second cancers and heart disease risk. Int J Radiat Oncol Biol Phys 2015;92:161-168.

$^{3}$ Horn S, Fournier-Bidoz N, Pernin V, et al. Comparison of passive-beam proton therapy, helical tomotherapy and 3D conformal radiation therapy in Hodgkin's lymphoma female patients receiving involved-field or involved site radiation therapy. Cancer Radiother 2016;20:98-103.

$^{4}$ Voong KR, McSpadden K, Pinnix CC, et al. Dosimetric advantages of a "butterfly" technique for intensity-modulated radiation therapy for young female patients with mediastinal Hodgkin's lymphoma. Radiat Oncol 2014;9:94.

$^{5}$ Ho CK, Flampouri S, Hoppe BS. Proton therapy in the management of lymphoma. Cancer J 2014;20:387-392.

6 Andolino DL, Hoene T, Xiao L, et al. Dosimetric comparison of involved-field three-dimensional conformal photon radiotherapy and breast-sparing proton therapy for the treatment of Hodgkin's lymphoma in female pediatric patients. Int J Radiat Oncol Biol Phys 2011;81:e667-671.

7. Hoppe BS, Flampouri S, Zaiden R, et al. Involved-node proton therapy in combined modality therapy for Hodgkin lymphoma: results of a phase 2 study. Int J Radiat Oncol Biol Phys 89;2014;1053-1059.

8. Hoppe BS, Hill-Kayser CE, Tseng YD, et al. Consolidative proton therapy after chemotherapy for patients with Hodgkin lymphoma. Ann Oncol 2017;28:2179-2184.

9. Tseng YD, Cutter DJ, Plastaras JP, et al. Evidence-based review on the use of proton therapy in lymphoma from the Particle Therapy Cooperative Group (PTCOG) Lymphoma Subcommittee. Int J Radiat Oncol Biol Phys 2017;99:825-842.

$^{10}$ Aznar MC, Maraldo MV, Schut DA, et al. Minimizing late effects for patients with mediastinal Hodgkin lymphoma: deep inspiration breath-hold, IMRT, or both? Int J Radiat Oncol Biol Phys 2015;92:169-174.

$^{11}$ Boda-Heggemann J, Knopf AC, Simeonova-Chergou A, et al. Deep inspiration breath hold-based radiation therapy: A clinical review. Int J Radiat Oncol Biol Phys 2016;94:478-492.

$^{12}$ Petersen PM, Aznar MC, Berthelsen AK, et al. Prospective phase II trial of image-guided radiotherapy in Hodgkin lymphoma: benefit of deep inspiration breath-hold. Acta Oncol 2015;54:60-66.

13 Claude L, Malet C, Pommier P, et al. Active breathing control for Hodgkin's disease in childhood and adolescence: feasibility, advantages, and limits. Int J Radiat Oncol Biol Phys 2007;67:1470-1475.

14 Nanda R, Flampouri S, Mendenhall NP, et al. Pulmonary toxicity following proton therapy for thoracic lymphoma. Int J Radiat Oncol Biol Phys 2017;99:494-497.

15 Pinnix CC, Smith GL, Milgrom S, et al. Predictors of radiation pneumonitis in patients receiving intensity modulated radiation therapy for Hodgkin and non-Hodgkin lymphoma. Int J Radiat Oncol Biol Phys 2015;92:175-182.

16 Christperson H, Gunther J, Fang P, et al. Decreased heart dose with deep inspiration breath hold for the treatment of gastric lymphoma with IMRT. Clin Transl Radi Oncol 2020;24:79-82.

17 Illige T, Specht L, Yahalom J, et al. Modern radiation therapy for nodal non-Hodgkin lymphoma-target definition and dose guidelines from the International Lymphoma Radiation Oncology Group. Int J Radiat Oncol Biol Phys 2014;89:49-58.

18 Yahalom J, Illidge T, Specht L, et al. Modern radiation therapy for extranodal lymphomas: field and dose guidelines from the International Lymphoma Radiation Oncology Group. Int J Radiat Oncol Biol Phys 2015;92:11-31.

19 Hoskin PJ, Kirkwood AA, Popova B, et al. 4 Gy versus 24 Gy radiotherapy for patients with indolent lymphoma (FORT): a randomised phase 3 non-inferiority trial. Lancet Oncol 2014;15:457-463.

20 Lowry L, Smith P, Qian W, et al. Reduced dose radiotherapy for local control in non-Hodgkin lymphoma: A randomised phase III trial. Radiother Oncol 2011;100:86-92.

21 Teckie, Si Q, S1, Lovie, S et al. Long-term outcomes and patterns of relapse of early-stage extranodal marginal zone lymphoma treated with radiation therapy with curative intent. Int J Radiat Oncol Biol Phys 2015;92:130-137.

22 Goda JS, Gospodarowicz M, Pintilie M, et al. Long-term outcome in localized extranodal mucosa-associated lymphoid tissue lymphomas treated with radiotherapy. Cancer 2010;116:3815-3824.

$^{23}$ Pinnix CC, Daba BS, Gunther JR, et al. Response-adapted ultralow-dose radiation therapy for orbital indolent B-cell lymphoma: A Phase 2 Nonrandomized Controlled Trial. JAMA Oncol 2024:10:1195-1203.

24 Park J, Yea JW, Oh SA, Kim MK, et al. Prospective study of 4 Gy radiotherapy for Orbital Mucosa-Associated Lymphoid Tissue Lymphoma (FORMAL). Cancers (Basel) 2022;14:4274.

25 Dabaja BS, Zelenetz AD, Ng AK, et al. Early-stage mantle cell lymphoma: a retrospective analysis from the International Lymphoma Radiation Oncology Group (ILROG). Ann Oncol 2017;28:2185-2190.

26 Huang CC, Wan Z, Niedzwiecki D, et al. Long-term update of a phase 2 study of dose-reduced radiation in diffuse large B-cell lymphoma. Int J Radiat Oncol Biol Phys 2025;122:1202-1206.

$^{27}$ Ng A, Neish D, Niedzwiecki D, et al. Decreasing the dose of consolidation radiation therapy in DLBCL/HGBL: A Phase II trial by the International Lymphoma Radiation Oncology Group [abstract]. Int J Radiat Oncol Biol Phys 2025;123:Abstract S33.

28 Ng AK, Yahalom J, Goda JS, et al. Role of radiation therapy in patients with relapsed/refractory diffuse large B-cell lymphoma: Guidelines from the International Lymphoma Radiation Oncology Group. Int J Radiat Oncol Biol Phys 2018;100:652-669.

Note: All recommendations are category 2A unless otherwise indicated.

NHODG-D

NCCN National Comprehensive Cancer Network®

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B-Cell Lymphomas

NCCN Guidelines Index Table of Contents Discussion

Classification

Table 1

|The International Consensus Classification (ICC) of Mature Lymphoid Neoplasms (2022)|WHO Classification of Hematolymphoid Tumors: Lymphoid Neoplasms (2024; 5th edition)| |---|---| |Mature B-cell lymphomas|Mature B-cell lymphomas| |Pre-neoplastic and neoplastic small lymphocytic proliferations|| |Monoclonal B-cell lymphocytosis • Chronic lymphocytic leukemia type • Non-chronic lymphocytic leukemia type|Monoclonal B-cell lymphocytosis| |Chronic lymphocytic leukemia/small lymphocytic lymphoma|Chronic lymphocytic leukemia/small lymphocytic lymphoma| |B-cell prolymphocytic leukemia|Not included| |Splenic B-cell lymphomas and leukemias|| |Hairy cell leukemia|Hairy cell leukemia| |Splenic marginal zone lymphoma|Splenic marginal zone lymphoma| |Splenic B-cell lymphoma/leukemia, unclassifiable • Splenic diffuse red pulp small B-cell lymphoma • Hairy cell leukemia-variant|Splenic diffuse red pulp small B-cell lymphoma| |Lymphoplasmacytic lymphoma|| |Lymphoplasmacytic lymphoma • Waldenström macroglobulinemia|Lymphoplasmacytic lymphoma| |Marginal zone lymphoma|| |Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma)|Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue| |Primary cutaneous marginal zone lymphoproliferative disorder|Primary cutaneous marginal zone lymphoma| |Nodal marginal zone lymphoma • Pediatric nodal marginal zone lymphoma|Nodal marginal zone lymphoma| |Nodal marginal zone lymphoma • Pediatric nodal marginal zone lymphoma|Pediatric nodal marginal zone lymphoma|

Continued

Arber DA, Borowitz MJ, Cook JR, et al. The International Consensus Classification of Mature Lymphoid Neoplasms. Lippincott Williams & Wilkins; 2025.

WHO Classification of Tumours Editorial Board. Haematolymphoid tumours. (WHO classification of tumours series, 5th ed; vol 11). Lyon (France): International Agency for Research on Cancer; 2024.

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B-Cell Lymphomas

NCCN Guidelines Index Table of Contents Discussion

Classification

Table 1

Continued

Arber DA, Borowitz MJ, Cook JR, et al. The International Consensus Classification of Mature Lymphoid Neoplasms. Lippincott Williams & Wilkins; 2025. WHO Classification of Tumours Editorial Board. Haematolymphoid tumours. (WHO classification of tumours series, 5th ed; vol 11). Lyon (France): International Agency for Research on Cancer; 2024.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

B-Cell Lymphomas

NCCN Guidelines Index Table of Contents Discussion

Classification

Table 1

|The International Consensus Classification (ICC) of Mature Lymphoid Neoplasms (2022)|WHO Classification of Hematolymphoid Tumors: Lymphoid Neoplasms (2024; 5th edition)| |---|---| |Mature B-cell lymphomas|Mature B-cell lymphomas| |Large B-cell lymphomas|| |Diffuse large B-cell lymphoma, NOS • Germinal center B-cell • Activated B-cell|Diffuse large B-cell lymphoma, NOS| |High-grade B-cell lymphoma with MYC and BCL6 rearrangements|Not included| |High-grade B-cell lymphoma with MYC and BCL2 rearrangements|Diffuse large B-cell lymphoma/high-grade B-cell lymphoma with MYC and BCL2 rearrangements| |High-grade B-cell lymphoma, NOS|High-grade B-cell lymphoma, NOS| |T-cell/histocyte-rich large B-cell lymphoma|T-cell/histocyte-rich large B-cell lymphoma| |ALK-positive large B-cell lymphoma|ALK-positive large B-cell lymphoma| |Large B-cell lymphoma with IRF4 rearrangement|Large B-cell lymphoma with IRF4 rearrangement| |Large B-cell lymphoma with 11q aberration|High-grade B-cell lymphoma with 11q aberrations| |Epstein-Barr virus-positive mucocutaneous ulcer|See Lymphoid proliferations and lymphomas associated with immune deficiency and dysregulation| |EBV-positive diffuse large B-cell lymphoma, NOS|EBV-positive diffuse large B-cell lymphoma| |Diffuse large B-cell lymphoma associated with chronic inflammation • Fibrin-associated diffuse large B-cell lymphoma|Diffuse large B-cell lymphoma associated with chronic inflammation| |Diffuse large B-cell lymphoma associated with chronic inflammation • Fibrin-associated diffuse large B-cell lymphoma|Fibrin-associated large B-cell lymphoma| |HHV8 and EBV-negative primary effusion-based lymphoma|Fluid overload-associated large B-cell lymphoma| |Lymphomatoid granulomatosis|Lymphomatoid granulomatosis| |Plasmablastic lymphoma|Plasmablastic lymphoma| |Primary DLBCL of the central nervous system|Primary large B-cell lymphoma of immune-privileged sites • Primary LBCL of the CNS • Primary LBCL of the vitreoretina • Primary LBCL of the testis| |Primary DLBCL of the testis|Primary cutaneous diffuse large B-cell lymphoma, leg type| |Primary cutaneous diffuse large B-cell lymphoma, leg type|Prinvascular large B-cell lymphoma| |Intravascular large B-cell lymphoma|Intravascular large B-cell lymphoma| |Primary mediastinal large B-cell lymphoma|Primary mediastinal large B-cell lymphoma| |Mediastinal grey zone lymphoma|Mediastinal grey zone lymphoma|

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

B-Cell Lymphomas

NCCN Guidelines Index Table of Contents Discussion

Classification

Table 1

|The International Consensus Classification (ICC) of Mature Lymphoid Neoplasms (2022)|WHO Classification of Hematolymphoid Tumors: Lymphoid Neoplasms (2024; 5th edition)| |---|---| |Mature B-cell lymphomas|Mature B-cell lymphomas| |Burkitt lymphoma|Burkitt lymphoma| |Burkitt lymphoma|Burkitt lymphoma| |HHV-8-associated lymphoproliferative disorders|KSHV/HHV8-associated B-cell lymphoid proliferations and lymphomas| |Multicentric Castleman disease|See Tumour-like lesions with B-cell predominance| |Primary effusion lymphoma|Primary effusion lymphoma| |HHV8-positive diffuse large B-cell lymphoma, NOS|KSHV/HHV8-positive diffuse large B-cell lymphoma| |HHV8-positive germinotropic lymphoproliferative disorder|KSHV/HHV8-positive germinotropic lymphoproliferative disorder| |Immunodeficiency-associated lymphoproliferative disorders|Lymphoid proliferations and lymphomas associated with immune deficiency and dysregulation| |Posttransplant lymphoproliferative disorders|Hyperplasias arising in immune deficiency/dysregulation| |Nondestructive posttransplant lymphoproliferative disorders|Hyperplasias arising in immune deficiency/dysregulation| |Plasmacytic hyperplasia posttransplant lymphoproliferative disorder|Polymorphic lymphoproliferative disorders arising in immune deficiency/dysregulation| |Infectious mononucleosis posttransplant lymphoproliferative disorder|EBV-positive mucocutaneous ulcer| |Florid follicular hyperplasia posttransplant lymphoproliferative disorder|Lymphomas arising in immune deficiency / dysregulation| |Polymorphic posttransplant lymphoproliferative disorder|Lymphomas arising in immune deficiency / dysregulation| |Monomorphic posttransplant lymphoproliferative disorder (B-cell and T-cell/ NK-cell types)|Inborn error of immunity-associated lymphoid proliferations and lymphomas| |Other iatrogenic immunodeficiency-associated lymphoproliferative disorders|Tumour-like lesions with B-cell predominance| ||Reactive B-cell-rich lymphoid proliferations that can mimic lymphoma| |Not included|IgG4-related disease| |Not included|Unicentric Castleman disease| |See HHV8-associated lymphoproliferative disorders|Idiopathic multicentric Castleman disease| |See HHV8-associated lymphoproliferative disorders|KSHV/HHV8-associated multicentric Castleman disease|

Continued

NCCN Guidelines Version 1.2026 B-Cell Lymphomas

NCCN Guidelines Index Table of Contents Discussion

ST-5

Staging

*Extent of disease is determined by PET-CT for avid lymphomas, and CT for non-avid histologies.

Note: Tonsils, Waldeyer’s ring, and spleen are considered nodal tissue.

**Whether II bulky is treated as limited or advanced disease may be determined by histology and a number of prognostic factors.

Categorization of A versus B has been removed from the Lugano Modification of Ann Arbor Staging.

evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol 2014;32:3059-3068.

Lugano Modification of Ann Arbor Staging System* (for primary nodal lymphomas)

Stage

Involvement

Extranodal (E) status

Limited

Stage I

One node or a group of adjacent nodes

Single extranodal lesions without nodal involvement

Stage II

Two or more nodal groups on the same side of the

diaphragm

Stage I or II by nodal extent with limited contiguous

extranodal involvement

Stage II bulky** II as above with “bulky” disease

Not applicable

Advanced

Stage III

Nodes on both sides of the diaphragm

Not applicable

Nodes above the diaphragm with spleen involvement

Stage IV

Additional non-contiguous extralymphatic involvement

Not applicable

NCCN Guidelines Version 1.2026 B-Cell Lymphomas

NCCN Guidelines Index Table of Contents Discussion

3D-CRT three-dimensional conformal radiation therapy

4D-CT four-dimensional computed tomography

5-PS

five-point scale

ALC

absolute lymphocyte count

ALCL

anaplastic large cell lymphoma

ANC

absolute neutrophil count

ART

antiretroviral therapy

ASCR autologous stem cell rescue AVN

avascular necrosis

AYA

adolescent and young adult

B-ALL B-cell acute lymphoblastic leukemia BL

Burkitt lymphoma

BMD

bone mineral density

BTKi

BTK inhibitor

BUN

blood urea nitrogen

C/A/P

chest/abdomen/pelvis

CAR

chimeric antigen receptor

CBC

complete blood count

cFL

classic follicular lymphoma

CHL

classic Hodgkin lymphoma

CLL

chronic lymphocytic leukemia

CMV

cytomegalovirus

CNS

central nervous system

complete response

CRS

cytokine release syndrome

ctDNA circulating tumor DNA CTL

cytotoxic T-lymphocyte

CTV

clinical target volume

DAA

direct-acting antiviral

dFL

FL with predominantly diffuse growth pattern DLBCL diffuse large B-cell lymphoma

EBER Epstein-Barr virus-encoded RNA

EBERISH

Epstein-Barr virus-encoded RNA in situ hybridization

EBV

Epstein-Barr virus

EMZL

extranodal marginal zone lymphoma

FDC

follicular dendritic cell

FFS

failure-free survival

FISH

fluorescence in situ hybridization

follicular lymphoma

FLBCL follicular large B-cell lymphoma FNA

fine-needle aspiration

FRAX

Fracture Risk Assessment Tool

G6PD

glucose-6-phosphate dehydrogenase

germinal center

gastrointestinal

GCB

germinal center B-cell

G-CSF granulocyte colony-stimulating factor GTV

gross tumor volume

HBcAb hepatitis B core antibody HBsAg hepatitis B surface antigen HBV

hepatitis B virus

HCL

hairy cell leukemia

HCT

hematopoietic cell transplant

HCV

hepatitis C virus

HDT

high-dose therapy

HGBL high-grade B-cell lymphoma HHV8 human herpesvirus 8

HIV

human immunodeficiency virus

H&P

history and physical

ICC

International Consensus Classification

ICRU International Commission on

Radiation Units and Measurements Ig

immunoglobulin

IHC

immunohistochemistry

IMRT intensity-modulated radiation therapy

IMH

infectious mononucleosis-like hyperplasia IPI

International Prognostic Index ISRT involved-site radiation therapy IT

intrathecal

ITV

internal target volume

IVF

in vitro fertilization

IVIG

intravenous immunoglobulin

ABBR-1

ABBREVIATIONS

NCCN Guidelines Version 1.2026 B-Cell Lymphomas

NCCN Guidelines Index Table of Contents Discussion

JCV

John Cunningham virus

Kaposi sarcoma

KSHV Kaposi sarcoma-associated herpesvirus

LANA latency-associated nuclear antigen

LBCL

large B-cell lymphoma

LDH

lactate dehydrogenase

LDi

longest transverse diameter of a lesion

lymphoblastic lymphoma

LPL

lymphoplasmacytic lymphoma

mAb

monoclonal antibody

MCL

mantle cell lymphoma

mycosis fungoides

MGPT multigene panel testing

MGZL mediastinal gray zone lymphoma MRD

minimal residual disease MUGA multigated acquisition MZL

marginal zone lymphoma

NHL

non-Hodgkin lymphoma

natural killer

NOS

not otherwise specified

NMZL nodal marginal zone lymphoma NR

no response

OAR

organ at risk

PCDLBCL

primary cutaneous diffuse large B-cell

lymphoma

PCFCL primary cutaneous follicle center lymphoma

PCH

plasmacytic hyperplasia

PCMZL primary cutaneous marginal zone lymphoma

PCR

polymerase chain reaction

PEL

primary effusion lymphoma

PFS

progression-free survival

PJP

pneumocystis jirovecii pneumonia

PMBL primary mediastinal large B-cell

lymphoma

PML

progressive multifocal leukoencephalopathy

PPD

cross product of the LDi and perpendicular diameters

partial response

PTCL

peripheral T-cell lymphoma

PTFL

pediatric-type follicular lymphoma

PTLD

posttransplant lymphoproliferative disorders

PTV

planning target volume

RIS

reduction of immunosuppression

SDi

shortest axis perpendicular to the LDi

SDRPL splenic diffuse red pulp small B-cell lymphoma

SIFE

serum immunofixation electrophoresis

SLL

small lymphocytic lymphoma

smIPI stage modified International

Prognostic Index

SMZL splenic marginal zone lymphoma SPD

sum of product of greatest

perpendicular diameters

SPEP serum protein electrophoresis

Sézary syndrome

T-ALL T-cell acute lymphoblastic leukemia T-LBL T-cell lymphoblastic leukemia

TLS

tumor lysis syndrome

ULN

upper limit of normal

uMRD undetectable minimal residual disease VMAT volumetric modulated arc therapy

VZV

varicella zoster virus WBC white blood cell

Waldenström macroglobulinemia

ABBR-2

ABBREVIATIONS

NCCN Guidelines Version 1.2026 B-Cell Lymphomas

NCCN Guidelines Index Table of Contents Discussion

CAT-1

NCCN Categories of Evidence and Consensus

Category 1 Based upon high-level evidence (≥1 randomized phase 3 trials or high-quality, robust meta-analyses), there is uniform NCCN consensus (≥85% support of the Panel) that the intervention is appropriate.

Category 2A Based upon lower-level evidence, there is uniform NCCN consensus (≥85% support of the Panel) that the intervention is appropriate.

Category 2B Based upon lower-level evidence, there is NCCN consensus (≥50%, but <85% support of the Panel) that the intervention is appropriate.

Category 3 Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.

All recommendations are category 2A unless otherwise indicated.

NCCN Categories of Preference

Preferred

Interventions that are based on superior efficacy, safety, and evidence; and, when appropriate,

affordability.

Other recommended Other interventions that may be somewhat less efficacious, more toxic, or based on less mature data;or significantly less affordable for similar outcomes.

Useful in certain

circumstances

Other interventions that may be used for selected patient populations (defined with recommendation).

All recommendations are considered appropriate.

Discussion

Overview .............................................................................................................................................................................................................. MS-2

Guidelines Update Methodology ........................................................................................................................................................................... MS-2

Sensitive/Inclusive Language Usage .................................................................................................................................................................... MS-3

Supportive Care ................................................................................................................................................................................................... MS-7

Follicular Lymphoma .......................................................................................................................................................................................... MS-22

Marginal Zone Lymphomas ................................................................................................................................................................................ MS-55

Mantle Cell Lymphoma ....................................................................................................................................................................................... MS-81

Diffuse Large B-Cell Lymphomas...................................................................................................................................................................... MS-110

ALK-Positive Large B-Cell Lymphomas............................................................................................................................................................. MS-130

Mediastinal Gray Zone Lymphomas .................................................................................................................................................................. MS-131

Primary Mediastinal Large B-Cell Lymphoma .................................................................................................................................................... MS-148

Histologic Transformation of Indolent Lymphomas to DLBCL ..................................................................................

MS-156

High-Grade B-Cell Lymphomas ........................................................................................................................................................................ MS-165

Burkitt Lymphoma ............................................................................................................................................................................................ MS-173

HIV-Related B-Cell Lymphomas ....................................................................................................................................................................... MS-184

Post-Transplant Lymphoproliferative Disorders ................................................................................................................................................. MS-199

This discussion corresponds to the NCCN Guidelines for B-Cell Lymphomas. Last updated: August 18, 2025.

Discussion

ALK-Positive Large B-Cell Lymphomas............................................................................................................................................................. MS-130

Primary Mediastinal Large B-Cell Lymphoma .................................................................................................................................................... MS-148

Histologic Transformation of Indolent Lymphomas to DLBCL ..................................................................................

MS-156

Post-Transplant Lymphoproliferative Disorders ................................................................................................................................................. MS-199

This discussion corresponds to the NCCN Guidelines for B-Cell Lymphomas. Last updated: August 18, 2025.

Overview

Non-Hodgkin lymphomas (NHL) are a heterogeneous group of

lymphoproliferative disorders originating in B lymphocytes, T lymphocytes, or natural killer (NK) cells (NK/T-cell lymphomas are very rare). In 2025, an estimated 80,350 people will be diagnosed with NHL and there will be approximately 19,390 deaths due to the disease.1 Diffuse large B-cell

lymphoma (DLBCL; 32%), follicular lymphoma (FL; 17%), marginal zone lymphoma (MZL; 8%) and mantle cell lymphoma (MCL; 4%), were the

major subtypes of B-cell lymphomas diagnosed in the United States

between 1998 and 2011.2

In 2020, an estimated 544,000 people were diagnosed with NHL

worldwide, and approximately 260,000 people died from the disease.3 The incidence of NHL has declined worldwide, and mortality rates have also

decreased since 2000 with the introduction of anti-CD20 monoclonal

antibody (mAb), rituximab.4 However, the mortality rates continue to be

higher in regions with limited resources, mainly related to the prevalence and distribution of underlying risk factors, and level of access to diagnostic techniques and treatment approaches.3

NHL (along with Kaposi sarcoma [KS], and lung cancer) are the most

common cancer types diagnosed in people with human

immunodeficiency virus (HIV) in the United States, with the largest

declines in incidence rates are projected for NHL and KS through

2030.5,6 DLBCL, Burkitt lymphoma (BL), and primary central nervous

system lymphoma (PCNSL) are the most common subtypes of B-cell

lymphomas in people with HIV (PWH).7

The National Comprehensive Cancer Network (NCCN®) Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for B-Cell Lymphomas were

developed as a result of meetings convened by a multidisciplinary Panel of experts, with the aim to provide recommendations for diagnostic workup, treatment, and surveillance strategies for the most common subtypes of Bcell lymphomas, in addition to a general discussion on the classification

systems and supportive care considerations.

The most common subtypes that are covered in the NCCN Guidelines® for B-Cell Lymphomas are listed below:

• Follicular lymphoma (FL)

• Marginal zone lymphomas (MZLs)

◊ Extranodal marginal zone lymphoma (EMZL) of the stomach

◊ EMZL of non-gastric sites (noncutaneous)

◊ Nodal MZL

◊ Splenic MZL

• Mantle cell lymphoma (MCL)

• Diffuse large B-cell lymphoma (DLBCL)

• ALK-positive large B-cell lymphomas

• Mediastinal gray zone lymphomas (MGZL)

• Primary mediastinal large B-cell lymphoma (PMBL)

• Histologic transformation of indolent lymphomas to DLBCL

• High-grade B-cell lymphomas (HGBL)

• Burkitt lymphoma (BL)

• HIV-related B-cell lymphomas

• Post-transplant lymphoproliferative disorders (PTLD)

Guidelines Update Methodology

The complete details of the Development and Update of the NCCN Guidelines are available at www.NCCN.org.

This discussion corresponds to the NCCN Guidelines for B-Cell Lymphomas. Last updated: August 18, 2025.

Sensitive/Inclusive Language Usage

NCCN Guidelines strive to use language that advances the goals of

equity, inclusion, and representation. NCCN Guidelines endeavor to use

language that is person-first; not stigmatizing; anti-racist, anti-classist, antimisogynist, anti-ageist, anti-ableist, and anti-weight-biased; and inclusive of individuals of all sexual orientations and gender identities. NCCN

Guidelines incorporate non-gendered language, instead focusing on

organ-specific recommendations. This language is both more accurate

and more inclusive and can help fully address the needs of individuals of all sexual orientations and gender identities. NCCN Guidelines will

continue to use the terms men, women, female, and male when citing

statistics, recommendations, or data from organizations or sources that do not use inclusive terms. Most studies do not report how sex and gender

data are collected and use these terms interchangeably or inconsistently. If sources do not differentiate gender from sex assigned at birth or organs present, the information is presumed to predominantly represent cisgender individuals. NCCN encourages researchers to collect more specific data in future studies and organizations to use more inclusive and accurate

language in their future analyses.

Classification

The 2001 World Health Organization (WHO) Classification of

Hematopoietic and Lymphoid Neoplasms represented the first

international consensus on classification of hematologic malignancies.

After consideration of cell lineage (B, T, or NK), the classification

subdivided lymphoid neoplasms into precursor versus mature lymphomas. The classification was further refined based on clinical, cytogenetic, and molecular features to aid in defining the diagnosis of specific subtypes of lymphomas.

Cytogenetic features detected by karyotype or fluorescence in situ

hybridization (FISH) and molecular analysis are increasingly important in

defining specific subtypes. In addition, detection of viruses, particularly

Epstein-Barr virus (EBV), HHV8, and HTLV1, is often necessary to

establish a specific diagnosis. The WHO Classification was revised in

2008, 2017, and 2022 to include new disease entities and better define

some of the heterogeneous and ambiguous subtypes, based on the

evolving genetic and molecular landscape of various subtypes of B-cell

lymphomas.8-10

In 2022, in addition to the newly revised WHO Classification of

Hematolymphoid Tumors (WHO5),10 another new classification system known as International Consensus Classification (ICC) was also

published.11 While both the ICC and WHO5 continue to classify the

lymphomas based on morphology, clinical features, cell lineage

(immunophenotype), and cytogenetic and molecular features, there are differences between the two classifications in terms of nomenclature and diagnostic criteria. These are discussed under the respective subtypes of B-cell lymphomas.

Diagnosis

An accurate pathologic diagnosis of the subtype is the most important

first step in the management of B-cell lymphomas. The basic pathologic evaluation is the same for each subtype, although some further

evaluation may be useful in certain circumstances to clarify a particular diagnosis; these are outlined in the pathologic evaluation of the

individual Guidelines.

An excisional or incisional lymph node biopsy is preferred for the definitive diagnosis and histologic grading of B-cell lymphomas. Fine-needle

aspiration (FNA) biopsy alone is insufficient for the initial diagnosis or

histologic grading of lymphoma but can be a valuable method for the initial screening of enlarged lymph nodes.12-15 Core needle biopsy (multiple

biopsies preferred) is an appropriate alternative to excisional or incisional

biopsy especially when a clinical situation dictates that this is the only safe means of obtaining diagnostic tissue (ie, when a lymph node is not easily accessible for excisional or incisional biopsy or if surgical biopsy would

cause significant morbidity or substantial treatment delays). In such

instances, a combination of core needle biopsy (multiple biopsies

preferred) and FNA biopsies in conjunction with appropriate ancillary

techniques (immunohistochemistry [IHC], flow cytometry, karyotype or

fluorescence in-situ hybridization [FISH], and molecular studies) may be

sufficient for the differential diagnosis.16-20

Next-generation sequencing (NGS) can be used if a high suspicion of a

clonal process remains and other techniques have not resulted in a clear identification of a clonal process.

Hematopathology review of all slides (with at least one paraffin block

representative of the tumor) is recommended. Rebiopsy of lymph node

(preferably the most fluorodeoxyglucose [FDG]-avid, accessible lymph

node) should be done if consult material is nondiagnostic.

Immunophenotyping is essential for the differentiation of various

subtypes of B-cell lymphomas to establish the proper diagnosis. It can be performed by flow cytometry and/or IHC; the choice depends on the

antigens as well as the expertise and resources available to the

hematopathologist.21 Cytogenetic or molecular genetic analysis may be necessary under certain circumstances to identify chromosomal

rearrangements or gene mutations that are characteristic of some

subtypes of B-cell lymphomas or to establish clonality.

The NCCN Guidelines Panel developed a series of algorithms for the

use of immunophenotyping and genetic testing to provide guidance for

surgical pathologists and clinicians in the interpretation of pathology

reports. These algorithms should be used in conjunction with clinical and pathologic correlation. See Use of Immunophenotyping/Genetic Testing

in Differential Diagnosis of Mature B-Cell and NK/T-Cell Neoplasms in the algorithm.

Workup

Essential workup procedures include a complete physical exam with

particular attention to node-bearing areas and the size of liver and

spleen, symptoms present, performance status, and laboratory studies including complete blood count (CBC), serum lactate dehydrogenase

(LDH), hepatitis B virus (HBV) testing (see below), comprehensive

metabolic panel, and chest/abdomen/pelvis CT with oral and intravenous contrast (unless coexistent renal insufficiency). Multigated acquisition

(MUGA) scan or echocardiograms are recommended when

anthracyclines and anthracenedione-containing regimens are used.

HBV reactivation (resulting in liver failure and death) has been reported

with anti-CD20 mAb-based regimens.22 HBV carriers with lymphoid

malignancies have a high risk of HBV reactivation and disease, especially those treated with anti-CD20 mAb-based regimens.23 The Panel has

included testing for hepatitis B surface antigen (HBsAg) and hepatitis B

core antibody (HBcAb) as part of essential workup prior to initiation of

treatment in all patients who will receive anti-CD20 mAb-based

regimens. See Hepatitis B Virus Reactivation in the Supportive Care

section.

Large population-based or multicenter case-control studies have

demonstrated a strong association between seropositivity for hepatitis C virus (HCV) and the development of B-cell lymphomas.24-31 The

prevalence of HCV seropositivity was consistently increased among

patients with DLBCL and MZL.24,25,29,30 HCV testing is needed in patients with high-risk disease and in patients with splenic MZL. See Hepatitis C

Virus-Associated B-Cell Lymphomas in the Supportive Care section.

Optional workup procedures (depending on specific lymphoma type) include beta-2-microglobulin, CT or PET/CT scans, endoscopic

ultrasound, head CT, or brain MRI and lumbar puncture to analyze cerebrospinal fluid (CSF). Discussion of fertility issues and sperm

banking should be addressed in the appropriate circumstances.32

Role of PET Scans

Staging

PET has a high positivity and specificity when used for the staging and restaging of lymphoma.33 PET is nearly universally positive at diagnosis in DLBCL, FL, and nodal MZL, but less sensitive for extranodal MZL.34,35 However, a number of benign conditions including sarcoid, infection, and inflammation can result in false-positive PET scans, complicating the

interpretation. Lesions <1 cm are not reliably visualized with PET scans. Although PET scans may detect additional disease sites at diagnosis,

the clinical stage is modified only in 15% to 20% of patients and a

change in treatment in only 8% of patients.

The combined PET/CT scans have distinct advantages in both staging

and restaging compared to full-dose diagnostic CT or PET alone.36,37 In a retrospective study, PET/CT performed with low-dose non–

contrast-enhanced CT was found to be more sensitive and specific than contrast-enhanced CT for the evaluation of lymph node and organ

involvement in patients with Hodgkin lymphoma or high-grade B-cell

lymphomas.36 Preliminary results of a prospective study (47 patients;

patients who had undergone prior diagnostic CT were excluded) also

showed a good correlation between low-dose non–contrast-enhanced

PET/CT and full-dose contrast-enhanced PET/CT for the evaluation of

lymph nodes and extranodal disease in lymphomas.37

PET/CT should be done with contrast-enhanced diagnostic CT and is

recommended for initial staging and restaging of all fluorodeoxyglucose

(FDG)-avid lymphomas.38,39 PET/CT is particularly important for staging before consideration of radiation therapy (RT), and baseline PET/CT will aid in the interpretation of post-treatment response evaluation based on

the 5-point scale (5-PS) as described below.39

Response Assessment

The guidelines for response criteria for lymphoma, first published in 1999 by the International Working Group (IWG), were revised in 2007 by the

International Harmonization Project to incorporate IHC, flow cytometry,

and PET scans in the definition of response for lymphoma.40,41 In the

revised guidelines, the response category of complete response uncertain (CRu) was essentially eliminated and response is categorized as complete response (CR), partial response (PR), stable disease (SD), and relapsed disease or progressive disease (PD) based on the result of a PET scan.

In 2014, revised response criteria, known as the Lugano response

criteria, were introduced for response assessment using PET/CT scans according to the 5-PS.38,39 The 5-PS is based on the visual assessment of FDG uptake in the involved sites relative to that of the mediastinum

and the liver.42-44 A score of 1 denotes no abnormal FDG avidity, while a score of 2 represents uptake less than the mediastinum. A score of 3

denotes uptake greater than the mediastinum but less than the liver,

while scores of 4 and 5 denote uptake greater than the liver, and greater than the liver with new sites of disease, respectively. Different clinical

trials have considered scores of either 1 to 2 or 1 to 3 to be

PET-negative, but a score of 1 to 3 is now widely considered to be PET negative. Scores of 4 to 5 are universally considered PET positive. A

score of 4 on an interim or end-of-treatment restaging scan may be

consistent with a PR if the FDG avidity has declined from initial staging, while a score of 5 denotes PD.

However, the application of PET/CT to response assessment is limited to FDG-avid lymphomas and the revised response criteria have thus far

only been validated for DLBCL and Hodgkin lymphoma. The application of the revised response criteria to other histologies requires validation and the original IWG guidelines should be used.40,41 False-positive PET scans may be observed related to infectious or inflammatory conditions. Biopsy of affected sites remains the gold standard for confirming new or

persistent disease at end of treatment (EOT).

Principles of Radiation Therapy

RT can be delivered with photons, electrons, or protons, depending upon clinical circumstances.45 Advanced RT techniques emphasize tightly

conformal doses and steep gradients next to organs at risk (OAR).

Therefore, accurate target delineation and careful monitoring of treatment delivery are critical to avoid the risk of underdosing the clinical target

volume (CTV) and subsequent decrease in tumor control. Image guidance may be required to facilitate accurate treatment delivery.

Preliminary results from single-institution studies have shown that

significant dose reduction to OAR (eg, lungs, heart, breasts, kidneys,

spinal cord, esophagus, carotid artery, bone marrow, stomach, muscle,

soft tissue, and salivary glands) can be achieved with advanced RT

planning and delivery techniques such as 4D-CT simulation, image-guided RT, intensity-modulated RT (IMRT)/volumetric modulated arc therapy

(VMAT), and proton therapy.46-54 In mediastinal and abdominal lymphoma, the use of respiratory motion management techniques such as respiratory gating or breath-hold techniques, and image-guided RT have been shown to decrease incidental dose to OAR such lung, heart, liver, and kidneys.55-

Thus, the use of advanced RT and motion management techniques offer significant and clinically relevant advantages in specific instances to spare OAR and reduce the risk of late complications from normal tissue damage.

This is especially important for patients being treated with curative intent or who have long life expectancies following therapy.

Randomized prospective studies to test these concepts are unlikely to be done since these techniques are designed to decrease late effects, which usually develop ≥10 years after completion of treatment. Therefore, the

guidelines recommend that RT delivery techniques that are found to best reduce RT dose to OAR in a clinically meaningful manner without

compromising target coverage should be considered.

Involved-site RT (ISRT) is recommended as the appropriate field for B-cell lymphomas as it limits the radiation exposure to adjacent uninvolved

organs (such as lungs, bone, muscle, or kidney) when lymphadenopathy regresses following chemotherapy, thus minimizing the potential long-term complications.59,60 ISRT targets the initially involved nodal and extranodal sites detectable at presentation.59,60 Larger RT fields utilizing elective

nodal irradiation should be considered for limited-stage indolent B-cell

lymphomas, often treated with RT alone.59

Treatment planning for ISRT requires the use of CT-based simulation. The incorporation of additional imaging techniques such as PET and MRI often improves the accuracy of treatment planning. The OAR should be outlined for optimizing treatment plan decisions. The treatment plan is designed

using conventional, 3D conformal, or IMRT/VMAT techniques using

clinical treatment planning considerations of coverage and dose

reductions for OAR.59

The principles of ISRT are similar for both nodal and extranodal disease. The gross tumor volume (GTV) defined by radiologic imaging prior to

biopsy, chemotherapy, or surgery provides the basis for determining the CTV.61 Possible movement of the target by respiration as determined by 4D-CT or fluoroscopy should also influence the final CTV. Larger CTV

should be considered for the treatment of early-stage indolent B-cell

lymphomas treated with RT alone to encompass potential microscopic

disease in adjacent lymph nodes or the immediate vicinity. The planning

treatment volume (PTV) is an additional expansion of the CTV that

accounts only for setup variations. In the case of extranodal disease,

particularly for MZL, the whole organ comprises the CTV in some

circumstances (eg, stomach, salivary gland, thyroid). Partial organ ISRT

may be appropriate if the disease is well localized on imaging (eg, orbit

and breast).

The general dose guidelines for individual subtypes of B-cell lymphomas are outlined in the Principles of Radiation Therapy section of the algorithm. Recommendations for normal tissue dose constraints can be found in the Principles of Radiation Therapy section of the NCCN Guidelines for

Hodgkin Lymphoma.

Supportive Care

Tumor Lysis Syndrome

Tumor lysis syndrome (TLS) is a potentially serious complication of

anticancer therapy characterized by metabolic and electrolyte

abnormalities caused by the disintegration of malignant cells by

anticancer therapy and rapid release of intracellular contents into

peripheral blood. It is usually observed within 12 to 72 hours after start of

chemoimmunotherapy.62

Laboratory TLS is defined as a 25% increase in the levels of serum uric acid, potassium, or phosphorus or a 25% decrease in calcium levels.63

Clinical TLS refers to laboratory TLS with clinical toxicity that requires

intervention. Hyperkalemia, hyperuricemia, hyperphosphatemia, and

hypocalcemia are the primary electrolyte abnormalities associated with TLS. Clinical symptoms may include nausea and vomiting, diarrhea,

seizures, shortness of breath, renal insufficiency, or cardiac arrhythmias. Untreated TLS can induce profound metabolic changes resulting in

cardiac arrhythmias, seizures, loss of muscle control, acute renal failure,

and even death.

TLS is best managed if anticipated and when treatment is started prior to chemoimmunotherapy. Histologies of BL, lymphoblastic lymphoma and occasionally DLBCL, bone marrow involvement, bulky tumors that are

chemosensitive, rapidly proliferative or aggressive hematologic

malignancies, an elevated leukocyte count or pretreatment LDH,

pre-existing elevated uric acid, renal disease, or renal involvement of

tumor are considered as risk factors for developing TLS.64 TLS

prophylaxis should be considered for patients with any of these risk

factors. Frequent monitoring of electrolytes and aggressive correction

are essential.

The cornerstone of TLS management is hydration and the management of hyperuricemia. Allopurinol, febuxostat, and rasburicase are highly

effective for the management of hyperuricemia.65-67 There are data to

suggest that single fixed dose (6 mg or 3 mg) or single weight-based

dose of rasburicase (0.05–0.15 mg/kg) are effective in adult patients with hyperuricemia or high-risk factors for TLS.68-73

Allopurinol or febuxostat is recommended for patients with low-risk or

intermediate-risk disease. Allopurinol and febuxostat should be started 2 to 3 days prior to the initiation of chemoimmunotherapy and continued for 10 to 14 days. Rasburicase is recommended for intermediate-risk

disease (if renal dysfunction and uric acid, potassium, and/or phosphate greater than upper limit of normal [ULN]) or high-risk disease. A single

dose of rasburicase (3 mg or 6 mg) is adequate in most circumstances

and repeat dosing should be individualized based on the presence of any of the following risk factors: bulky disease requiring immediate therapy; adequate hydration is not possible; or acute renal failure. Rasburicase is contraindicated in patients with G6PD deficiency due to an increased risk of methemoglobinemia or hemolysis.74 G6PD testing should be

considered prior to the initiation of rasburicase. Rasburicase should be substituted with allopurinol if there is G6PD deficiency.

Hepatitis B Virus Reactivation

Patients with malignancies and HBV infection (HBsAg-positive or HBcAbpositive) are at risk for HBV reactivation with cytotoxic chemotherapy.75-85 A meta-analysis and evaluation of the U.S. Food and Drug Administration (FDA) safety reports concerning HBV reactivation in patients with

lymphoproliferative disorders reported that HBcAb positivity was correlated with increased incidence of rituximab-associated HBV reactivation.76 In

patients with B-cell lymphomas treated with rituximab-containing

regimens, HBV reactivation was observed in patients with a positive test

for HBcAb (with or without HBsAb positivity), even among patients with a negative test for HBsAg prior to initiation of treatment.77,83,84

False-negative HBsAg results may occur in patients with chronic liver

disease; therefore, patients with a history of hepatitis in need of

chemoimmunotherapy should be assessed by viral load measurement.86 HBsAb positivity is generally equated with protective immunity, although

reactivated HBV disease may occur in the setting of significant

immunosuppression in individuals with HBV infection that is HBcAb

positive.82,87 Vaccination against HBV should be strongly considered in

patients without HBV infection (ie, negative for HBsAg, HBsAb, and

HBcAb).82,88

Antiviral prophylaxis or pre-emptive antiviral therapy are the recommended strategies for the management of HBV reactivation in patients with

hematologic malignancies undergoing immunosuppressive therapy.

Antiviral prophylaxis involves administration of antiviral therapy for patients with HBV infection (HBsAg positive or HBcAb positive), regardless of viral load or presence of clinical manifestations of HBV reactivation.

Lamivudine has been shown to reduce the risks for HBV reactivation in

patients with HBV infection (HBsAg-positive) and hematologic

malignancies treated with immunosuppressive cytotoxic agents.23,89-91

Entecavir has been shown to be more effective than lamivudine in

preventing rituximab-associated HBV reactivation.92-94 Pre-emptive therapy involves close surveillance with a highly sensitive quantitative assay for

HBV, combined with antiviral therapy given at the time of serological

evidence of HBV reactivation based upon a rising HBV DNA load.82

Testing for HBsAg and HBcAb can determine if an individual has HBV

infection. HBsAb positivity is of limited value because of the widespread

use of the hepatitis B vaccine; however, in rare circumstances, HBsAb

levels can help to guide therapy. The Panel recommends HBsAg and

HBcAb testing for all patients with B-cell lymphomas planned for treatment with anti-CD20 mAb-containing regimens. In individuals who test positive for HBsAg and/or HBcAb, baseline quantitative polymerase chain reaction (PCR) for HBV DNA should be obtained to determine viral load. However, a negative baseline PCR does not preclude the possibility of reactivation. Patients receiving intravenous immunoglobulin (IVIG) may have a positive test for HBcAb as a consequence of IVIG therapy.95

Entecavir prophylaxis is recommended for patients with HBV infection

(HBsAg positive) receiving anti-lymphoma therapy.92,93 Entecavir

prophylaxis is also the preferred approach for patients with HBV infection (HBsAg negative but HBcAb positive); however, in the presence of

concurrently high levels of HBsAb, appropriate supportive care

interventions (monitoring with serial measurements of HBV viral load and treatment with pre-emptive antivirals upon increasing viral load) may be

necessary. Lamivudine should be avoided due to the risks for the

development of resistance.96-98 Other antivirals such as adefovir,

telbivudine, and tenofovir have also demonstrated antiviral efficacy in

patients with chronic HBV infection and are acceptable alternatives.99-102

The optimal choice of prophylactic antiviral therapy will be driven by

institutional standards or recommendation from hepatology or an

infectious disease consultant. The appropriate duration of prophylaxis

remains undefined, but the Panel recommended that surveillance and

antiviral prophylaxis should be continued for up to 12 months after the

completion of oncologic treatment.82 During the treatment period, viral load should be monitored monthly with PCR and then every 3 months after

completion of treatment. If viral load is consistently undetectable,

prophylaxis with antivirals should be continued. If viral load fails to drop or a previously undetectable PCR becomes positive, consultation with a

hepatologist and discontinuation of anti-CD20 mAb therapy is

recommended.

Hepatitis C Virus-Associated B-Cell Lymphomas

As noted earlier, large population-based or multicenter case-control

studies have demonstrated a strong association between seropositivity for HCV and development of B-cell lymphomas.24-31 The prevalence of HCV seropositivity was consistently increased among patients with DLBCL and MZL.24,25,29,30 In a retrospective study, based on multivariable analysis,

persistent HCV infection remained a significant independent factor

associated with development of malignant lymphomas and the

achievement of sustained virologic response (SVR) with interferon-based therapy may reduce the incidence of malignant lymphoma in people with HCV infection.27

Several published reports suggested that treatment with antivirals

(typically interferon with or without ribavirin) led to regression of lymphoma in people with HCV infection, which provides additional evidence for the

involvement of HCV infection in the pathogenesis of lymphoproliferative

diseases.103-109 Thus, in patients with HCV infection and indolent B-cell

lymphomas not requiring immediate treatment with chemoimmunotherapy, initial treatment with interferon (with or without ribavirin) appeared to

induce lymphoma regression in a high proportion of patients. In patients

with HCV-infection and B-cell lymphomas in remission after

anti-lymphoma therapy, subsequent antiviral therapy may be associated with lower risk of disease relapse.

The optimal management of B-cell lymphomas in people with HCV

infection remains to be defined. Patients with indolent B-cell lymphomas may benefit from initial antiviral therapy, as demonstrated in several

reports.103,105,107,109,110 In patients with aggressive B-cell lymphomas, an

earlier analysis of pooled data from GELA clinical studies (prior to the

rituximab era) suggested that HCV seropositivity in patients with DLBCL was associated with significantly decreased survival outcomes, due, in

part, to severe hepatotoxicity among those with HCV infection.111

Subsequent studies in the rituximab era showed that HCV seropositivity was not predictive of outcomes in terms of PFS or OS in patients with

DLBCL.112,113 However, the incidence of hepatotoxicity with

chemoimmunotherapy was higher among people with HCV infection,

confirming the observation made from the GELA studies.

The treatment of chronic HCV infection has improved with the advent of newer antiviral agents, especially those that target carriers of HCV

genotype 1. Direct-acting antiviral agents (DAA) administered in

combination with standard antivirals (pegylated interferon and ribavirin)

have shown significantly higher rates of SVR compared with standard

therapy alone in chronic carriers of HCV genotype 1.114-117 Telaprevir and boceprevir are DAA that are approved by the FDA for the treatment (in

combination with pegylated interferon and ribavirin) of patients with HCV genotype 1 infection. The updated guidelines for the management of HCV infection from the American Association for the Study of Liver Diseases

(AASLD) recommended that DAA be incorporated into standard antiviral therapy for patients infected with HCV genotype 1.118

The Panel recommends initial antiviral therapy in asymptomatic patients with HCV-positive low-grade B-cell lymphomas. For those with HCV

genotype 1, triple antiviral therapy with inclusion of DAAs should be

considered as per AASLD guidelines. Patients with HCV-positive

aggressive B-cell lymphomas should initially be treated with appropriate chemoimmunotherapy regimens according to the NCCN Guidelines for BCell Lymphomas. Liver function and serum HCV RNA levels should be

closely monitored for the development of hepatotoxicity during and after chemoimmunotherapy. Antiviral therapy should then be considered in

patients who achieve a CR after completion of chemoimmunotherapy.

Progressive Multifocal Leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML) is a rare but serious and usually fatal CNS infection caused by reactivation of the latent JC

polyomavirus. PML generally occurs in individuals who are severely

immunocompromised, as in the case of people with HIV and in patients with low CD4+ T-cells prior to or during anti-lymphoma treatment.119-121 PML has been reported in patients with B-cell lymphomas treated with

rituximab (usually in combination with chemotherapy) or brentuximab

vedotin or chemotherapy with purine analogs or alkylating agents.119,122

PML is clinically suspected based on neurologic signs and symptoms

that may include confusion, motor weakness or poor motor coordination, visual changes, and/or speech changes.119 PML is usually diagnosed

with PCR of CSF or, in certain circumstances, by the analysis of brain

biopsy material. There is no effective treatment for PML. Patients should be carefully monitored for the development of any neurologic symptoms. There is currently no consensus on pretreatment evaluations that can be

undertaken to predict the subsequent development of PML.

Methotrexate Toxicity

Glucarpidase should be used for patients with significant renal dysfunction receiving high-dose methotrexate and the guidelines recommend the use of a web-based tool to optimize the administration of glucarpidase (based

on the plasma concentrations of methotrexate) for patients receiving high-dose methotrexate.123

Anti-CD20 Monoclonal Antibody Therapy Intolerance

Rare complications such as mucocutaneous reactions including

paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid

dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis can occur in patients treated with anti-CD20 mAb. Expert consultation with a dermatologist is recommended.

Re-challenge with the same anti-CD20 mAb is not recommended in

patients experiencing the aforementioned complications to chosen

anti-CD20 mAb (rituximab or obinutuzumab). An alternative anti-CD20

mAb (obinutuzumab) could be used for patients with intolerance to

rituximab, including those experiencing severe hypersensitivity reactions requiring discontinuation of chosen anti-CD20 mAb, regardless of

histology.124-126 However, it is unclear if such a substitution poses the

same risk of recurrence.

An FDA-approved biosimilar is an appropriate substitute for rituximab in all subtypes of B-cell lymphomas. Rituximab and hyaluronidase injection for subcutaneous use is approved by the FDA for the treatment of patients

with previously untreated and relapsed/refractory FL and previously

untreated DLBCL, only for patients who have received at least one full

dose of intravenous rituximab.127,128 The guidelines recommend that

rituximab and hyaluronidase injection for subcutaneous use may be

substituted for intravenous rituximab after patients have received the first full dose of rituximab by intravenous infusion. Switching to subcutaneous rituximab is not recommended until a full intravenous dose of rituximab is successfully administered without experiencing severe adverse reactions.

Bone Health in Patients Receiving Steroid-Containing Regimens

Steroid-containing systemic therapy regimens have been associated with increased risk of fractures and treatment-induced bone loss in patients

with B-cell lymphomas.129-131 The risk of treatment-induced bone loss is

higher among young females with chemotherapy-induced premature

menopause and older patients receiving chemotherapy.132,133 In addition, patients with newly diagnosed B-cell lymphomas are also at risk of low

bone mineral density (BMD), which may worsen during treatment with

steroid-based systemic therapy.134 Referral to an endocrinologist with

expertise on bone health and initiation of treatment as per National

Osteoporosis Foundation guidelines is recommended for patients with

osteoporotic BMD, with a history of hip or vertebral fractures, or with

asymptomatic vertebral compression deformity (as seen on imaging

studies).135

Evaluation of vitamin D levels and post-treatment BMD evaluation using a fracture risk assessment tool is recommended for patients receiving

steroid-based systemic therapy.136,137 Adequate calcium intake is essential since corticosteroids block calcium absorption and increase the risk of

fracture. Raloxifene or hormone replacement therapy up until the expected time of natural menopause could be considered in appropriate patients

with premature menopause. Bisphosphonates should be used as first-line pharmacologic treatment for osteoporosis.138,139 Denosumab is an effective alternative option to prevent osteoporotic fractures in patients who cannot tolerate or whose symptoms do not improve with bisphosphonate

therapy.140

References

134. Paccou J, Merlusca L, Henry-Desailly I, et al. Alterations in bone

mineral density and bone turnover markers in newly diagnosed adults with lymphoma receiving chemotherapy: a 1-year prospective pilot study. Ann Oncol 2014;25:481–486. Available at:

https://www.ncbi.nlm.nih.gov/pubmed/24401926.

135. Cosman F, de Beur SJ, LeBoff MS, et al. Clinician's guide to

prevention and treatment of osteoporosis. Osteoporos Int 2014;25:2359–

2381. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25182228.

136. Shaikh AJ, Memon WA. Bone health in survivors of lymphoma,

treated with high dose steroids - is there a need for clearer guidelines on bone care? Asian Pac J Cancer Prev 2011;12:1105–1106. Available at:

https://www.ncbi.nlm.nih.gov/pubmed/21790261.

137. Ottanelli S. Prevention and treatment of bone fragility in cancer

patient. Clin Cases Miner Bone Metab 2015;12:116–129. Available at:

https://www.ncbi.nlm.nih.gov/pubmed/26604936.

138. Kim SH, Lim SK, Hahn JS. Effect of pamidronate on new vertebral

fractures and bone mineral density in patients with malignant lymphoma receiving chemotherapy. Am J Med 2004;116:524–528. Available at:

https://www.ncbi.nlm.nih.gov/pubmed/15063813.

139. Westin JR, Thompson MA, Cataldo VD, et al. Zoledronic acid for

prevention of bone loss in patients receiving primary therapy for

lymphomas: a prospective, randomized controlled phase III trial. Clin

Lymphoma Myeloma Leuk 2013;13:99–105. Available at:

https://www.ncbi.nlm.nih.gov/pubmed/23276888.

140. Cummings SR, San Martin J, McClung MR, et al. Denosumab for

prevention of fractures in postmenopausal women with osteoporosis. N

Engl J Med 2009;361:756–765. Available at:

https://www.ncbi.nlm.nih.gov/pubmed/19671655.

Follicular Lymphoma

Follicular lymphoma (FL) is the most common subtype of indolent

non-Hodgkin lymphoma (NHL) accounting for about 22% of all newly

diagnosed NHLs.1 About 90% of FL have a t(14;18) translocation, which juxtaposes BCL2 with the immunoglobulin heavy chain IGH locus resulting in the deregulated expression of BCL2. In the 2022 WHO Classification of Hematolymphoid Tumors (WHO5), the vast majority of FL that have the

t(14;18) translocation are termed as classic FL (cFL), and another

category called FL with uncommon features (uFL) has been added to

include some of the subtypes of t(14;18)-negative FL.2

Pathologic grading based on the number of centroblasts per high-power

field (HPF) is considered to be a clinical predictor of outcome. In the 2017 WHO classification, FL was divided into three grades (FL1-2, FL3A, and

FL3B) based on the number of centroblasts.3 Since the clinical outcomes for FL1 and FL2 do not differ, FL1 and FL2 were grouped under a single grade (FL1-2) and FL3 was stratified into either 3A (centrocytes still

present) or 3B (sheets of centroblasts). The International Consensus

Classification (ICC) has retained the grading for FL as described in the

2017 WHO classification.4 However, in the updated WHO classification

(WHO5), pathologic grading is no longer required and FL3B has been

renamed as follicular large B-cell lymphoma (FLBL).2 In FL3, classification as FL3A is favored over FL3B in the presence of BCL2-rearrangment

(BCL2-R) and CD10 positivity.4 Accordingly, in one study, FL3B with BCL2 rearrangement was shown to have a clinical course similar to FL1-3A,

whereas FL3B with BCL6 rearrangements had a more aggressive course akin to diffuse large B-cell lymphoma (DLBCL).5

FL1-2 should be managed according to the treatment recommendations

for cFL/low-grade FL. There is no uniform consensus regarding the

optimal treatment approach of FL3A and treatment options need to be

individualized.6-8 FL3B (ICC/FLBL[WHO5]) is commonly treated according to the treatment recommendations for DLBCL.9,10 Any area of DLBCL in an FL of any grade should be diagnosed and treated as a DLBCL.

FL with a predominantly diffuse pattern is often characterized by the

absence of the t(14;18) translocation (BCL2-R negative), presence of

STAT6 mutations, 1p36 deletion or TNFRSF14 mutation, pelvic/inguinal

lymph node involvement, uniform CD23 expression, and low clinical

stage.11-14 As such, the ICC designates these cases under the new

provisional entity, BCL2-R negative, CD23-positive follicle center

lymphoma.4 It is typically grade 1–2 with a good prognosis and should be managed according to treatment recommendations for cFL. This variant is not recognized as a distinct entity in the WHO5.2

Large B-cell lymphoma (LBCL) with IRF4 rearrangement, which occurs

most commonly in children and young adults, is considered as a definite

entity in ICC and WHO5.2,4 These lymphomas are characterized by strong expression of IRF4/MUM1, and may have a follicular, follicular and diffuse, or pure diffuse growth pattern resembling FL3B or DLBCL.15 Patients

typically present with Waldeyer’s ring and/or cervical lymph node or

gastrointestinal (GI) tract involvement, and low clinical stage. They have

locally aggressive disease that responds well to chemotherapy with or

without radiation therapy (RT). LBCL with IRF4 rearrangement should be managed according to treatment recommendations for DLBCL.

Pediatric-type FL (PTFL) is a biologically and clinically distinct indolent

lymphoma and can also occur in adults.2,4 PTFL is characterized by lack of BCL2, BCL6, and IRF4 rearrangements.16-19 MAP2K1 and TNFRSF14

mutations are the most frequent genetic alterations found in PTFL.20-22 The diagnosis and management of PTFL in adults is discussed on MS-18.

This discussion corresponds to the NCCN Guidelines for B-Cell Lymphomas. Last updated: August 18, 2025.

In situ follicular neoplasia (ISFN) is characterized by the presence of

FL-like B-cells in the germinal centers of morphologically reactive lymph

nodes; preservation of the lymph node architecture, with the incidental

finding of focal strongly positive staining for BCL2 (restricted to germinal

centers) and CD10 in the involved follicles; and the detection of t(14;18) by fluorescence in situ hybridization (FISH).2,4,23-25 ISFN has been reported in patients with prior FL or concurrent FL (at other sites), as well as in

individuals with no known history of FL, and the prevalence of ISFN in the general population has been reported to be 2%.23,24,26 Although

uncommon (5%–6%), the development of or progression to overt

lymphoma has been reported in patients reported to have ISFN.27,28 The

significance or potential for malignancy of ISFN in patients without known FL remains unclear. These instances may potentially represent the tissue counterpart of circulating B cells with t(14;18), or may represent a very

early lesion with t(14;18) but without other genetic abnormalities that lead to overt lymphoma.27,29 If the diagnosis of ISFN is determined in lymph

node pathology, it is recommended that the patient be evaluated for the

presence of FL elsewhere, with consideration for ongoing follow-up.

Duodenal type FL is a distinct entity that is typically localized to the small intestine. The morphology, immunophenotype, and genetic features are

similar to those of nodal FL1-2. However, most patients have clinically

indolent and localized disease. Survival appears to be excellent even

without treatment. In many of the other extranodal sites, the morphology, immunophenotype, and genetic features are similar to those of nodal FL. Patients usually have localized disease and systemic relapses are rare.

Literature Search Criteria

Prior to the update of this version of the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for B-Cell Lymphomas an electronic

search of the PubMed database was performed to obtain key literature in FL published since the previous Guidelines update. The PubMed

database was chosen as it remains the most widely used resource for

medical literature and indexes peer-reviewed biomedical literature.30

The search results were narrowed by selecting studies in humans

published in English. Results were confined to the following article types: Clinical Trial, Phase II; Clinical Trial, Phase III; Clinical Trial, Phase IV;

Guideline; Randomized Controlled Trial; Meta-Analysis; Systematic

Reviews; and Validation Studies.

The data from key PubMed articles as well as articles from additional

sources deemed as relevant to these Guidelines as discussed by the

Panel during the Guidelines update have been included in this version of the Discussion section. Recommendations for which high-level evidence is lacking are based on the Panel’s review of lower-level evidence and

expert opinion.

Diagnosis

Immunophenotyping using immunohistochemistry (IHC) and/or flow

cytometry for cell surface marker analysis is required to establish a

diagnosis. FL has a characteristic immunophenotype, which includes

CD20+, CD10+, BCL2+, CD23+/-, CD43-, CD5-, CCND1-, and BCL6+.

Occasionally, FL may be CD10- or BCL2-. The diagnosis is easily

established on histologic grounds, but immunophenotyping is encouraged to distinguish FL from mantle cell lymphoma (MCL), marginal zone

lymphoma (MZL), or small lymphocytic lymphoma (SLL).

IHC for Ki-67, IRF4/MUM1 and cyclin D1, molecular genetic analysis to

detect BCL2 rearrangement, and karyotype or FISH to identify t(14;18), BCL6, 1p36, and IRF4/MUM1 gene rearrangements may be useful under certain circumstances. Low-grade FL with a high proliferation index (Ki-67

≥30% as determined by immunostaining) has been shown to be

associated with an aggressive clinical behavior in some studies.31,32 There is no evidence, however, that high Ki-67 should guide the selection of

therapy. As discussed above, LBCL with IRF4 rearrangement, which

occurs most commonly in the pediatric population (children and young

adults), is associated with favorable outcomes and consistently expresses IRF4/MUM1.33,34 Therefore, in young patients with FL3B expressing

IRF4/MUM1, LBCL with IRF4 rearrangement should be included in the

differential diagnosis and evaluation for IRF4 alterations is recommended. In patients with localized disease that lacks t(14;18), the differential

diagnosis may include PTFL; BCL2-R negative/CD23-positive follicle

center lymphoma and LBCL with IRF4/MUM1 rearrangement.

The Follicular Lymphoma International Prognostic Index (FLIPI) is a

prognostic scoring system that divides patients into three distinct

prognostic groups. FLIPI1 is based on age, Ann Arbor stage, and number of nodal sites involved; hemoglobin level; and serum lactate

dehydrogenase (LDH) level.35 FLIPI1 was developed in the pre-rituximab era, but it has also been shown to retain its prognostic significance in the modern chemoimmunotherapy era.36 FLIPI-2 was developed based on

prospective collection of data from patients with newly diagnosed FL

treated in the rituximab era and is based on age, hemoglobin level, longest diameter of largest involved lymph node, beta-2 microglobulin level, and

bone marrow involvement.37 FLIPI-2 was highly predictive of treatment

outcomes, and separated patients into three distinct risk groups with

5-year progression-free survival (PFS) rates of 79%, 51%, and 20% for

patients with low-risk disease, intermediate-risk disease, and high-risk

disease, respectively (P < .00001). The FLIPI-2 also defined distinct risk

groups among the subgroup of patients with FL treated with

rituximab-containing regimens, with 5-year PFS rates of 98%, 88%, and

77% for patients with low-risk disease, intermediate-risk disease, and

high-risk disease, respectively (P < .0001).37 Thus, FLIPI-2 may be useful for assessing prognosis in patients receiving active therapy with

rituximab-based regimens. A simpler prognostic index incorporating only

the baseline serum beta 2-microglobulin and LDH levels has been

developed, which is easier to apply and also appears to be as predictive of outcomes as the FLIPI-1 and FLIPI-2 indices.38 Although these index

scores predict for prognosis, they have not yet been established as a

means of selecting treatment options.

Another risk model (m7-FLIPI) incorporating the mutation status of seven genes (EZH2, ARID1A, MEF2B, EP300, FOXO1, CREBBP, and

CARD11), FLIPI, and Eastern Cooperative Oncology Group (ECOG)

performance status has been developed to improve risk stratification in

patients with advanced-stage FL receiving first-line

chemoimmunotherapy.39,40 The m7-FLIPI was prognostic in patients

receiving RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) or RCVP (rituximab, cyclophosphamide, vincristine,

prednisone) and EZH2 mutation status was also associated with longer

PFS in patients treated with CHOP (cyclophosphamide, doxorubicin,

vincristine, prednisone) or CVP (cyclophosphamide, vincristine,

prednisone) with rituximab or obinutuzumab; however, the prognostic

significance of m7-FLIPI or the EZH2 mutation was not retained in patients treated with bendamustine-based regimens.40 These findings need to be confirmed in larger validation studies.

A next-generation sequencing (NGS) panel including EZH2, TNFRSF14, and STAT6 will be useful in selected patients to confirm the differential

diagnosis or for the selection of treatment with an EZH2 inhibitor.

Workup

The initial workup should include a thorough physical examination with

attention to node-bearing areas, and evaluation of performance status and

constitutional symptoms. Laboratory assessments should include

complete blood count (CBC) with differential and a comprehensive

metabolic panel, in addition to measurements of serum LDH levels.

Testing for hepatitis B virus (HBV) should be performed for all patients.

HBV testing is indicated due to the risk of viral reactivation in patients

receiving chemoimmunotherapy. Measurement of uric acid, serum beta-2 microglobulin (necessary for calculation of FLIPI-2), and testing for

hepatitis C virus (HCV) may be useful in certain circumstances.

Bone marrow biopsy with aspirate is essential to document clinical stage I–II disease. Adequate bone marrow aspiration and biopsy should be

obtained for initial staging evaluation. However, in patients with low-tumorburden indolent lymphoma with radiographic clinical stage III disease, an initial staging bone marrow evaluation can be deferred if active

surveillance is the initial option as it will not change the clinical

recommendations.

Chest/abdomen/pelvis CT with contrast of diagnostic quality and/or

whole-body PET/CT scan are recommended as part of initial diagnostic

workup. PET/CT scan is essential if RT is planned for stage I–II disease. CT scan of the neck may also assist in defining the extent of local disease. Multigated acquisition (MUGA) scan or echocardiogram is recommended for patients being considered for treatment regimens containing

anthracyclines.

Role of PET/CT in FL

Diagnosis and Workup

PET/CT scans are more accurate than CT scans alone in the detection of disease in patients with indolent lymphomas, and several studies have

reported high sensitivity (94%–98%) and specificity (88%–100%) for

PET/CT scans for indolent lymphomas.41-43

PET scans may also be useful for the detection of histologic

transformation of FL to DLBCL, since standard fluorodeoxyglucose (FDG) uptake values (SUVs) on PET scans have been reported to be higher

among transformed than non-transformed indolent lymphomas.44-48 In one retrospective study, maximum standardized uptake values (SUVmax) >10

and >13 were associated with high specificity for the detection of histologic transformation.46 The presence of sites of disease with discordantly high SUVmax on PET scan (baseline SUVmax >10 or >20) should raise the

suspicion of histologic transformation to DLBCL, and can be used to direct the optimal site of biopsy for histologic confirmation.45,46,48

However, a retrospective analysis of the GALLIUM study that assessed

the relationship between SUVmax at baseline PET scans and the risk of

histologic transformation showed that higher baseline SUVmax was not

associated with subsequent histologic transformation.49 In another

retrospective analysis, the use of SUVmax along with total lesion

glycolysis (TLG) and serum LDH improved the identification of histologic transformation of indolent lymphomas.50 These findings suggest that

higher SUVmax on PET scan alone may not be indicative of histologic

transformation. Therefore, PET scan findings alone are not sufficient for

the diagnosis of transformation. Histologic confirmation and evaluation of

clinical features are necessary to determine the presence of histologic

transformation.

Post-treatment Response Evaluation

The prognostic utility of post-treatment PET scans (PET negativity was

associated with a longer PFS compared to PET positivity) has also been demonstrated in several studies.51-57

In a retrospective study in patients with FL treated with RCHOP, PET/CT imaging was found to be more accurate than CT imaging in detecting both nodal and extranodal lesions at staging and in assessing response to

treatment.54 Post-treatment PET/CT negativity was associated with more favorable PFS outcomes; median PFS was 48 months if the PET/CT was negative compared with 17 if the PET/CT was positive (P < .001).54

An exploratory retrospective analysis of the prognostic value of

post-induction PET/CT scans was conducted based on data obtained from

MS-26

the PRIMA trial of patients with FL. 55 Among patients with a post-induction PET/CT scan (n = 122), those with a positive PET/CT scan had a significantly inferior PFS rate compared with those who were PET negative (33% vs. 71% at 42 months; P < .001). The median PFS was 21 months and not reached, respectively. Among the patients randomized to observation, the 42-month PFS rate was 29% for patients with positive PET/CT scans compared with 68% for patients with negative PET/CT scans; median PFS was 30 months and 52 months, respectively. Among the patients randomized to rituximab maintenance (n = 47), PET/CT positivity was associated with inferior (but not statistically significant) PFS outcomes compared with PET/CT negativity (56% vs. 77% at 41 months); median PFS has not yet been reached in the subgroups of patients with either positive PET/CT or negative PET/CT scans. PET/CT status was also associated with overall survival (OS) outcomes in this exploratory analysis. Patients with positive PET/CT scans after induction therapy had significantly inferior OS compared to patients with negative PET/CT scans (79% vs. 97% at 42 months; P = .001).

The prognostic value of PET scans in patients with high-tumor-burden FL treated with first-line therapy with 6 cycles of RCHOP (n = 121; no rituximab maintenance administered) was also evaluated in a prospective study. 56 PET scans were performed after 4 cycles of RCHOP (interim PET) and at the end of treatment (final PET), and all scans were centrally reviewed. A positive PET scan was defined as a Deauville score of ≥4. Among patients with an interim PET scan (n = 111), 76% had a PET-negative response. Among patients with a final PET scan (n = 106), 78% had a PET-negative response. 56 At the end of treatment, nearly all patients (98%) who achieved a complete response (CR) based on International Working Group (IWG) response criteria also achieved a PET-negative response. Interim PET was associated with significantly higher 2-year PFS (86% for PET-negative vs. 61% for PET-positive; P = .0046) but no significant difference in terms of OS. Final PET negativity was associated with both significantly higher 2-year PFS (87% vs. 51%; P < .001) and higher OS (100% vs. 88%; P = .013). 56 ese studies suggest that post-treatment imaging studies may have a role as a predictive factor for survival outcomes in patients with FL. End-of-treatment PET/CT scan is now considered a standard part of post-treatment response evaluation in patients with indolent lymphomas. Further prospective studies are warranted to determine whether interim PET scans have a role in guiding post-induction therapeutic interventions.

Surveillance

Little data exist on the potential role of follow-up surveillance imaging for detection of relapse in patients with indolent NHL. In an early retrospective study, patients with stage I to stage III FL with a CR after induction were evaluated with clinical, laboratory, and imaging studies during routine follow-up (n = 257). 58 Patients underwent CT scans of the abdomen and/or pelvis during follow-up visits. Follow-up was typically performed every 3 to 6 months for the first 5 years of treatment, and then annually thereafter. The median follow-up time was 80 months. Relapse was detected in 78 patients, with the majority of relapses (77%) occurring within the first 5 years of treatment. 58 Eleven of the relapses were detected with abdomen and/or pelvis CT scans alone. Thus, in this analysis, 4% of patients with an initial CR had recurrence determined by routine surveillance with CT scans. 58 e role of surveillance PET scans in patients with lymphomas (Hodgkin lymphoma and NHL) with a CR after induction was also evaluated in a prospective study. 59 PET scans were performed every 6 months for the first 2 years after completion of induction, then annually thereafter. In the cohort of patients with indolent NHL (n = 78), follow-up PET scans detected true relapses in 10% of patients at 6 months, 12% at 12 months, 9% at 18 months, 9% at 24 months, 8% at 36 months, and 6% at 48 months. Among 13 patients with a positive PET scan without a

References

MS-27

Abstract

corresponding abnormality on CT scan, relapse was documented by biopsy in 8 patients. Of the 47 patients with PET-positive disease relapse, disease relapse was detected on CT for 38 patients and disease relapse was detected clinically (at the same time as the PET scan) for 30 patients. It is unclear whether this earlier detection of relapse in a proportion of patients translates to improved outcomes.

In the absence of evidence demonstrating improved survival outcomes with early PET detection of relapse, PET scans are not recommended for routine surveillance in patients who have achieved a CR after treatment. When a disease can only be visualized on PET/CT scan (eg, bone), it is appropriate to proceed with PET/CT scans for surveillance.

Stage I-II

] [62] The 15-year PFS outcomes were influenced by disease stage (66% for stage I vs. 26% for stage II disease) and maximal tumor size (49% for tumors < 3 cm vs. 29% for ≥3 cm). The OS rate was not significantly different between extended-field RT compared with involved-filed RT (49% vs. 40%, respectively), and the reduction in radiation field (RT of involved nodes only) did not impact PFS or OS outcomes. 61,62 A multicenter retrospective study conducted by the International Lymphoma Radiation Oncology Group also established RT alone (≥24 Gy) as a potentially curative treatment option for patients with untreated stage I-II FL (512 patients staged by PET/CT; 410 patients had stage I disease). 63 The 5-year freedom-from-progression (FFP) and OS rates were 69% and 96% for the entire study population, after a median follow-up of 52 months. The 5-year FFP rate was 74% for patients with stage I FL compared to 49% for those with stage II FL (P < .0001).

[66] [67] [68] [69] [70] Long-term outcomes from a study of RT in patients with early-stage grade 1-2 FL (with or without chemotherapy) reported a median OS of 19 years and a 15-year OS rate of 62%. 65 In this study, the majority of patients (74%) had stage I disease and 24% had received chemotherapy with RT, which may have resulted in the higher OS rate reported compared with the other studies. The results of a multicenter observation study (n = 94) showed that the addition of rituximab to involved-site RT (ISRT) significantly prolongs PFS in patients with stage I-II disease. 69 The 10-year PFS rates were 65% and 51% for rituximab + RT and RT alone, respectively (P < .05). However, the OS rates were not significantly different between the treatment groups. In the phase III randomized trial of the Trans-Tasman Radiation Oncology Group (TROG 99.03) that evaluated IFRT versus IFRT followed by CVP (cyclophosphamide, vincristine, and prednisone) + rituximab (RCVP) in 150 patients with early-stage FL, at a median follow-up of 10 years, IFRT followed by RCVP was associated with superior PFS compared to IFRT alone. 70 The 10-year PFS rates were 59% and 41%, respectively. However, the 10-year OS rate was not significantly different between the treatment arms (95% and 87%, respectively).

In retrospective studies that have evaluated the outcomes of patients with stage I-II FL with various treatment approaches (active surveillance, RT, rituximab monotherapy, chemoimmunotherapy, and combined modality with RT), no differences in OS outcomes were observed between the various management approaches. 71, 72 Carefully selected patients (requirement of large abdominal radiation field, advanced age, concern for xerostomia, or patient refusal) with stage I-II disease who did not receive

References

immediate treatment had comparable outcomes to those who were treated with RT.73

Stage I or Stage II Disease (contiguous)

ISRT (24–30 Gy) is the preferred treatment option. Initiation of systemic

therapy can improve FFS, but has not been shown to improve OS.71,72

ISRT in combination with CD20-directed monoclonal antibody (mAb) with or without chemotherapy is included as an alternate option. CD20-directed mAb with or without chemotherapy can be considered in selected patients with bulky intra-abdominal or mesenteric stage I disease. Active

surveillance may be appropriate in circumstances where potential toxicity of ISRT or systemic therapy outweighs potential clinical benefit.73

No further treatment is necessary for patients achieving CR or partial

response (PR) to initial therapy. Clinical follow-up with a complete history and physical exam and laboratory assessment is recommended every 3 to 6 months for the first 5 years, and then annually (or as clinically indicated) thereafter. Surveillance imaging with CT scans can be performed no more than every 6 months up to the first 2 years following completion of

treatment, and then no more than annually thereafter.

Patients with disease not responding to initial therapy with ISRT should

receive treatment as described for stage III or IV disease. Patients with

disease not responding to initial therapy with CD20-directed mAb with or without chemotherapy should be treated with second-line or subsequent therapy. Rebiopsy to rule out histologic transformation is recommended

prior to the initiation of second-line or subsequent therapy.

Stage II Disease (non-contiguous)

CD20-directed mAb with or without chemotherapy is recommended for

patients with non-contiguous stage II disease. ISRT can be used in

combination with systemic therapy for local palliation. Active surveillance may be appropriate in circumstances where the toxicity of systemic

therapy ± ISRT for local palliation outweighs potential clinical benefit.73

Clinical follow-up and surveillance imaging (as described above) are

recommended for patients achieving CR to initial therapy.

ISRT can be considered if not previously given, for patients with a PR or no response to initial therapy. Clinical follow-up and surveillance imaging (as described above) are recommended for patients with disease

responding to ISRT. Patients with disease not responding to ISRT should be treated with second-line or subsequent therapy. Rebiopsy to rule out histologic transformation is recommended prior to the initiation of secondline or subsequent therapy as described for relapsed or progressive

disease.

Stage III–IV

Several prospective randomized trials did not demonstrate OS benefit with immediate treatment versus watchful waiting in patients with advancedstage, low-tumor-burden, or asymptomatic FL.74-78 Although immediate

treatment with rituximab monotherapy results in significantly longer

median time to initiation of new treatment compared with watchful waiting, it does not improve OS.75-78

In an analysis of the data from the F2-study registry of the International

Follicular Lymphoma Prognostic Factor Project, outcomes in a cohort of

patients with asymptomatic, advanced-stage, low-tumor-burden FL who

were initially observed (“watch and wait” approach; n = 107) were

compared with the outcomes of patients who had low tumor burden,

asymptomatic FL, but were initially treated with rituximab-containing

regimens (n = 242).75 The endpoint for the comparison was freedom from treatment failure (FFTF), which was defined as the time from diagnosis to one of the following events: progression during treatment, initiation of

second-line therapy, relapse, or death from any cause. In the “watch and wait” cohort, initiation of first-line therapy was not considered an event for

FFTF. The 4-year FFTF rate was 79% in the “watch and wait” cohort

compared to 69% in the cohort of patients initially treated with

rituximab-containing regimens; the difference was not significant after

adjusting for differences in baseline disease factors between the cohorts. In addition, the 5-year OS rates were similar (87% vs. 88%, respectively).

The role of immediate treatment with rituximab (with or without additional rituximab maintenance) versus watchful waiting in patients with advancedstage, asymptomatic, low-tumor-burden FL was evaluated in a

randomized phase III intergroup trial (187 patients were assigned to

watchful waiting; 192 patients were assigned to maintenance rituximab;

and 84 patients were assigned to the induction therapy with rituximab,

though this arm was closed early).76,77 The primary endpoint of this trial

was time to initiation of new treatment from randomization. Long-term

follow-up data showed that there was a significant difference in the

percentage of patients not needing new treatment between the treatment arms. At 15 years, the percentage of patients not needing new treatment was 34% in the watchful waiting group, 48% in the rituximab induction

group (P < .0001), and 65% in the rituximab maintenance group (P <

.0001), suggesting that rituximab monotherapy should be considered for patients with asymptomatic, advanced-stage, low-tumor-burden FL.77 The 4-year PFS rates were also higher in the two treatment arms (57% for

rituximab induction and 78% for rituximab maintenance) compared to

watchful waiting (32%). However, no differences in OS were observed

between the study arms. The 15-year OS rates were 68%, 66%, and 73%for the watchful waiting group, rituximab induction group and rituximab

maintenance group, respectively. The endpoint chosen for this trial,

however, is also rather controversial considering that one arm of the trial involved initiation of early therapy; a more justifiable endpoint for this study could have been “time to initiation of second therapy.”

A report from the National LymphoCare Study that compared the

outcomes of patients with stage II–IV FL who were observed (“watchful

waiting”; n = 386), received rituximab monotherapy (n = 296), or received rituximab plus chemotherapy (n = 1072) as an initial management strategy

also confirmed that there was no signiﬁcant difference in OS between the

3 different management strategies.78 With a median follow-up of 8 years, the estimated 8-year OS rates were 74%, 67%, and 72% for the watchful waiting group, rituximab monotherapy group, and rituximab plus

chemotherapy group, respectively.

Collectively, findings from clinical studies suggest that immediate initial

treatment with rituximab monotherapy is effective in delaying time to next treatment (TTNT) in patients with advanced-stage, low-tumor-burden FL but does not improve OS.

Active surveillance is still the standard practice outside the context of

clinical trials for patients with advanced-stage, low-tumor-burden FL

without indications for treatment and treatment should only be initiated

when a patient presents with indications for treatment: symptoms

attributable to FL (not limited to B symptoms); threatened end-organ

function; clinically significant or progressive cytopenia secondary to

lymphoma; clinically significant bulky disease (any nodal or extranodal

tumor mass with a diameter ≥7 cm); and steady or rapid progression.

Suggested treatment regimens for first-line therapy are discussed below. Regimens are stratified into 3 categories (based on the evidence, efficacy, and toxicity; preexisting comorbidities; and access to certain agents):

Preferred, Other Recommended, and Useful in Certain Circumstances.

Active surveillance or optional consolidation or extended therapy are

included as options for patients achieving CR or PR to first-line therapy

Options are discussed under First-Line Consolidation or Extended

Therapy. Patients with disease not responding to first-line therapy or those

with progressive disease should be treated with second-line or subsequent therapy regimens as described for relapsed or progressive disease.

Rebiopsy to rule out histologic transformation is recommended prior to the initiation of second-line or subsequent therapy.

Chimeric antigen receptor (CAR) T-cell therapy or bispecific antibody

therapy is an option for patients with PR, refractory or progressive disease after ≥2 prior systemic therapy regimens. See Relapsed or Progressive

Disease: Third-Line Therapy.

First-Line Therapy: Preferred Regimen (low tumor burden)

Rituximab

While active surveillance is a reasonable option for patients with lowtumor-burden FL, rituximab monotherapy is a proactive and effective

strategy supported by several studies.77,79-83

Long-term follow-up data from the international randomized trial

evaluating immediate treatment with rituximab (with or without additional rituximab maintenance) versus watchful waiting showed that rituximab

induction is effective in delaying TTNT and was also associated with

superior PFS rates compared to watchful waiting (although this did not

translate into OS benefit).77 A short course (4 weekly courses) of

rituximab, as compared with extended treatment in the RESORT trial,

may optimize the benefit/risk ratio and reduce inconvenience, with similar

long-term survival.82,83

Rituximab is also available in a subcutaneous formulation, though

potentially subject to formulary and payer considerations. The results of

the phase III randomized LYSA study (n = 100, subcutaneous rituximab; n = 100, intravenous rituximab) showed that induction with subcutaneous

rituximab followed by short maintenance improved PFS in patients with

low-tumor-burden FL.84 The 4-year PFS rate was 58% and 41% for

subcutaneous and intravenous rituximab arms, respectively (P = .0076).

CR rates were 59% and 36% for the two treatment arms respectively (P = .001). TTNT and OS were not significantly different, and improved

outcomes were strongly associated with drug exposure in the first 3

months (superior with the subcutaneous administration).

While rituximab monotherapy is a preferred regimen for treatment of lowtumor-burden FL, it has not demonstrated a proven benefit over active surveillance in terms of OS or decreased risk of histologic

transformation.

First-Line Therapy: Preferred Regimens (high tumor burden)

Chemoimmunotherapy With CD20-Directed mAb (obinutuzumab or rituximab)

Based on the results from phase III randomized trials (discussed below),

bendamustine, CHOP, or CVP with obinutuzumab or rituximab and

lenalidomide + rituximab are included as preferred regimens for patients

with advanced-stage, high-tumor-burden FL in patients with indications for treatment.

In randomized studies that have compared chemoimmunotherapy

regimens, no statistically significant difference in OS benefit was observed between the chemoimmunotherapy regimens.85-88

The phase III randomized trial of the Italian Lymphoma group (FOLL-05

Trial) evaluated the efficacy of RCVP and RCHOP compared to

fludarabine-based chemoimmunotherapy (RFM; rituximab, fludarabine,

and mitoxantrone) as a first-line treatment option in patients with

advanced-stage FL (n = 534).85 The primary endpoint of this study was

time to treatment failure (TTF). RCHOP and RFM were superior to RCVP

in terms of 3-year TTF and PFS rates. After a median follow-up of 34

months, the 3-year TTF rate was 46% for patients randomized to RCVP,

compared to 62% (P = .003) and 59% (P = .006), respectively, for RCHOP and RFM. The 3-year PFS rates were 52%, 68%, and 63%, respectively

Abstract

No significant differences were observed between treatment arms for overall response rate (ORR), CR rates, or 3-year OS rate. The 3-year OS rate was 95% for all patients in this study. 85 However, RFM was much more toxic than RCHOP or RCVP, with grade 3 or 4 neutropenia occurring in 64% of patients, compared with 50% with RCHOP and only 28% with RCVP. In addition, the incidences of secondary malignancies were also more common with RFM (8%) than with RCVP (2%) or RCHOP (3%).

The multicenter randomized StiL NHL1 phase III study showed that BR (bendamustine and rituximab) was superior to RCHOP in terms of PFS in all histologic subtypes (indolent and MCL). 86 At a median follow-up of 45 months, the median PFS was 69 months and 31 months (P < .0001), respectively, for BR and RCHOP. 86 The ORR was similar between treatment arms (93% with BR; 91% with RCHOP), although the CR rate was significantly higher in the BR arm (40% vs. 30%; P = .021). BR was associated with less frequent grade 3 or 4 neutropenia (29% vs. 69%) or infections (any grade; 37% vs. 50%), whereas erythema (16% vs. 9%) and allergic skin reactions (15% vs. 6%) were more common with BR compared with RCHOP. The incidence of secondary malignancies was similar (8% with BR and 9% with RCHOP). However, the OS outcomes were not significantly different between treatment arms, even after long-term follow-up; the estimated 10-year survival rates were 71% and 66%, respectively, for BR and RCHOP.

Another multicenter, randomized, open-label, phase III study (BRIGHT) that evaluated the efficacy and safety of the BR compared with RCHOP or RCVP in patients with previously untreated indolent lymphoma or MCL (419 patients; 154 patients with FL were randomized to BR and 160 patients were randomized to RCHOP or RCVP) also showed that BR was non-inferior to RCHOP or RCVP with regard to CR rate and PFS. 87 The CR rates (assessed by an independent review committee) were 30% and 25%, respectively (P = .02) for BR and RCHOP/RCVP in the subgroup of patients with FL. At a median follow-up of 5 years, the corresponding 5-year PFS rates were 70% and 62%, respectively (P = .05) for the subgroup of patients with indolent lymphomas and the 5-year OS rate was not statistically different between the treatment groups (82% and 85%, respectively; P = .5461). In addition, the incidence of opportunistic infections and secondary malignancies was also slightly higher in patients receiving BR.

The phase III randomized GALLIUM trial compared the efficacy and safety of obinutuzumab and rituximab when used in combination with chemotherapy (bendamustine, CHOP, or CVP) in patients with previously untreated advanced-stage FL (1202 patients were randomized [1:1] to receive obinutuzumab or rituximab in combination with chemotherapy). 88 atients with disease responding to induction chemoimmunotherapy received maintenance treatment with the same antibody for up to 2 years. However, this trial was not designed to compare the chemotherapy regimens. A planned interim analysis (after a median follow-up of 34 months) and the final analysis (after a median follow-up of 8 years) showed that obinutuzumab-based chemoimmunotherapy was associated with significantly longer PFS and lower risk of progression and relapse than rituximab-based chemoimmunotherapy. 88, 89 The estimated 7-year PFS rates were 63% and 56%, respectively (P = .006). However, response rates at the end of induction treatment were not significantly different between the two groups (88% for the obinutuzumab-based chemoimmunotherapy and 87% for rituximab-based chemoimmunotherapy) and OS was similar in both groups (7-year OS rates were 89% and 87%, respectively; P = .36). In addition, grade ≥3 treatment-emergent adverse events (TEAEs) were higher with obinutuzumab than with rituximab (infections, 20% vs. 16%; neutropenia, 46% vs. 39%; and infusion-related reactions, 12% vs. 7%) and bendamustine was associated with higher rates of grade 3 to 5 infections

References

and secondary cancers.88 Non-relapse–related fatal adverse events were also more common with bendamustine (6% in the obinutuzumab group

and 4% in the rituximab group) than with CHOP or CVP (2% for both

regimens when used in combination with obinutuzumab or rituximab).

The Panel acknowledged that chemoimmunotherapy with CD20-directed mAb (obinutuzumab or rituximab) is an appropriate first-line therapy for patients with advanced-stage FL requiring treatment. However, in the

absence of data from randomized trials showing significant OS benefit

for one chemoimmunotherapy regimen over another, the Panel

concluded that the available data are not strong enough to designate

obinutuzumab-based chemoimmunotherapy as superior to

rituximab-based chemoimmunotherapy. The Panel consensus was to list all of the chemoimmunotherapy regimens as preferred regimens with

category 2A recommendation.

The selection of a chemoimmunotherapy should be highly individualized

according to the patient’s age, extent of disease, presence of comorbid

conditions, and the goals of therapy. When choosing an initial therapy,

care should be given to avoid excessively myelotoxic regimens in patients who may subsequently be candidates for high-dose therapy

(HDT)/autologous stem cell rescue (ASCR). Chemoimmunotherapy

regimens may be associated with risks for HBV reactivation, which can

lead to hepatitis and hepatic failure. Therefore, prior to initiation of therapy, HBV testing (including HBsAg and HBcAb testing) should be performed for all patients; viral load should be monitored routinely for patients with

positive test results. In addition, the use of empiric antiviral therapy or

upfront prophylaxis should be incorporated into the treatment plan. In the GALLIUM study, there was an increased risk of mortality from

opportunistic infections and secondary malignancies in patients receiving bendamustine, and the rates of severe infections were also higher with

bendamustine than with CHOP or CVP during the maintenance and

follow-up phases.88 The Panel recommends that prophylaxis for

pneumocystis jirovecii pneumonia (PJP) and varicella zoster virus (VZV) should be administered for patients receiving bendamustine.

Lenalidomide + Rituximab

The results from the multicenter, international, randomized phase III study (RELEVANCE) showed that the efficacy of lenalidomide + rituximab was similar to that of chemotherapy + rituximab in patients with previously

untreated advanced-stage FL.90,91 In this study, 1030 patients were

randomized to receive lenalidomide + rituximab (n = 513) or chemotherapy

+ rituximab (investigator’s choice of one of the 3 regimens: RCHOP,

RCVP, or BR; n = 517) followed by maintenance therapy with rituximab.

The ORR (84% for lenalidomide + rituximab and 89% for chemotherapy +rituximab), CR rate at 120 weeks (48% and 53%, respectively; P = .13),

estimated 6-year PFS rate (60% and 59%, respectively), and OS rate

(89% for both groups) were similar in the two treatment groups.

Lenalidomide + rituximab was associated with lower rates of grade 3 or 4 neutropenia (32% vs. 50%) and febrile neutropenia of any grade (2% vs.

7%) than chemotherapy + rituximab. Grade 3 or 4 cutaneous reactions

were higher with lenalidomide + rituximab (7% vs. 1%).

Although the RELEVANCE trial (which was designed as a superiority trial) did not show that lenalidomide + rituximab was superior to chemotherapy

+ rituximab in terms of efficacy, this trial confirmed lenalidomide +

rituximab as an effective alternative to chemoimmunotherapy for patients with previously untreated FL.90,91 Based on the results of this study, the

Panel consensus was to include lenalidomide + rituximab as an option for preferred regimen with a category 2A recommendation.

First-Line Therapy: Other Recommended Regimens

Lenalidomide + Obinutuzumab

In the phase II GALEN study (n = 100), first-line induction therapy with

lenalidomide + obinutuzumab resulted in an ORR of 92% (20% CR).92 At a median follow-up of 4 years, the 3-year PFS and OS rates were 82% and 94, respectively. Neutropenia was the most common grade ≥3 adverse

event reported in 47% of patients.

Lenalidomide + obinutuzumab is included as an option with a category 2B recommendation.

First-Line Consolidation or Extended Therapy

Several studies have reported that prolonged administration of rituximab (or rituximab maintenance) significantly improved event-free survival

(EFS) in patients who have not received chemotherapy with disease

responding to initial rituximab induction, although this benefit did not

translate to OS advantage.93-96

The phase III randomized trial (E4402 study; RESORT) compared

rituximab maintenance versus rituximab retreatment in patients with

previously untreated low-burden FL responding to rituximab induction

therapy.82 In this study, 289 patients were randomized to receive

maintenance with rituximab or rituximab retreatment. Patients receiving

rituximab retreatment were eligible for retreatment at each disease

progression until treatment failure. The primary endpoint of this trial was

TTF. At a median follow-up of 5 years, the estimated TTF was similar for patients receiving rituximab maintenance and rituximab retreatment (4

years for both treatment arms; P = .54). The 3-year freedom from cytotoxic therapy was 95% and 84%, respectively, for those receiving rituximab

maintenance and rituximab retreatment (P = .03). These results suggest that rituximab retreatment provides comparable disease control to

rituximab maintenance in patients with low-burden FL. Long-term data

from RESORT trial confirmed that maintenance rituximab does not confer an OS advantage in low-tumor-burden FL, a finding consistent with that

reported in other studies that have evaluated maintenance rituximab.83

The phase III randomized PRIMA trial evaluated the role of rituximab

maintenance in patients with FL responding to first-line

chemoimmunotherapy.97 In this study, patients with FL responding to

first-line chemoimmunotherapy (RCVP, RCHOP, or RFCM [rituximab,

fludarabine, cyclophosphamide, and mitoxantrone]) were randomized to observation only or rituximab maintenance for 2 years (n = 1018). After a median follow-up of 36 months, the 3-year PFS rate was 75% in the

rituximab maintenance arm and 58% in the observation arm (P = .0001). Two years after randomization, 71% of patients in the rituximab

maintenance arm were in CR/CR unconfirmed (CRu) compared with 52% in the observation group. However, no significant difference was observed in OS between the two groups. Based on multivariate analysis, induction therapy with RCHOP or RFCM was one of the independent factors

associated with improved PFS, suggesting that RCVP induction was not as beneficial in this study. Long-term follow-up data confirmed that

rituximab maintenance is associated with significant PFS benefit over

observation.98 At 10 years, median PFS was 10.5 years in the rituximab

maintenance arm compared to 4 years in the observation arm. The OS

estimates were identical (80%) in both treatment arms. The benefit of

rituximab maintenance for PFS was significant irrespective of quality of

response to chemoimmunotherapy.

The GALLIUM trial (discussed above) demonstrated that

obinutuzumab-based chemoimmunotherapy followed by obinutuzumab

maintenance resulted in significantly longer PFS than rituximab-based

chemoimmunotherapy followed by rituximab maintenance.88 But the OS was not significantly different between the two treatment approaches.

Patients achieving CR or PR to first-line therapy can either be observed or treated with optional consolidation or extended therapy:

• Rituximab maintenance (one dose every 8 weeks up to 2 years) is

included as an option with a category 1 recommendation for patients

with high tumor burden treated with RCVP and RCHOP based on the

PRIMA study.97,98 There are not enough data to support the use of

rituximab maintenance in patients achieving CR after first-line therapy

with BR. In a multicenter real-world analysis that evaluated

maintenance rituximab versus observation following first-line treatment

with BR, rituximab maintenance was associated with a significant

improvement in PFS only in patients achieving PR but not in patients

achieving CR.99

• Obinutuzumab maintenance is included with a category 2A

recommendation based on the results of the GALLIUM trial.88

• Consolidation with rituximab should be considered if initially treated

with single-agent rituximab.

Clinical follow-up with a complete physical exam and laboratory

assessment (every 3–6 months for the first 5 years, and then annually [or as clinically indicated]) is recommended. Surveillance imaging with CT

scans can be performed no more than every 6 months up to the first 2

years following completion of treatment, and then no more than annually (or as clinically indicated) thereafter.

Relapsed or Progressive Disease

Frequently, patients with disease relapse or progression of disease (POD) after first-line therapy will benefit from a second period of active

surveillance. Considerations and indications for treatment of

relapsed/refractory or progressive disease include: symptoms attributable

to FL (not limited to B symptoms); threatened end-organ function; clinically significant or progressive cytopenia secondary to lymphoma; clinically

significant bulky disease (any nodal or extranodal tumor mass with a

diameter of ≥7 cm); and steady or rapid progression.

Progressive disease should be histologically documented to exclude

transformation, especially in the presence of raising LDH levels,

disproportional growth in one area, development of extranodal disease, or development of new constitutional symptoms. Areas of high SUV,

especially in values in excess of 13, should raise suspicion for the

presence of transformation.46 However, a positive PET/CT scan does not replace a biopsy; rather, the results of the PET/CT scan should be used to direct the optimal site of biopsy for histologic confirmation to enhance the diagnostic yield from the biopsy.

POD ≤24 months of diagnosis and inability to achieve EFS at 12 months (EFS12) after initial treatment with chemoimmunotherapy have been

identified as prognostic indicators of poor survival.100-102 In the National LymphoCare Study, the 5-year OS rate was 50% for patients with POD ≤2 years after first-line therapy with RCHOP compared with 90% for

those with POD >2 years.100 In a population-based analysis of relative

survival of patients with FL compared to age-and-sex-matched controls (from U.S. and French datasets), the group of patients achieving EFS12 following initial management had similar OS outcomes compared to

age-and-sex-matched general populations, whereas patients who did not achieve EFS12 had lower subsequent OS.101

Systemic therapy options for patients with FL at first relapse with high

tumor burden or symptomatic disease include alternate non–

cross-resistant, CD20-directed, mAb-based chemoimmunotherapy or a

combination of lenalidomide and rituximab.103-107 The phase III

AUGUMENT trial (discussed below) established lenalidomide + rituximab as an effective second-line therapy option for patients with previously

treated FL that is not refractory to rituximab.107

Duration of response (DOR) to first-line therapy is an important factor in the selection of second-line therapy. Rituximab monotherapy may be

appropriate for patients with late relapse as well, particularly if disease

burden is low. Patients with POD ≤2 years after first-line therapy should be considered for treatment with lenalidomide-based regimens, novel

approaches including clinical trials, or referral for the consideration of

HDT/ASCR.108-110

PI3K inhibitors including copanlisib, duvelisib, idelalisib, and umbralisib

had previously received accelerated FDA approval for relapsed/refractory FL based on the improved ORR and PFS as shown in preliminary clinical trials.111-115 However, there was later a voluntary withdrawal of this FDA indication for copanlisib, duvelisib, idelalisib, and umbralisib based on the substantial toxicity of PI3K inhibitors having a detrimental impact on OS in recent clinical trials; these are not recommended for the treatment of

relapsed/refractory FL.116

Allogeneic hematopoietic cell transplant (HCT) results in lower relapse

rates than HDT/ASCR, but it is associated with high transplant-related

mortality (TRM) rate.117-119 Allogeneic HCT may also be considered as

third-line consolidation therapy in selected patients.

Second-Line Therapy: Preferred Regimens

Chemoimmunotherapy With CD20-Directed Monoclonal Antibody

In a randomized phase III study of 230 patients with relapsed or refractory indolent lymphoma or MCL (114 patients assigned to BR and 105 patients assigned to FR [fludarabine + rituximab]), BR was more effective than FR in terms of PFS.120 At a median follow-up of 96 months, the median PFS was 34 months and 12 months, respectively, for BR and FR.

Obinutuzumab-based chemoimmunotherapy has also been evaluated in patients with relapsed or refractory FL.103-105

The safety and efficacy of CHOP + obinutuzumab in patients with relapsed

or refractory FL was demonstrated in a randomized study (56 patients

were randomized to obinutuzumab in combination with CHOP or FC

[fludarabine and cyclophosphamide]).103 The ORRs were 96% and 93%, respectively, for CHOP + obinutuzumab and FC + obinutuzumab. The

corresponding CR rates were 39% and 50%, respectively. In the CHOP + obinutuzumab group, 25% of patients with rituximab-refractory disease

achieved CR and in the FC + obinutuzumab group, 30% achieved CR. All of the patients with rituximab-refractory disease achieved at least PR. FC

+ obinutuzumab was associated with more TEAEs than CHOP +

obinutuzumab.

The phase III randomized trial (GADOLIN) compared bendamustine +

obinutuzumab versus bendamustine monotherapy in patients with

rituximab-refractory indolent lymphoma (413 patients; 335 patients had FL; 164 patients were randomized to bendamustine + obinutuzumab; 171

patients were randomized to bendamustine monotherapy).104,105 Patients without POD in the bendamustine + obinutuzumab group received

obinutuzumab maintenance. After a median follow-up of 32 months, the

median PFS was significantly longer with bendamustine + obinutuzumab than with bendamustine monotherapy (26 vs. 14 months; P < .001) in

patients with FL.112 The median OS was not reached in the bendamustine

+ obinutuzumab group compared to 54 months for the bendamustine

group. The most frequent grade ≥3 TEAEs were neutropenia (33% for

bendamustine + obinutuzumab vs. 26% for bendamustine monotherapy),

thrombocytopenia (11% vs. 16%), anemia (8% vs. 10%), and

infusion-related reactions (11% vs. 6%).

Given the concerns for increased incidences of opportunistic infections

and secondary malignancies after first-line therapy with BR,87,88 BR is not

recommended as an option for second-line therapy if it was previously

used as first-line therapy.

NCCN Guidelines Version 1.2026 B-Cell Lymphomas

In the multicenter, double-blind, randomized phase III study (AUGMENT; n = 358; 295 patients had FL), lenalidomide + rituximab was superior to rituximab monotherapy in terms of PFS in all histologic subtypes of previously treated indolent lymphomas except MZL. 107 At median follow-up of 28 months, the median PFS was 39 months for lenalidomide + rituximab compared to 14 months for rituximab monotherapy (P < .0001) in the subgroup of patients with previously treated FL. The ORRs were 80% (35% CR) and 55% (20% CR), respectively (P < .0001). The estimated 2-year OS rates were 95% and 86%, respectively, for lenalidomide + rituximab and rituximab monotherapy.

Infections (63% vs. 49%), cutaneous reactions (32% vs. 12%), constipation (26% vs. 14%), thrombocytopenia (15% vs. 4%), and tumor flare reaction (11% vs. 1%) were more common with lenalidomide + rituximab, with neutropenia (50% vs. 13%) and leukopenia (7% vs. 2%) being the most common grade 3 or 4 toxicities.

Tafasitamab + Lenalidomide + Rituximab

Tafasitamab is a CD19-directed mAb approved for the treatment of relapsed or refractory DLBCL in combination with lenalidomide. The results of the phase III randomized inMIND study demonstrated that the addition of tafasitamab to lenalidomide + rituximab resulted in significantly improved PFS compared to lenalidomide + rituximab in patients with relapsed or refractory FL. 121 In this study, 548 patients were randomly assigned to tafasitamab + lenalidomide + rituximab (n = 272) and lenalidomide + rituximab + placebo (n = 275). After a median followup of 14 months, the median PFS was not reached for patients assigned to tafasitamab + lenalidomide + rituximab vs. 16 months for lenalidomide + rituximab (P < .0001). The PFS benefit was consistent across all subgroups of patients including those with POD24, refractory disease to multiple prior therapies including anti CD20 mAb. Tafasitamab + lenalidomide + rituximab also resulted in higher ORR (84% vs. 72%; P = 0.0014), CR rate (49% vs. 40%; P = .029), improved DOR (21 months vs.14 months), and longer TTNT (not reached vs. 29 months).

The incidences of TEAEs, including rates of grade 3-4 neutropenia and infection, were similar between treatment arms.

Based on the results of this trial, the Panel agreed that tafasitamab + lenalidomide + rituximab is an appropriate option for relapsed or refractory FL in patients who are considered candidates for lenalidomide + rituximab, and the Panel consensus supported the inclusion of this combination as a preferred treatment option (in addition to lenalidomide + rituximab).

Loss of CD19/CD20 expressions has been suggested as a possible mechanism of resistance to CD19-and CD20-directed mAb therapy and may also have an impact on response to CAR T-cell therapy. 122, 123 The Panel acknowledged that the potential risk of loss of CD19 expression in patients with relapsed or refractory disease should be considered and emphasized that further follow-up is needed to confirm the incidences of relapse and loss of CD19 expression following treatment with tafasitamab + lenalidomide + rituximab. At the present time, it is unclear whether treatment with CD19-directed mAb therapy would have a negative impact on the efficacy of subsequent CD19-directed CAR T-cell therapy. Rebiopsy to confirm CD19 positivity is recommended prior to the initiation of CD19-directed CAR T-cell therapy.

Second-Line Therapy: Other Recommended Regimens

Lenalidomide ± Obinutuzumab

In a phase II trial of patients with relapsed/refractory indolent NHL (n = 43), lenalidomide monotherapy induced an ORR of 23% (7% CR). 124 The ORR was 27% among the subgroup of 22 patients with FL. The median DOR was > 16 months and has not been reached. Median PFS for all NCCN 授权医脉通提供NCCN指南全文下载。wmlsyy于2025/12/23,21:20在医脉通平台下载，仅供个人使用，严禁分发。2025 美国国家综合癌症网络版权所有。

References

MS-37

Abstract

patients was 4 months. Lenalidomide monotherapy is recommended for patients who are not candidates for CD20-directed mAb therapy.

Abstract

The efficacy of lenalidomide + obinutuzumab in patients with relapsed/refractory FL was established in the phase II GALEN study (n = 89), including those with early relapse. 125 The ORR was 87% (38% CR) among the 86 patients evaluable for efficacy. At the median follow-up of 3 years, the 2-year PFS and OS rates were 65% and 87%, respectively. Asthenia (61%), neutropenia (43%; grade ≥3, 5%), bronchitis (41%), diarrhea (40%), and muscle spasms (39%) were the most common TEAEs.

Abstract

Lenalidomide monotherapy is an option for patients who are not candidates for anti-CD20 mAb therapy.

Rituximab or Obinutuzumab

[128] In a multiinstitutional study of 166 patients with relapsed/refractory FL, rituximab monotherapy resulted in a response rate of 48%. 126 The median follow-up of 12 months and the estimated median time to progression was 13 months in patients with responding disease. Grade ≥3 infusion-related reactions were reported in 12% of patients.

The phase II randomized GAUSS study evaluated the efficacy of obinutuzumab and rituximab in patients with relapsed indolent lymphomas with previous response to a rituximab-containing regimen (n = 175; FL, n = 149). 128 ORR was higher with obinutuzumab compared to rituximab in patients with FL (45% vs. 33%; P = .08). However, this did not translate into improvement in PFS. At a median follow-up period of 32 months, the 2-year PFS rates were 46% (median PFS was 18 months) and 50% (median PFS was 25 months) for obinutuzumab and rituximab, respectively. Obinutuzumab was also associated with a higher rate of infusion-related reactions (74% vs. 51%) than rituximab.

Second-Line Consolidation or Extended Dosing

Two large, randomized trials have demonstrated a PFS advantage with rituximab maintenance over observation following second-line therapy. 129, 130 a prospective phase III randomized study by the German Low Grade Lymphoma Study Group (GLSG), rituximab maintenance after second-line treatment with RFCM significantly prolonged DOR in the subgroup of patients with recurring or refractory FL (n = 81); median PFS with rituximab maintenance was not reached compared with 26 months in the observation arm (P = .035). 129 a phase III randomized Intergroup trial (EORTC 20981) in patients with relapsed or resistant FL (n = 334) responding to CHOP or RCHOP induction therapy, rituximab maintenance significantly improved median PFS (4 years vs. 1 year; P < .001) compared with observation alone. 130 This PFS benefit was observed regardless of the induction therapy employed (CHOP or RCHOP). With a median follow-up of 6 years, the 5-year OS rate was not significantly different between study arms (74% vs. 64%, respectively). 130 In the GADOLIN study (discussed above), obinutuzumab maintenance following second-line therapy with bendamustine + obinutuzumab improved PFS in patients with rituximab-refractory FL. 104, 105 In a randomized study that evaluated the benefit of rituximab maintenance versus rituximab retreatment at progression in patients with indolent lymphomas previously treated with chemotherapy (n = 114), rituximab maintenance significantly improved PFS compared with rituximab retreatment (31 vs. 7 months; P = .007). 131 However, the

References

duration of benefit was similar in both treatment groups (31 vs. 27

months). Therefore, either approach (maintenance or rituximab

retreatment at progression) could be beneficial for this patient

population.

Patients achieving CR or PR to second-line or subsequent therapy can either be observed or treated with optional consolidation or extended

therapy.

• Rituximab maintenance (one dose every 12 weeks up to 2 years) is

included with a category 1 recommendation.129,130,132 However, the

Panel recognizes that the efficacy of rituximab maintenance in the

second-line setting would likely be impacted by a patient’s response to

first-line maintenance with rituximab. The clinical benefit of rituximab

maintenance in the second-line setting is likely very minimal in patients

with POD during or within 6 months of first-line maintenance with

rituximab.

• Obinutuzumab maintenance (1 g every 8 weeks for a total of 12

doses) is preferred for patients with rituximab refractory disease, which

includes POD on or within 6 months of prior rituximab therapy.104,105

• HDT/ASCR as consolidation therapy has been shown to prolong OS

and PFS in patients with relapsed or refractory disease and is an

appropriate consolidation therapy for patients with second or third

remission.119,133-137

Clinical follow-up with a complete physical exam and laboratory

assessment (every 3 to 6 months for the first 5 years, and then annually [or as clinically indicated]) is recommended. Surveillance imaging with CT scans can be performed no more than every 6 months up to the first 2 years following completion of treatment, and then no more than

annually (or as clinically indicated) thereafter.

Third-Line Therapy: Preferred Regimens

CAR T-Cell Therapy

Axicabtagene ciloleucel, tisagenlecleucel, and lisocabtagene maraleucel are the CD19-directed CAR T-cell therapies that are FDA-approved for the

treatment of relapsed/refractory FL following ≥2 lines of systemic therapy

based on the results of the ZUMA-5, ELARA, and TRANSCEND FL trials (described below).

ZUMA-5 was a phase II trial that evaluated the efficacy of axicabtagene ciloleucel in patients with relapsed/refractory indolent lymphoma (FL, n =

127; MZL, n = 31) after ≥2 prior lines of systemic therapy. Axicabtagene

ciloleucel resulted in an ORR of 92% (74% CR) among the 104 patients

with indolent lymphoma evaluable for efficacy (FL, n = 84; MZL, n = 20).138 The ORR was 94% (80% CR) for patients with FL (median age was 61

years; 38% of patients had ECOG PS 1; 86% of patients had stage III/IV

disease). Cytopenias and infections were the most common grade ≥3

TEAEs reported in 70% and 18% of patients, respectively.138 Grade ≥3

CRS and neurologic events were reported in 7% and 19% of patients,

respectively. Notably, deaths due to TEAEs occurred in 3% patients, one of which was due to treatment-related multisystem organ failure. After

median follow-up of 42 months for patients with FL, the ORR was 94%

(similar to that reported in the primary analysis) and the median PFS was 40 months.139 In an updated analysis, with a median follow-up of 5 years, the median PFS was 62 months and the estimated 60-month PFS rate

was 50% for patients with FL, consistent regardless of the presence of

high-risk features including POD24.140 The 60-month OS rate was 69% for patients with FL.

The phase II ELARA trial evaluated tisagenlecleucel in patients with

relapsed/refractory FL after ≥2 lines of systemic therapy including a

CD20-directed mAb and an alkylating agent or disease relapse after

HDT/ASCR. At a median follow-up of 29 months, among the 94

MS-39

Abstract

evaluable patients, the ORR was 86% (68% CR) and the median PFS was not reached. 141 The estimated 24-month PFS and OS rates were 57% and 88%, respectively. Elevated tumor burden at baseline, POD24, and > 4 nodal areas at inclusion were associated with inferior long-term outcomes. After a median follow-up of 17 months, grade ≥3 CRS, neurological events, and immune effector cell-associated neurotoxicity syndrome (ICANS) were reported in 49%, 37%, and 4% of patients, respectively (with no safety signals reported with longer follow-up).

Lisocabtagene maraleucel was evaluated in the phase II TRANSCEND FL trial in patients with relapsed or refractory FL (n = 101). 142 After a median follow-up of 19 months, lisocabtagene maraleucel resulted in an ORR of 97% (94% CR) in patients with relapsed or refractory FL after ≥2 prior lines of therapy. The median DOR and median PFS were not reached after a median follow-up of 17 months and 18 months, respectively. At 12 months, response was maintained in 82% of patients and the 12-month PFS rate was 81%. The median OS was not reached, and the 12-month OS rate was 96%. Neutropenia (grade ≥3; 65%), prolonged cytopenia (grade ≥3; 22%), infection (grade ≥3; 5%), CRS (grade 3; 58%), and neurological events (grade 3; 15%) were the most common TEAEs. The 2year follow-up data also confirmed the safety and efficacy of lisocabtagene maraleucel for patients with relapsed or refractory FL after ≥2 prior lines of therapy. 143 xicabtagene ciloleucel, tisagenlecleucel, and lisocabtagene maraleucel are included as options for third-line and subsequent therapy for relapsed/refractory FL in fir patients.

Bispecific Antibodies

Mosunetuzumab

Mosunetuzumab (CD3 X CD20 bispecific antibody) is FDA-approved for relapsed/refractory FL. 144, 145 In a single-arm, multicenter, phase II study (n = 90), mosunetuzumab (intravenous; fixed-duration treatment) resulted in high response rates and durable remissions in patients with relapsed or refractory FL after ≥2 lines of therapy including an CD20-directed mAb and an alkylating agent. 144 The ORR assessed by the institutional review committee (IRC) was 80% (60% CR). Patients achieving a CR after 8 cycles completed treatment with no additional cycles, whereas those with a PR or stable disease received a total of 17 cycles. Mosunetuzumab resulted in favorable response rates across all subgroups including those with high-risk disease and EZH2 mutated FL. At the median follow-up of 18 months, IRC-assessed median PFS was 18 months. The estimated EFS and OS rates were 61% and 90%, respectively. In addition, the efficacy of mosunetuzumab was also better compared to the patient's last prior therapy. The updated follow-up data also confirmed durability of responses and safety profile of mosunetuzumab. 145 After a median follow-up of 37 months, the investigator-assessed ORR was 78% (60% CR) and the median PFS was 24 months for mosunetuzumab. The estimated 36-month OS rate was 82%. Peripheral blood B-cell depletion following treatment with mosunetuzumab occurred in all patients and B-cell recovery was observed after a median of 18 months following end of treatment.

Cytokine release syndrome (CRS; 42%), fatigue (37%), headache (30%), and pyrexia (28%) were the most common grade 1-2 events. Grade 3-4 neutropenia was reported in 13% of patients. 144 CRS (grade 1-2) was predominantly confined to cycle 1 of step-up dosing. Among the 42% of patients who developed CRS, grade 3 was reported in 2% of patients and it resolved in all patients. Corticosteroids or tocilizumab were used for the management of CRS in 15% and 8% of patients, respectively, and combination of both was used in 10% of patients. ICANS were very rare, and all were low grade (grade 1-2 confusion rate was reported in 3% of patients with no incidences of aphasia, seizures, encephalopathy, or cerebral edema).

References

The safety profile enables the outpatient administration of mosunetuzumab, and the safety profile after long-term follow-up was similar to that reported in the primary analysis. Mosunetuzumab is included as an option for relapsed/refractory FL after ≥2 prior lines of therapy. Loss of CD20 expression has been suggested as a possible mechanism of resistance to CD20-directed mAb therapy (including bispecific antibody therapy). 146 The efficacy of CD3 x CD20 bispecific antibody therapy is unclear in the setting of CD20-negative lymphomas. Rebiopsy to confirm CD20 positivity is recommended prior to the initiation of CD3 x CD20 bispecific antibody therapy.

Epcoritamab

In the EPCORE NHL-1 trial, epcoritamab (subcutaneous; CD3 x CD20 bispecific antibody) resulted in an ORR of 82% (63% CR) in patients with relapsed or refractory FL after ≥2 prior lines of therapy (n = 128). 147 The ORRs were consistent across prespecified high-risk subgroups including double refractory FL (76%; 56% CR), refractory disease to last prior therapy (74%; 51% CR), and POD24 (79%; 64% CR). At 18 months after initiation of therapy, the estimated PFS rate was 49% for all patients and 74% for those with a CR. CRS (grades 1-2, 65%; grade 3, 2%), injection-site reaction (57%), fatigue (grades 1-2, 28%; grade 3, 2%), neutropenia (grades 1-2, 3%; grade 3, 13%; grade 4, 13%), diarrhea (grades 1-2, 25%; grade 3, 2%), pyrexia (grades 1-2, 23%; grade 3, 2%), and headache (20%) were the most common TEAEs. ICANS was reported in 6% of patients and resolved without leading to discontinuation of treatment.

Epcoritamab is included as an option for relapsed/refractory FL after ≥2 prior lines of therapy. As discussed earlier with the use mosunetuzumab, the activity of CD3 x CD20 bispecific antibody therapy is unclear in the setting of CD20-negative lymphomas. Rebiopsy to confirm CD20 positivity is recommended prior to the initiation of CD3 x CD20 bispecific antibody therapy.

Third-Line Therapy: Other Recommended Regimens

Tazemetostat Tazemetostat (EZH2 inhibitor) is FDA-approved for relapsed/refractory FL after ≥2 prior systemic therapies and it is an appropriate third-line treatment option for patients who are not eligible for CAR T-cell therapy. 148 a phase II trial of 99 patients with relapsed/refractory FL (45 patients with EZH2-mutated FL; 54 patients with EZH2 wild-type) after ≥2 systemic therapies including PI3K inhibitor or an immunomodulatory drug, tazemetostat resulted in an ORR of 69% (13% CR; 56% PR; 29% stable disease) in the EZH2-mutated cohort (median follow-up was 22 months) and 35% (4% CR; 31% PR; 33% stable disease) in the EZH2 wild-type cohort. 148 With a median follow-up of 36 months, the median PFS was 14 months and 11 months for EZH2-mutated and EZH2 wild-type cohorts, respectively. The median OS was not reached in either cohort. The ORR was higher for patients with EZH2-mutated FL than those with EZH2 wildtype FL in all subgroups: POD within 24 months of diagnosis (POD 24; 63% vs. 25%); double-refractory disease (no objective response to rituximab-based regimen and relapse within 6 months or refractory to alkylating agent-based chemotherapy; 78% vs. 27%); and refractory to rituximab (no objective response to rituximab-based regimens or progressive disease within 6 months of completion of rituximab-based therapy; 59% vs. 31%). Notably, this study was not designed to compare the outcomes based on the EZH2 mutation status.

Tazemetostat had a favorable safety profile, with thrombocytopenia (3%), neutropenia (3%), and anemia (2%) being the most common grade ≥3 TEAEs and serious TEAEs reported in only 4% of patients.

References

Tazemetostat is included as an option for third-line and subsequent therapy for patients with relapsed/refractory FL irrespective of EZH2 mutation status. Testing for EZH2 mutation status for patients with relapsed/refractory FL after 2 prior therapies is feasible using

paraffin-embedded tissue and should be performed by an approved sequencing assay.

Zanubrutinib + Obinutuzumab

The combination of zanubrutinib and obinutuzumab is FDA-approved for relapsed/refractory FL after ≥2 prior systemic therapies based on the

results of the phase II randomized ROSEWOOD trial (217 patients;

zanubrutinib + obinutuzumab, n = 145; obinutuzumab, n = 72).149 ORR

and CR rates were significantly higher with zanubrutinib + obinutuzumab (69%; 39% CR) compared to obinutuzumab (46%; 19% CR). After a

median follow-up of 20 months, the median PFS was 28 months for

zanubrutinib + obinutuzumab and 10 months for obinutuzumab.

Grade ≥3 thrombocytopenia (15% vs. 7%), pneumonia (10% vs. 4%),

diarrhea (3% vs. 1%), and dyspnea (2% vs. 0%) were more frequent with zanubrutinib + obinutuzumab whereas grade ≥3 neutropenia (24% vs.

23%) and anemia (5% vs. 6%) were similar between the treatment arms. The incidence of grade ≥3 infusion-related reactions and pyrexia were

substantially lower with zanubrutinib + obinutuzumab. This combination was also associated with lower incidences of atrial fibrillation and

hypertension (both reported in 3% of patients) and this safety profile was consistent with that observed in studies that have evaluated zanubrutinib

in other B-cell malignancies. Zanubrutinib + obinutuzumab is included as an option for third-line and subsequent therapy for patients with

relapsed/refractory FL.

Loncastuximab Tesirine + Rituximab

In a phase II single-arm trial (39 patients with relapsed or refractory FL

including those presenting with POD24 after first-line therapy and

transformed FL relapsing with indolent component), the combination of

loncastuximab tesirine + rituximab resulted in a CR rate of 67%.150

Patients met one or more GELF criteria (92%) or had POD24 after the

first line of therapy (51%). After a median follow-up of 18 months, the

median DOR was 16 months and the 12-month PFS rate was 95%.

Lymphopenia (21%) and neutropenia (13%) were the most common grade ≥3 treatment-related toxicities.

Given the availability of FDA-approved third-line therapy options for

relapsed or refractory FL that have been evaluated in prospective

randomized trials (eg, CAR T-cell therapy, bispecific antibody therapy,

zanubrutinib + obinutuzumab), a few Panel members felt that

loncastuximab + tesirine should not be included as a treatment option at

this time, citing the single-arm trial design with the small sample size and the need for these findings to be confirmed in a prospective randomized

trial.

While CAR T-cell therapy (requiring single infusion of CAR T cells) and mosunetuzumab are fixed-duration treatment options, epcoritamab and zanubrutinib are given continuously until disease progression. In terms of safety profile, CRS, ICANS, and prolonged cytopenias (which may be

associated with the use of bridging chemotherapy required for disease

control in the majority of patients) are common TEAEs of CAR T-cell

therapy. Bispecific antibodies are “off-the-shelf” immunotherapies with a better overall safety profile and very few incidences of ICANS. They are also more readily available than CAR T cells, thus obviating the need for bridging chemoimmunotherapy. However, step-up-dosing schedule (over a period of time before reaching the effective target dose) is required for

all bispecific antibodies to mitigate the risk of CRS, which can be

challenging in patients with rapidly progressing disease.151 In addition, loss of CD20 expressions has been suggested as a possible mechanism of

resistance to CD20-directed mAb therapy (including bispecific antibody

therapy) and the activity of CD3 x CD20 bispecific antibody therapy in the setting of CD20-negative lymphomas is unclear.146

Based on the efficacy and the favorable safety profile demonstrated in the aforementioned phase II study, some Panel members felt that

loncastuximab tesirine + rituximab is an appropriate third-line therapy

option especially for patients who are either considered not candidates for CAR T-cell therapy or do not have access to CAR T-cell therapy or

bispecific antibodies, acknowledging that long-term follow-up is needed to confirm that there is no loss of CD19 expression following treatment with this combination. The findings from the LOTIS-2 trial (that evaluated

loncastuximab tesirine in patients with relapsed or refractory DLBCL)

showed that CD19 antigen loss after loncastuximab tesirine is not

common suggesting that the use of loncastuximab tesirine does not

preclude responses to subsequent CD19-directed CAR T-cell therapy.152 However, these preliminary results need to be confirmed in a larger cohort of patients.

The Panel consensus supported the inclusion of loncastuximab tesirine + rituximab as an option for third-line therapy (other recommended

regimens) with a category 2B recommendation. It is unclear if CD19-

directed mAb therapy would have a negative impact on the efficacy of

subsequent CD19-directed CAR T-cell therapy. Rebiopsy is recommended to confirm CD19 positivity prior to initiation of CD19-directed CAR T-cell

therapy.

Suggested Treatment Regimens for Patients who are Older or Infirm

As discussed earlier, rituximab monotherapy has demonstrated

single-agent activity in patients with previously untreated low-burden FL

and advanced-stage FL as well as in patients with relapsed/refractory

disease.79,80,126 In a retrospective study of 75 patients with newly

diagnosed FL, chlorambucil + rituximab resulted in an ORR of 97% (75% CR). The 5-year EFS and OS rates were 71% and 98%, respectively.153 Single-agent cyclophosphamide was associated with similar OS and CR rates compared with cyclophosphamide-based combination

chemotherapy.154

Rituximab monotherapy is the preferred first-line therapy for older or infirm patients who are not able to tolerate any of the chemoimmunotherapy

regimens recommended for first-line therapy. Alkylating agent-based

chemotherapy (cyclophosphamide or chlorambucil) with or without

rituximab is included as an alternative option for first-line therapy.

Rituximab monotherapy and tazemetostat are the preferred treatment

options for second-line and subsequent therapy. Cyclophosphamide with or without rituximab is included as an alternate option.

Pediatric-Type Follicular Lymphoma in Adults

PTFL is characterized by lack of BCL2, BCL6, and IRF4

rearrangements.16-19 BCL2 expression may be observed in approximately 40% to 50% of cases, and BCL6 expression can be seen in the majority of PTFL.16-19

Histologically, PTFL is associated with large expansive follicles with a

“starry sky” pattern, effacement of architecture, absence of diffuse area,

high histologic grade (grade 3), and a high proliferation index.17-19 In young patients with BCL2-negative localized disease, the diagnosis of PTFL may be considered. Analysis of BCL6 rearrangement may be useful for

evaluating the diagnosis of PTFL.

In adult patients without BCL2 rearrangement but with high proliferation

index, PTFL has a highly indolent disease course (stage I disease with no disease progression or relapse) compared to PTFL with BCL2

rearrangement and/or low proliferation index (Ki-67 <30%; stage III or IV disease and majority of patients experience disease progression or

recurrence).18 PTFL without BCL2 rearrangements is generally

associated with favorable prognosis with only rare instances of disease progression or relapse and is primarily managed with excision (preferred) or ISRT. RCHOP is recommended for patients with extensive local

disease who are not candidates for excision or ISRT.155

Restaging with PET/CT is recommended after completion of ISRT or

RCHOP. No further treatment is necessary following excision or CR to

ISRT or RCHOP. There are no data to support maintenance therapy. If patients have an excellent prognosis, no surveillance imaging is

necessary. Patients with less responsive disease (<CR) should receive treatment as described for progressive FL.

References

Abstract

60. Mac Manus MP, Hoppe RT. Is radiotherapy curative for stage I and II low-grade follicular lymphoma? Results of a long-term follow-up study of patients treated at Stanford University.

References

Marginal zone lymphomas (MZLs) originate in the marginal zone of lymphoid follicles found in the mucosa-associated lymphoid tissues (MALT), spleen, and lymph nodes. 1, 2 Extranodal MZLs (EMZL) of stomach (gastric MALT lymphoma), EMZLs of non-gastric sites (non-gastric MALT lymphoma), nodal MZL (NMZL), and splenic MZL (SMZL) are the three distinct subtypes of MZLs. In a SEER database analysis that assessed the incidence rates (IRs) of different subtypes of MZLs in the United States (2001-2009), NMZL and extranodal MZL were diagnosed in 4081 (IR = 5.7) and 8821 (IR = 12.3) individuals, respectively. 3 The most common sites were stomach (IR = 3.8), spleen (IR = 1.6) and ocular adnexa (IR = 1.4) followed by lung, skin, and salivary glands (IR = 0.9-1.0). The etiology of MZLs has been associated with chronic immune stimulation due to infectious agents or inflammation. Helicobacter pylori has been implicated in the pathogenesis of EMZL of stomach and other infectious agents such as Chlamydia psittaci, Campylobacter jejuni, and Borrelia burgdorferi have also been implicated in the pathogenesis of MZLs. 4 MZLs are also characterized by a high prevalence of hepatitis C virus (HCV) infection and HCV seroprevalence has been reported in about 22% to 35% of patients with NMZL, SMZL, and EMZLs of non-gastric sites. 5, 6 ] [9] [10] [11] In a retrospective analysis of 123 patients with a diagnosis of MZLs and WM/LPL, MYD88 mutation was found in 67% of patients with WM/LPL (18 of 27) compared to 4% of patients with SMZL (2 out of 53), 7% of patients with MALT lymphomas (2 out of 28), and 0% of patients with NMZL. 9 Immunoglobulin heavy chain variable (IGHV) gene sequencing clearly distinguished SMZL and WM/LPL. SMZL was characterized by overrepresentation of IGHV1-2 gene rearrangements with low or intermediate mutation rates, whereas WM/LPL was associated with overrepresentation of IGHV3-23 rearrangements and high mutation rates. 9 10] [11] The NCCN Guidelines provide recommendations for the diagnosis, workup, and treatment for EMZL, NMZL, and SMZL.

Literature Search Criteria

Prior to the update of this version of the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ® ) for B-Cell Lymphomas an electronic search of the PubMed database was performed to obtain key literature in MZLs published since the previous Guidelines update, using the following search terms: MALT lymphoma, gastric MALT lymphoma, non-gastric MALT lymphoma, nodal marginal zone lymphoma, and splenic marginal zone lymphoma. The PubMed database was chosen as it remains the most widely used resource for medical literature and indexes peer-reviewed biomedical literature. 12 e search results were narrowed by selecting studies in humans published in English.

References

MS-56 abstracts)

Abstract

. Recommendations for which high-level evidence is lacking are based on the Panel's review of lower-level evidence and expert opinion.

Extranodal Marginal Zone Lymphomas

The gastrointestinal (GI) tract is the most common site of involvement with the stomach being the most common primary site; salivary/parotid glands, skin, ocular adnexa, head and neck, lung, thyroid, and breast are the other common non-gastric sites. 3 Bone marrow involvement has been reported in about 15% to 20% of EMZL. 13, 14 though EMZL are localized in most patients, about a third of patients present with disseminated disease and localized disease is more frequently observed with gastric subtype than with non-gastric subtype. 13, 14 MZL tend to be indolent, with similar long-term outcomes reported between gastric and non-gastric subtypes and between patients with disseminated and localized disease. 13, 15 More recent retrospective data, however, reported better progression-free survival (PFS) outcomes in patients with EMZL of stomach and in patients with localized disease. 16 t(11;18), t(1;14), t(14;18), and t(3;14) are the most common genetic alterations implicated in the pathogenesis of EMZL. 17 t(11;18), resulting in the formation of the chimeric fusion gene, API2-MALT1, is frequently detected in EMZL of stomach and lung. 18,19 t(1;14) results in the overexpression of BCL10 protein and occurs in 1% to 2% of EMZL, usually detected in EMZL of the stomach, lung, and skin. 20 The presence of both t(11;18) and BCL10 overexpression is associated with locally advanced disease, which is less likely to respond to H. pylori eradication with antibiotic therapy in EMZLs of stomach. 21 t(3;14) results in the upregulation of the FOXP1 gene and is associated with the EMZL of thyroid, ocular adnexa, and skin. 23 The clinical significance of t(14;18) and t (3;14) is unknown.

EMZL of Stomach

Diagnosis

An endoscopic biopsy is required to establish the diagnosis of EMZL of stomach, as fine-needle aspiration (FNA) is not adequate for diagnosis. Endoscopy may reveal erythema, erosions, or ulcerations. 24 Adequate hematopathology review of biopsy material and immunophenotyping are needed to establish a diagnosis. The recommended markers for an immunohistochemistry (IHC) panel include CD20, CD3, CD5, CD10, CD21 or CD23, kappa/lambda, cyclin D1, BCL2, and BCL6; the recommended markers for flow cytometry analysis include CD19, CD20, CD5, CD23, and CD10. The typical immunophenotype for MALT lymphoma is CD5-, CD10-, CD20+, CD23-/+, CD43 -/+, cyclin D1-, and BCL2-germinal centers.

5] [26] Therefore, staining for detection of H. pylori should be performed. If the H. pylori infection status is negative based on histopathologic evaluation, other noninvasive testing methods may be used to confirm negative status (ie, stool antigen test, urea breath test, blood antibody test). Nondiagnostic atypical lymphoid infiltrates that are H. pylori positive should be rebiopsied to confirm or exclude lymphoma prior to treatment of H. pylori.

However, H. pylori infection is not evident in approximately 5% to 10% of patients with gastric MALT lymphomas and the translocation t(11;18) was reported to occur at a high frequency in patients without H. pylori infection and EMZL of stomach. 27 This chromosomal abnormality has been associated with disseminated disease and resistance to antibiotic treatment in patients with H. pylori associated EMZL of stomach. 28, 29 CN 授权医脉通提供NCCN指南全文下载。wmlsyy于2025/12/23,21:20在医脉通平台下载，仅供个人使用，严禁分发。2025 美国国家综合癌症网络版权所有。

References

Abstract

Molecular analysis by polymerase chain reaction (PCR) or fluorescence in situ hybridization (FISH) for the evaluation of t(11;18) is recommended. In certain circumstances, molecular analysis for the detection of IGHV gene rearrangements, MYD88 mutation analysis and cytogenetic or FISH evaluation for t(3;14), t(1;14) and t(14;18) may also be useful.

A comprehensive physical examination should be performed with attention to non-gastric sites such as the eyes and skin, and performance status should be assessed. Laboratory evaluations should include a complete blood count (CBC) with differentials and platelets, comprehensive metabolic panel, and measurement of serum lactate dehydrogenase (LDH) levels. Evaluation of bone marrow biopsy, with or without aspirates, may be useful under certain circumstances. Testing for HCV and hepatitis B virus (HBV) should be performed for all patients. HBV testing is indicated due to the risk of viral reactivation in patients receiving chemoimmunotherapy. Appropriate imaging studies include chest/abdomen/pelvis CT scan with contrast of diagnostic quality and/or PET/CT (especially if involved-site radiation therapy [ISRT] is anticipated). A multigated acquisition (MUGA) scan/echocardiogram should be performed if the patient is being considered for treatment with regimens containing anthracycline or anthracenedione. Special aspects of the workup for EMZL of stomach include direct endoscopic assessment of the GI tract and additional evaluation of the tumor specimen for the presence of H. pylori. At some NCCN Member Institutions, endoscopic ultrasound (EUS) is used to complement conventional endoscopy at the time of the initial workup and at follow-up. EUS provides information regarding the depth of involvement in the gastric wall, which provides essential information for some of the currently used staging systems; it also helps to distinguish benign lymphoid aggregates from lymphoma associated with H. pylori infection. 30 In addition, EUS staging is also useful in predicting the efficacy of H. pylori eradication therapy. 31, 32 EUS with multiple biopsies of anatomic sites is particularly useful for patients with H. pylori infection because the likelihood of tumor response to antibiotic therapy is related to depth of tumor invasion.

Staging

It is unknown whether staging for EMZL should follow the standard Ann Arbor staging systems used for nodal lymphomas. The widely used Lugano staging system for GI lymphomas is a modification of the original Ann Arbor staging system. 33 Ann Arbor stage III has been removed. The TNM staging system corresponds to the staging system utilized in primary gastric cancers and the depth of the lymphoma infiltration is measured by EUS. Stage I refers to disease confined to the GI tract (single primary or multiple non-contiguous lesions (stage I1, the infiltration is limited to mucosa or submucosa and in stage I2, infiltration is present in the muscularis propria, serosa, or both). Stage II refers to disease extending into the abdomen (stage II1, localized nodal involvement [perigastric lymph nodes] and in stage II2, distant nodal involvement). Stage IIE refers to penetration of serosa to involve adjacent organs or tissues; subscripts (1 or 2) may be added to the designation if both the lymph nodes and adjacent organs are involved. Stage IV refers to disseminated extranodal involvement or concomitant supradiaphragmatic nodal involvement, and stage IV disease with disseminated nodal involvement appear to behave more like NMZL or follicular lymphoma (FL).

References

MS-58

eradication therapy generally comprises a proton pump inhibitor along with a combination of antibiotics including clarithromycin and amoxicillin (or metronidazole for patients allergic to penicillin). 24 In a multicenter cohort follow-up study of 420 patients with EMZL of stomach, the response rate was 77% for H. pylori eradication therapy and the estimated 10-year freedom from treatment failure (FFTF), overall survival (OS), and event-free survival (EFS) rates were 90%, 95%, and 86%, respectively. 38 he presence of t(11;18) translocation, H. pylori-negativity and submucosal invasion were independent predictors of resistance to H. pylori eradication therapy. 36, 38 1] [42] [43] [44] [45] [46] In the randomized controlled study of 241 patients with localized EMZL of stomach, after a median follow-up of 8 years, the 10-year EFS rates were 52%, 52%, and 87%, respectively, for patients treated with surgery, RT, and chemotherapy (P < .01). 40 The 10-year OS rate was not significantly different between the treatment groups (80% vs. 75% vs. 87%, respectively). In an analysis of registry data from a German multicenter study in patients with localized EMZL of stomach, extended-field RT (30 Gy followed by 10 Gy boost) alone resulted in an EFS and OS rate of 88% and 93%, respectively, in the subgroup of patients with EMZL of stomach. 41 These outcomes were not significantly different from patients with EMZL of stomach who received combined modality therapy with surgery and RT (EFS and OS rates of 72% and 83%, respectively). 41 This study had also included patients with EMZL of stomach who experienced treatment failure with H. pylori eradication therapy. In a retrospective study of 192 patients with localized (stage I-II) EMZL, the complete response (CR) rate was 99% in the group of patients treated with involved-field RT (IFRT) (30-35 Gy) alone. 43 After a median follow-up of 7 years, the estimated 10-year relapse-free survival (RFS) rate, disease-free survival (DFS) rate, and OS rate were 76%, 68%, and 87%, respectively. Patients with EMZL of thyroid and stomach had better outcome than patients with EMZL of non-gastric sites (P = .004). The 10-year RFS rate was 95% for thyroid, 92% for stomach, 68% for salivary glands, and 67% for orbit.

Reduced-dose RT (25 Gy) was also effective for the treatment of H. pylori-negative stage I-II disease or H. pylori-positive disease that is refractory to H. pylori eradication therapy. 47, 48 tuximab has demonstrated activity in patients not eligible for eradication therapy (H. pylori-negative disease) or in those with EMZL of stomach relapsed or refractory to H. pylori eradication therapy. 49, 50 In a prospective study of 27 patients with relapsed/refractory disease or H. pylori-negative disease (majority of patients [81%] had stage I or II1 disease), rituximab resulted in an overall response rate (ORR) of 77% (46% CR). At a median follow-up of 28 months from start of treatment, all patients were alive and 54% of patients were disease free. 49 In a retrospective study that evaluated treatment options for patients with persistent disease despite H. pylori eradication therapy or H. pylori-negative disease (n = 106; 28 patients were treated with rituximab), rituximab resulted in an ORR of 73% (64% CR). 50 After a median follow-up of 5 years, the 5-year PFS and OS rates were 70% and 95%, respectively.

Stage I1, or I2 or Stage II1 Disease

Antibiotic therapy for H. pylori infection is recommended as initial therapy for H. pylori positive disease regardless of t(11;18) status. However, it should be noted that t(11;18) is a predictor for lack of response to antibiotic therapy and patients with involvement of submucosa or regional lymph nodes are also much less likely to respond to antibiotic therapy. 29, 38 3] 47, 49 NCCN 授权医脉通提供NCCN指南全文下载。wmlsyy于2025/12/23,21:20在医脉通平台下载，仅供个人使用，严禁分发。2025 美国国家综合癌症网络版权所有。

References

ISRT (preferred) or rituximab (if ISRT is contraindicated) are also options

for patients with H. pylori-negative disease.

Evaluation of response with endoscopy and biopsy is recommended after 6 months following initial therapy for all patients. Biopsy is recommended to rule out evidence of diffuse large B-cell lymphoma (DLBCL). Any area of DLBCL should be treated according to recommendations for DLBCL.

There is increasing evidence that late relapses can occur after antibiotic

treatment and a longer duration of follow-up should be considered.

Restaging after antibiotic therapy

Clinical follow-up every 3 to 6 months for 5 years and then yearly or as

clinically indicated is recommended for patients with disease responding to initial antibiotic therapy that has become H. pylori negative and

lymphoma negative.

ISRT is recommended for patients with H. pylori negative disease and

persistent lymphoma following initial antibiotic therapy. Alternatively, active surveillance for another 3 months is appropriate for patients who are

asymptomatic as antibiotic therapy may result in a CR as early as 3

months after initiation of therapy but can also take longer to achieve (up to 18 months).51,52 If re-evaluation suggests slowly responding disease or

asymptomatic nonprogression, continued active surveillance may be

warranted (category 2B). Second-line antibiotic treatment is recommended for patients with persistent H. pylori infection and regressing or stable

lymphoma. Lastly, patients with persistent H. pylori infection and

progressive or symptomatic lymphoma should be treated with ISRT and

second-line antibiotics.

Second-line antibiotic treatment is recommended for patients with

persistent H. pylori infection and regressing lymphoma following ISRT or rituximab. Locoregional RT (if not previously given) is indicated for patients with no response to second-line antibiotic therapy. Patients with persistent

lymphoma (regardless of H. pylori status) following ISRT or rituximab

should be treated with systemic therapy as described for stage II or stage IV disease.

Stage II2, IIE, or IV

Treatment for distant nodal, advanced stage disease (which is uncommon) is similar to that described for patients with advanced stage FL.

Asymptomatic patients without indications for treatment are observed. The decision to treat is guided by end-organ dysfunction or the presence of

symptoms (such as GI bleeding, early satiety), bulky disease at

presentation, steady progression of disease, or patient preference.

Systemic therapy or palliative ISRT is recommended for patients with

indications for treatment.

Suggested treatment regimens for first-line therapy are discussed in

Systemic Therapy for Marginal Zone Lymphomas. Surgical resection is

generally limited to specific clinical situations such as life-threatening

hemorrhage or bowel obstruction. Although disease control is excellent

with total gastrectomy, the long-term morbidity has precluded routine

surgical resection.

Evaluation with endoscopy is recommended after completion of treatment. Recurrent disease should be managed with treatment regimens for

second-line therapy as discussed in Systemic Therapy for Marginal Zone Lymphomas.

EMZL of Non-gastric Sites

Diagnosis

Adequate hematopathology review of biopsy materials and

immunophenotyping are needed to establish a diagnosis. The

recommended markers for an IHC panel include CD20, CD3, CD5, CD10, CD21 or CD23, kappa/lambda, cyclin D1, and BCL2; the recommended

markers for flow cytometry analysis include CD19, CD20, CD5, CD23, and

Keywords

MS-60 CD10. The typical immunophenotype for MALT lymphoma is CD5-, CD10-, CD20+, CD23-/+, CD43 -/+, cyclin D1-, and BCL2-germinal centers

Abstract

Molecular analysis to detect IGHV gene rearrangement or t(11;18) and MYD88 mutation analysis may be useful in certain circumstances. In addition, cytogenetics or FISH for t(11;18), t(3;14), t(11;14), and t(14;18) may also be considered under certain circumstances.

Workup

The workup for EMZL of non-gastric sites is similar to the workup for other B-cell lymphomas. A comprehensive physical examination should be performed, and performance status should be assessed. Laboratory evaluations should include a CBC with differentials and platelets, comprehensive metabolic panel, and measurement of serum LDH levels. Evaluation of bone marrow biopsy, with or without aspirates, may be useful for patients with multifocal disease. In addition, endoscopy with multiple biopsies of anatomical sites may be useful in selected circumstances. Upper GI endoscopy should be considered where primary site is thought to be in head/neck or lungs. 53 Testing for HCV and HBV should be performed for all patients. HBV testing is indicated due to the risk of viral reactivation in patients receiving chemoimmunotherapy. Infectious pathogens such as C. jejuni and C. psittaci have been associated with EMZL of non-gastric sites, but testing for these pathogens is not required for disease workup or management. 4

Appropriate imaging studies include PET/CT or chest/abdomen/pelvis CT scan with contrast of diagnostic quality. A MUGA scan/echocardiogram should be performed if the patient is being considered for treatment with regimens containing anthracycline or anthracenedione. MRI with contrast should be done for neurologic evaluation or if CT with contrast is contraindicated.

Treatment

ISRT is an effective initial treatment for patients with EMZL of non-gastric sites. 43, 44, 54, 55 In a retrospective study of 167 patients with localized EMZL treated with RT with or without chemotherapy (EMZL of non-gastric sites, n = 142), the group who received IFRT alone (n = 144; dose range, 25-35 Gy; 25 Gy for orbit) had an estimated 10-year RFS rate and OS rate of 74% and 89%, respectively. 43 The 10-year RFS rates for patients with primary involvement of the thyroid, salivary gland, and orbital adnexa were 95%, 68%, and 67%, respectively. In another retrospective study of 208 patients with EMZL of non-gastric sites (Ann Arbor stage III-IV in 44%), the ORR among patients treated with chemotherapy, RT, or surgery were 65%, 76%, and 90%, respectively. 54 After a median follow-up of 3 years, the estimated 5-year EFS and OS rates were 37% and 83%, respectively. The 5-year OS rates were significantly higher among patients with Ann Arbor stage I-II disease compared with those with stage III-IV disease (94% vs. 69%; P = .001). On multivariate analysis, bone marrow involvement was the only significant independent predictor of inferior EFS and OS. 54 7] [58] The IELSG evaluated the clinical activity of single-agent rituximab in a phase II study in patients with untreated as well as relapsed EMZL (35 patients; 20 patients with EMZL of non-gastric sites). 56 Among patients with non-gastric MALT lymphoma, treatment with rituximab resulted in an ORR of 80% (55% CR and 25% partial response [PR]). For the entire study population, the ORR was significantly higher in patients who have not received chemotherapy than in patients previously treated with chemotherapy (87% and 45% respectively; P = .03).

Stage I-II

ISRT (24-30 Gy) is the preferred treatment for patients with stage IE or contiguous stage IIE disease and rituximab is an option for selected

References

patients.43,44,54-58 Reduced dose ISRT (4 Gy in 2 fractions) may be

considered as an alternative to 24 Gy for EMZL of orbital and salivary

gland MZL.59,60 Careful regular follow-up with a radiation oncologist and

ophthalmologist is essential when using this very-low-dose regimen.

Active surveillance may be considered for patients whose diagnostic

biopsy was excisional or in whom RT could result in significant morbidity.

Surgical excision may be appropriate treatment for certain extranodal sites (eg, lung, thyroid, colon, small intestine, breast) in patients with stage I–II disease.14 Active surveillance is recommended if there is no residual

disease following surgery and locoregional RT should be considered for

patients with positive surgical margins.

Stage IV

ISRT is also recommended for patients presenting with stage IV

disease.43,44,54 RT dose is site dependent, with lower doses usually

reserved for orbital and salivary gland involvement.59,60 Active surveillance is an option for patients whose diagnostic biopsy was excisional or in

whom RT could result in significant morbidity.

Definitive treatment of multiple sites and palliative treatment of

symptomatic sites may be indicated. Based on anecdotal responses to

antibiotics in ocular and cutaneous MZLs associated with bacterial

infection, some physicians may give an empiric course of doxycycline prior to initiating therapy.61-63

Follow-up and Treatment for Recurrent Disease

Clinical follow-up (including repeat diagnostic tests and imaging based on the site of disease and as clinically indicated) should be conducted every 3 to 6 months for 5 years and then annually thereafter (or as clinically

indicated).

Local recurrence may be treated with ISRT (if not previously received;

patients with EMZL of ocular or salivary glands initially treated with

reduced dose ISRT [4 Gy] could also receive additional RT for local

recurrence) or managed according to recommendations for

advanced-stage NMZL. In patients with systemic recurrence, active

surveillance is recommended for patients without any indications for

treatment. Systemic therapy is recommended for patients with indications for treatment. Suggested treatment regimens for first-line therapy or

second-line therapy (in patients who have received prior treatment with rituximab) are discussed in Systemic Therapy for Marginal Zone

Lymphomas.

Nodal Marginal Zone Lymphoma

Peripheral lymphadenopathy is present in nearly all patients with NMZL

(>95%); thoracic or abdominal lymph nodes may also be involved in about 50% of patients and involvement of bone marrow and peripheral blood

may be seen in about 30% to 40% and 10% of patients, respectively.64,65 Although about two-thirds of patients with newly diagnosed NMZL present with advanced-stage disease, most tumors are non-bulky and B symptoms are present in only about 15% of patients.64,65

NMZL has an indolent disease course and the treatment approach is

similar to that described for FL, but long-term survival outcomes appear

less favorable compared with EMZL.64,66 However, a cohort analysis has reported more favorable survival outcomes for patients treated with

rituximab (n = 56; 79% of patients presented with advanced-stage

disease).67 After a median follow-up of 38 months, the PFS was 42

months and the median OS was not reached. The estimated OS rate at

120 months after diagnosis was 72%.

Diagnosis

Adequate hematopathology review of biopsy materials and

immunophenotyping are needed to establish a diagnosis. The

recommended markers for an IHC panel include CD20, CD3, CD5, CD10, CD21 or CD23, kappa/lambda, CCND1, and BCL2; the recommended

markers for flow cytometry include CD19, CD20, CD5, CD23, and CD10. The typical immunophenotype for NMZL is CD5-, CD10-, CD20+,

CD23-/+, CD43 -/+, cyclin D1-, and BCL2-. Pediatric NMZL should be

considered with localized disease in young patients. Molecular analysis to detect IGHV gene rearrangement or t(11;18) and MYD88 mutation

analysis may be useful in certain circumstances. In addition, cytogenetics or FISH for t(11;18), t(3;14), t(11;14), t(14;18), del(13q), and del(7q) may also be considered under certain circumstances.

Workup

NMZL occurs primarily in the lymph nodes, although involvement of

additional extranodal sites are common.64,65 The diagnosis of NMZL

requires careful evaluation to rule out extranodal sites of primary disease and must be distinguished from nodal FL, mantle cell lymphoma (MCL),

chronic lymphocytic leukemia (CLL), and WM/LPL. A comprehensive

physical examination should be performed, and performance status should be assessed. Laboratory evaluations should include a CBC with

differentials and platelets, comprehensive metabolic panel, and

measurement of serum LDH levels. Evaluation of bone marrow biopsy

with aspirates should be performed to document clinical stage I–II disease. Bone marrow biopsy may be deferred until treatment is indicated. Testing for HCV and HBV should be performed for all patients. HBV testing is

indicated due to the risk of viral reactivation in patients receiving

chemoimmunotherapy.

Appropriate imaging studies include PET/CT (preferred) or

chest/abdomen/pelvis CT scan with contrast of diagnostic quality. A

MUGA scan/echocardiogram should be performed if the patient is being considered for treatment with regimens containing anthracycline or

anthracenedione.

First-line Treatment

Stage I–II

ISRT (24–30 Gy) is the preferred treatment option for patients with stage I or contiguous stage II disease. Initiation of systemic therapy can improve failure-free survival (FFS) but has not been shown to improve OS.68,69

ISRT in combination with anti-CD20 monoclonal antibody (mAb) with or

without chemotherapy is included as an option. Anti-CD20 mAb with or

without chemotherapy can be considered in selected patients with bulky

intra-abdominal or mesenteric stage I disease. Active surveillance may be appropriate in circumstances where the toxicity of ISRT or systemic

therapy outweighs potential clinical benefit. No further treatment is

necessary for patients achieving CR or PR to initial therapy. Clinical

follow-up with a complete history and physical examination and laboratory assessment is recommended every 3 to 6 months for the first 5 years, and then annually (or as clinically indicated) thereafter. Surveillance imaging

with CT scans can be performed no more than every 6 months up to the

first 2 years following completion of treatment, and then no more than

annually thereafter.

Patients with disease not responding to initial therapy with ISRT should

receive treatment as described for stage III or IV NMZL. Patients with

disease not responding to initial therapy with anti-CD20 mAb with or

without chemotherapy should be treated with second-line or subsequent therapy regimens. Rebiopsy to rule out histologic transformation is

recommended prior to the initiation of second-line or subsequent therapy.

Anti-CD20 mAb with or without chemotherapy is recommended for

patients with non-contiguous stage II disease. ISRT can be used in

combination with systemic therapy for local palliation. Active surveillance may be appropriate in circumstances where the toxicity of systemic

therapy ± ISRT for local palliation outweighs potential clinical benefit.70

Clinical follow-up and surveillance imaging (as described above) are

recommended for patients achieving CR to initial therapy.

responding to ISRT. Patients with disease not responding to ISRT should be treated with second-line or subsequent therapy regimens. Rebiopsy to rule out histologic transformation is recommended prior to the initiation of second-line or subsequent therapy.

Suggested treatment regimens for second-line or subsequent therapy are discussed in Systemic Therapy for Marginal Zone Lymphomas. Chimeric antigen receptor (CAR) T-cell therapy is an option for patients with

progressive or refractory disease after ≥2 prior systemic therapy

regimens (See Systemic Therapy for Marginal Zone Lymphomas - Thirdline therapy).71,72

Stage III–IV

Active surveillance is recommended for patients with no indications for

treatment. Treatment should only be initiated when a patient presents with indications for treatment: symptoms attributable to lymphoma (not limited to B symptoms); threatened end-organ function; clinically significant or

progressive cytopenia secondary to lymphoma; clinically significant bulky disease and steady or rapid progression.

Suggested treatment regimens for first-line therapy are discussed in

Systemic Therapy for Marginal Zone Lymphomas.

First-line Consolidation or Extended Therapy

Rituximab maintenance (single-dose rituximab every 3 months until

treatment failure) or retreatment with rituximab (rituximab weekly x 4 at the time of each progression until treatment failure) was evaluated in an

exploratory sub-study in patients with low-tumor-burden, non-follicular,

indolent B-cell lymphomas responding to induction therapy with

single-agent rituximab.73 The ORR after induction therapy with rituximab was 40% (52% for patients with MZL). After a median of 4 years from

randomization, maintenance rituximab significantly improved time to

treatment failure (TTTF) compared to rituximab retreatment (5 years and 1 year respectively; P = .012).

Active surveillance or rituximab maintenance (for patients initially treated with single agent rituximab) is recommended for patients achieving CR or PR to first-line therapy.

Second-line and Subsequent Therapy

Frequently, patients with disease relapse or progression of disease after first-line therapy will benefit from a second period of active surveillance

until indications for treatment develop. Indications for treatment of

relapsed/refractory or progressive disease is similar to that as described for first-line treatment.

Progressive disease should be histologically documented to exclude

transformation, especially in the presence of raising LDH levels,

disproportional growth in one area, development of extranodal disease, or development of new constitutional symptoms. Suggested treatment

regimens for second-line therapy are discussed under Systemic Therapy for Marginal Zone Lymphomas.

Consolidation or Extended Dosing

Obinutuzumab maintenance (1 g every 8 weeks for a total of 12 doses) is included as an option for patients with rituximab-refractory disease

treated with bendamustine + obinutuzumab based on the results of the GADOLIN study.74

High-dose therapy followed by autologous stem cell rescue (HDT/ASCR) has been associated with survival benefit in patients with relapsed or

refractory disease.75-77 HDT/ASCR is included as an option for

consolidative therapy for patients with disease responding to second-line therapy. Allogeneic hematopoietic cell transplant (HCT) may also be

considered as a third-line consolidation therapy for highly selected

patients.76,78

Splenic Marginal Zone Lymphoma

SMZL is characterized by the presence of splenomegaly in all patients,

which may become symptomatic when massive or when associated with

cytopenias.65,79 Peripheral lymph nodes are generally not involved while

splenic hilar lymph nodes are often involved.79 Involvement of thoracic or

abdominal lymph nodes may also be seen in about a third of patients with SMZL.65 In addition, bone marrow involvement is present in the majority of

patients (about 85%) and involvement of peripheral blood occurs in 30% to 50% of patients.65,79 The disease course of SMZL is generally indolent,

although most patients present with advanced-stage disease. In a

retrospective study that evaluated the clinical outcomes of 124 patients

with non-MALT–type MZL, the median time to progression (TTP) and

median OS were 7 years and 9 years, respectively, for the subgroup of 59 patients with SMZL.65 In a cohort analysis of 64 patients with SMZL

treated in the rituximab era, the estimated median PFS and OS were 53 months and 156 months, respectively, after a median follow-up of 38

months.80

Diagnosis

Adequate hematopathology review of biopsy materials and

immunophenotyping are needed to establish a diagnosis. SMZL is most

definitively diagnosed at splenectomy, since the immunophenotype is

nonspecific and morphologic features on the bone marrow may not be

diagnostic. However, in a patient with splenomegaly (small or no M

component) and a characteristic intra sinusoidal lymphocytic infiltration of the bone marrow, the diagnosis can strongly be suggested on bone

marrow biopsy, if the immunophenotype is consistent. Plasmacytoid

differentiation with cytoplasmic Ig detectable on paraffin sections may

occur. In such circumstances, the differential diagnosis may include

WM/LPL. MYD88 mutation analysis8-11 and BRAF mutation analysis can

be useful in selected circumstances for differentiating SMZL from WM/LPL and HCL, respectively.

On bone marrow biopsy, (with or without peripheral blood involvement)

SMZL is characterized by small lymphoid cells with immunoglobulin (Ig)

light chain restriction that lack characteristic features of other small B-cell neoplasms (ie, CD5, CD10, cyclin D1). The recommended markers for an IHC panel include CD20, CD3, CD5, CD10, CD21 or CD23, CD43,

kappa/lambda, IgD, CCND1, BCL2, annexin A1, and BRAFV600E; the

recommended markers for flow cytometry analysis include CD19, CD20, CD5, CD23, CD10, CD43, and CD103. The typical immunophenotype for SMZL is CD5-, CD10-, CD20+, CD23-/+, CD43-, cyclin D1-, BCL2-

germinal centers, annexinA1-, CD103-, BRAFV600E-, and with expression of both IgM and IgD. This lymphoma is distinguished from CLL by the

absence of CD5 expression, strong CD20 expression, and variable CD23 expression, and from hairy cell leukemia (HCL) by the absence of CD103, CCND1, or BRAFV600E expression.

Workup

The initial workup for SMZL is similar to the other indolent lymphomas. A comprehensive physical examination should be performed, and

performance status should be assessed. Laboratory evaluations should include a CBC with differentials and platelets, comprehensive metabolic

panel, and measurement of serum LDH levels. Serum protein

electrophoresis (SPEP) and/or measurement of quantitative Ig levels

should be performed. If elevated Ig or monoclonal Ig is detected, further characterization by immunofixation of blood may be useful. Evaluation of bone marrow biopsy with or without aspirates should be performed.

Testing for HCV and HBV should be performed for all patients. HBV

testing is indicated due to the risk of viral reactivation in patients receiving chemoimmunotherapy. Other useful evaluations may include cryoglobulin testing for detection of abnormal proteins frequently associated with

hepatitis C, and direct Coombs test for evaluation of autoimmune

hemolytic anemia.

Appropriate imaging studies include chest/abdomen/pelvis CT scan with contrast of diagnostic quality and/or whole-body PET/CT. A MUGA

scan/echocardiogram should be performed if the patient is being

considered for treatment with regimens containing anthracycline or

anthracenedione.

Treatment

Patients who are asymptomatic with no splenomegaly or progressive

cytopenias can be observed until indications for treatment develop.81,82

Patients presenting with splenomegaly should be treated depending on

their HCV serology status.

Hepatology evaluation is recommended for patients with HCV-positive

disease and appropriate antiviral therapy should be initiated for patients

without contradictions for treatment of hepatitis. Interferon (IFN)-based

antiviral therapy has been shown to induce virologic and hematologic

responses in patients with HCV-positive MZLs.83-88 In a retrospective

series of 134 patients with HCV-positive indolent B-cell lymphomas (36

patients with SMZL), among the patients who received antiviral therapy

with IFN or pegylated-IFN, with or without ribavirin as first-line therapy (n = 100; 23 patients with SMZL), the ORR and CR rates were 77% (65% for

patients with SMZL) and 47%, respectively, and a sustained virologic

response was observed in 78% of patients. The median duration of

response was 33 months. After a median follow-up of 4 years, the 5-year PFS and OS rates were 63% and 92%, respectively. IFN-free antiviral

therapy with a combination of direct-acting antivirals (DAAs) has also been reported to be effective, resulting in high lymphoproliferative disease

response rates in patients with HCV-positive MZLs.89 Patients with no

response to antiviral therapy or those with contraindications for treatment of hepatitis should be managed as described below for patients with

HCV-negative disease.

Patients with HCV-negative disease can be observed if they are

asymptomatic. Rituximab monotherapy (with or without maintenance

rituximab) is associated with high response rates with durable remissions and is the preferred treatment for patients who are symptomatic

(cytopenias or symptoms of splenomegaly, weight loss, early satiety, or

abdominal pain).90-94 In a retrospective study of 43 patients with SMZL that assessed rituximab either as monotherapy or in combination with

chemotherapy, rituximab monotherapy was equally effective as rituximab combination therapy (90% vs. 79% CR; P = .7) and was associated with

less toxicity compared to rituximab in combination with chemotherapy

(adverse event rates 13% vs. 83%; P = .002).92 The 3-year DFS was more favorable with rituximab-containing therapy, with or without splenectomy (79%) compared with splenectomy alone (29%) or chemotherapy alone

(25%).92 In this small retrospective study, patients who received

concurrent splenectomy and rituximab had a higher likelihood of attaining a CR (100%) than those who received only rituximab and did not undergo splenectomy (67%).

Given the high response rates associated with rituximab monotherapy in patients not having undergone concurrent splenectomy, splenectomy

should be considered only in select cases. Splenectomy is an option if the

disease is not responsive to rituximab. In retrospective studies,

splenectomy with or without chemotherapy has demonstrated favorable

outcomes with a median OS exceeding 10 years and a 10-year OS rate of 61% to 84%.5,82,95-99 Pneumococcal and meningococcal vaccination should be given at least 2 weeks before splenectomy.

Patients should be monitored on a regular basis following treatment.

Clinical follow-up (including repeat diagnostic tests and imaging studies,

as clinically indicated) should be performed every 3 to 6 months for 5

years and then annually or as clinically indicated thereafter. In patients

with recurrence, active surveillance is recommended for patients without any indications for treatment. Splenectomy, ISRT, or systemic therapy are recommended for patients with indications for treatment. Suggested

treatment regimens for first-line therapy or second-line therapy (in patients who have received prior treatment with rituximab) are discussed in

Systemic Therapy for Marginal Zone Lymphomas.

Systemic Therapy for Marginal Zone Lymphomas

The NCCN B-Cell Lymphomas Panel stratified all the regimens into 3

categories (based on the evidence, efficacy, toxicity, preexisting

comorbidities, and access to certain agents): preferred regimens, other

recommended regimens, and useful under certain circumstances.

As discussed earlier, rituximab has demonstrated activity in patients with EMZL of stomach,49,50 EMZL of non-gastric sites,56-58 and SMZL.90-94

Rituximab is included as a preferred treatment option for SMZL and NMZL (low burden disease). Rituximab is included as an option (other

recommended regimens) for EMZL.

Recommendations for other systemic therapy options are discussed

below.

First-line Therapy: Preferred Regimens

Chemoimmunotherapy with anti-CD20 Monoclonal Antibody

Bendamustine + rituximab (BR), RCHOP (cyclophosphamide, doxorubicin, vincristine, prednisone), or RCVP (cyclophosphamide, vincristine,

prednisone) are included as preferred regimens.

In the multicenter randomized phase III study (StiL NHL1 that included 67 patients with MZL), BR was superior to RCHOP in terms of PFS in all

histologic subtypes of indolent lymphomas except MZL (P = .32).100

The randomized phase III BRIGHT study (that demonstrated the

noninferiority of BR compared to RCHOP or RCVP with regard to CR rate and PFS in patients with previously untreated indolent lymphoma or MCL) included 46 patients with MZL (28 patients were randomized to BR and 18 patients were randomized to RCHOP or RCVP).101 The ORRs were 92% (20% CR) and 71% (24% CR), respectively, for BR and RCHOP/RCVP in the subgroup of patients with MZL.

BR and RCVP have also demonstrated efficacy as first-line therapy in

small clinical studies that have evaluated these regimens specifically in patients with MZL.102-107 In a multicenter phase II trial (MALT 2008-01) of 60 patients with previously untreated MALT lymphoma (20 patients with

gastric MALT lymphoma; 34 patients with non-gastric MALT lymphoma), after 3 cycles of treatment, BR resulted in an ORR of 100% (75% CR) and the CR rates were significantly higher for patients with gastric MALT

lymphoma as compared to the non-gastric subtype (90% vs. 62%; P =

.023).102 After completion of 6 cycles, the ORR and CR rates were 100% and 98%, respectively, with no significant differences according to

primary site of disease. After a median active surveillance of 82 months, the 7-year EFS rate was 88% for all patients (90% for patients with

gastric MALT lymphoma and 84% for those with non-gastric MALT

lymphoma). In a phase II study (BRISMA) of 56 patients with SMZL

treated with BR as first-line therapy, the ORR and CR rates were 91% and

73%, respectively. The 5-year PFS and OS rates were 83% and 93%,

respectively.105 In a phase II study of 40 patients with advanced-stage

MZL, RCVP resulted in an ORR of 88% (60% CR).106 After a median

follow-up of 38 months, the estimated 3-year PFS and OS rates were 59%

and 95%, respectively. RCVP regimen is also effective for the treatment of patients who are not candidates for H. pylori eradication therapy or those

with gastric MALT lymphoma that is resistant to H. pylori eradication

therapy.107

The phase III randomized GALLIUM trial that compared the efficacy and

safety of obinutuzumab and rituximab when used in combination with

chemotherapy in patients with previously untreated indolent B-cell

lymphomas included 195 patients with previously untreated MZL (99

patients were randomized to receive obinutuzumab-based

chemoimmunotherapy and 96 patients were randomized to receive

rituximab-based chemoimmunotherapy).108 In the subgroup of analysis of the GALLIUM trial, after a median follow-up of 59 months, there were no clinically relevant differences in ORR and PFS between the study arms.109

The ORR at the end of induction treatment was 80% for the

obinutuzumab-based chemoimmunotherapy and 88% for rituximab-based

chemoimmunotherapy (P = .82). The 4-year PFS rates were 73% and

64% for obinutuzumab-based chemoimmunotherapy and rituximab-based

chemoimmunotherapy, respectively (P = .35) and the 4-year OS rate was also similar between the treatment arms (82% and 78%, respectively).

However, grade 3 to 5 adverse events were higher with obinutuzumabbased chemoimmunotherapy than with rituximab-based

chemoimmunotherapy (86% vs. 77%). Based on this toxicity profile and

the comparable efficacy of the treatment arms, the GALLIUM study

investigators concluded that obinutuzumab-based chemoimmunotherapy may not be an appropriate first-line therapy option for patients with MZL.109

First-line Therapy: Other Recommended Regimens

Lenalidomide + Rituximab

In the phase II trial that evaluated lenalidomide + rituximab in patients with untreated, advanced-stage, indolent lymphoma (n = 110; 30 patients with MZL), the ORR was 89% (67% CR; 22% PR) and the median PFS was 54 months among the subgroup of patients with MZL.110 Lenalidomide in

combination with rituximab also has demonstrated activity in patients with MALT lymphoma, resulting in ORR of 80% (54% CR; 26% PR).111

Lenalidomide + rituximab in first-line therapy is included with a category

2B recommendation.

Rituximab

As discussed earlier, rituximab monotherapy has demonstrated activity in MALT lymphomas49,50,56-58 and SMZL.90-94 It is the preferred initial

treatment for patients with SMZL.

Second-line and Subsequent Therapy: Preferred Regimens

Chemoimmunotherapy with anti-CD20 Monoclonal Antibody

Chemoimmunotherapy regimens are also effective for the treatment of

patients with relapsed MZL.74,112,113

The GADOLIN study (413 total patients with 47 patients having MZL; 28 patients with MZL were randomized to bendamustine + obinutuzumab and 19 patients with MZL were randomized to bendamustine monotherapy)

confirmed that the combination of bendamustine + obinutuzumab followed by obinutuzumab maintenance significantly prolongs PFS compared to

bendamustine monotherapy in patients with rituximab-refractory indolent B-cell lymphomas.74 After a median follow-up of 32 months, the median

PFS was significantly longer with bendamustine + obinutuzumab than with bendamustine monotherapy for the overall intent-to-treat study population(26 vs. 14 months; P < .001).

Lenalidomide + Rituximab

Abstract

Alternate non-cross resistant chemotherapy regimens (bendamustine, CHOP or CVP) with obinutuzumab or rituximab are included as options for preferred regimens in second-line and beyond.

Abstract

Lenalidomide in combination with rituximab also has demonstrated activity in recurrent MZL. [114][1 ][116]

In the multicenter, double-blind, randomized phase III study (AUGMENT) that compared lenalidomide + rituximab versus rituximab monotherapy in patients with relapsed/refractory indolent lymphoma (n = 358; 63 patients had MZL), although the ORRs were higher with lenalidomide + rituximab (64% [29% CR; 35% PR]) compared to rituximab monotherapy (44% [13% CR; 31% PR] ) in the subgroup of patients with MZL, PFS improvements favored lenalidomide + rituximab all the histologic subtypes of indolent lymphomas except MZL. 115 After a median follow-up of 28 months, the estimated 2-year OS rates were 82% and 94%, respectively for lenalidomide + rituximab and rituximab monotherapy for the subgroup of patients with MZL.

In the MAGNIFY trial that evaluated lenalidomide + rituximab followed by maintenance therapy in patients with relapsed/refractory indolent B-cell lymphomas (394 patients; 76 patients with MZL), induction therapy with lenalidomide + rituximab resulted in an ORR of 64% (39% CR) in the subgroup of patients with MZL. 116 nalidomide + rituximab is included as an option for preferred regimens for second-line and subsequent therapy.

BTK Inhibitors

[119] In phase I/II trial of 43 patients with relapsed/refractory MZL, acalabrutinib resulted in an ORR of 53% (13% CR) among 40 patients evaluable for response. 117 After a median follow-up of 13 months, the estimated 12month PFS rate was 67%. Zanubrutinib was U.S. Food and Drug Administration (FDA)-approved for the treatment of relapsed or refractory MZL after at least one prior anti-CD20-mAB-based regimen, based on the results of the phase II MAGNOLIA trial (68 patients with relapsed/refractory MZL after ≥1 line of therapy including ≥1 anti-CD20-mAb-based regimen). 118, 120 Zanubrutinib resulted in an ORR of 68% (as assessed by independent review committee; 26% CR). Responses were observed in all subtypes with an ORR of 64% (40% CR), 76% (20% CR), 67% (8% CR), and 50% (25% CR) in extranodal, nodal, splenic, and indeterminate subtypes, respectively. At a median follow-up of 27 months, the 24-month PFS and OS rates were 71% and 86%, respectively. 120 The 24-month PFS rates were higher in patients who achieved a CR (87% vs. 65%).

Pirtobrutinib is a highly selective non-covalent inhibitor that is approved for the treatment of relapsed/refractory mantle cell lymphoma (MCL) and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). The safety and efficacy of pirtobrutinib in relapsed/refractory MZL was demonstrated in the phase I/II BRUIN study (n = 36; NMZL, n = 17; SMZL, n = 13; and EMZL, n = 6). 121 Pirtobrutinib resulted in an ORR of 50% (3% CR and 47% PR) and the ORR was 46% for patients with MZL previously treated with a covalent BTKi. The ORR in patients with NMZL, SMZL, and EMZL were 59%, 31%, and 67%, respectively. The median PFS was 17 months (after a median follow-up of 16 months). After a median follow-up of 22 months, the median OS was not reached and the estimated 24month OS rate was 78%.

References

Based on the results of this study, pirtobrutinib is included as an option for second-line therapy in patients with relapsed/refractory disease after prior covalent BTKi.

Second-line and Subsequent Therapy: Other Recommended Regimens

In a multicenter phase II study of 60 patients with relapsed or refractory

MZL (after prior therapy with an anti-CD20 MAB-based regimen), ibrutinib resulted in an ORR of 48% (3% CR and 45% PR).122 The ORRs were

63%, 47%, and 62% for EMZL, NMZL, and SMZL, respectively. After a

median follow-up of 33 months, the median PFS was 16 months, and the median OS was not reached. The estimated 33-month PFS rates were

32%, 24%, and 42% for EMZL, NMZL, and SMZL, respectively. The

corresponding OS rates were 76%, 69%, and 66%, respectively. The

incidences of atrial fibrillation (8%) and major bleeding (3%) reported in this phase II study was higher than that reported in phase I/II studies that have evaluated other covalent BTKi (no incidence of atrial

fibrillation/flutter or major hemorrhage with acalabrutinib and the rate of atrial fibrillation/flutter was 3% with zanubrutinib).117,120

In 2021, ibrutinib received accelerated approval for relapsed/refractory

MZL based on the results of the aforementioned phase II study.122 In April 2023, the accelerated approval status for ibrutinib for the treatment of

relapsed/refractory MCL and MZL was withdrawn following the results of the confirmatory phase III studies.123,124 Although the SHINE study met the primary end point of superior PFS in the ibrutinib arm, the OS was

not different in the two treatment arms, specifically due to more deaths related to adverse events in the ibrutinib group compared to the

placebo.123 The SELENE study (which was designed to evaluate if the

addition of ibrutinib to chemoimmunotherapy [BR or RCHOP] would

prolong PFS compared to chemoimmunotherapy alone in patients with previously treated follicular lymphoma or MZL) did not meet the primary end point of improved PFS in the ibrutinib-containing treatment arm.124

While the Panel acknowledged the change in the regulatory status of

ibrutinib, the consensus of the Panel was to continue the listing of

ibrutinib monotherapy as an option for second-line and subsequent

therapy based on the efficacy results from earlier phase II multicenter

study in relapsed or refractory MZL (discussed above).122 The Panel

consensus was to move ibrutinib to other recommended regimens based on the data from head-to-head clinical trials in other B-cell malignancies that have demonstrated a more favorable toxicity profile for acalabrutinib and zanubrutinib compared to ibrutinib without compromising

efficacy.125,126

Rituximab monotherapy (for relapse after a longer duration of remission) and lenalidomide + obinutuzumab127 are also included as options under

other recommended regimens.

Third-line Therapy PI3K Inhibitors

In 2022, umbralisib received accelerated FDA approval for

relapsed/refractory MZL after ≥1 prior line of therapy with anti-CD20

mAb-based regimen based on the results of the UNITY-NHL.128 Other P13K inhibitors (copanlisib, duvelisib, and idelalisib) that had received accelerated FDA approval for relapsed/refractory FL have shown

promising activity in relapsed/refractory MZL.129-131 However, there was later a voluntary withdrawal of FDA indications for copanlisib, duvelisib, idelalisib, and umbralisib based on the substantial toxicity of PI3K

inhibitors having a detrimental impact on OS in recent clinical trials; these are not recommended for the treatment of relapsed/refractory MZL.132

CAR T-cell Therapy

Axicabtagene ciloleucel is included as an option for third-line therapy based on the results of the phase II ZUMA-5 trial (158 patients with relapsed/refractory indolent lymphoma; FL, n = 127; MZL, n = 31).71,72

Among the 152 patients who received axicabtagene ciloleucel, the ORR was 90% (75% CR). After the median follow-up of 32 months for patients with MZL (n = 31), the ORR was 77% and the median PFS was not

reached.72 The estimated 36-month OS and lymphoma-specific PFS rates were 75% and 65%, respectively, for all patients with indolent lymphomas. The 4-year follow-up data also confirmed that axicabtagene ciloleucel

results in durable responses and long-term survival in patients with

relapsed/refractory MZLs.133

Suggested Treatment Regimens for Patients who Are Older or Infirm

Rituximab monotherapy is the preferred treatment option for untreated as well as relapsed/refractory disease in patients who are older or infirm.

Alkylating agent-based chemotherapy (cyclophosphamide or chlorambucil) with or without rituximab are also included as options under other

recommended regimens for previously untreated as well as

relapsed/refractory disease.134-136 In a study that evaluated chlorambucil +

rituximab versus rituximab monotherapy in 49 patients with EMZL of

stomach, chlorambucil + rituximab was more efficient than rituximab alone in patients with t(11;18)-positive disease, whereas rituximab alone is as

efficient as chlorambucil + rituximab in patients with t(11;18)-negative

disease.134 In the international randomized IELSG-19 trial that evaluated

the combination of chlorambucil + rituximab versus chlorambucil or

rituximab monotherapies in patients with EMZL not previously treated with

systemic anticancer therapy, the addition of rituximab to chlorambucil

resulted in significantly better EFS.135 At a median follow-up of 7 years, the

5-year EFS rate was 68% for chlorambucil + rituximab compared to 51%

and 50%, respectively, for chlorambucil and rituximab monotherapies. The

5-year OS rate was not significantly different between the treatment arms.

Cyclophosphamide + rituximab was effective in the treatment of SMZL in

patients who are frail and not fit for splenectomy resulting in an ORR of

87% with a median PFS of 20 months.136

Acalabrutinib, zanubrutinib, lenalidomide + rituximab, and rituximab

monotherapy are also included as preferred treatment options for patients with relapsed/refractory disease. Pirtobrutinib is included as an option for second-line therapy in patients with relapsed/refractory disease after prior covalent BTKi. Ibrutinib is included as an option under other

recommended regimens.

References

lymphoid tissue lymphoma according to t(11;18) status: a monocentric

non-randomized observational study. Leuk Lymphoma 2013;54:940–944. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22978684.

135. Zucca E, Conconi A, Martinelli G, et al. Final results of the IELSG-19 randomized trial of mucosa-associated lymphoid tissue lymphoma:

improved event-free and progression-free survival with rituximab plus

chlorambucil versus either chlorambucil or rituximab monotherapy. J Clin Oncol 2017;35:1905–1912. Available at:

https://www.ncbi.nlm.nih.gov/pubmed/28355112.

136. Cervetti G, Ghio F, Cecconi N, et al. How to treat splenic marginal

zone lymphoma (SMZL) in patients unfit for surgery or more aggressive therapies: experience in 30 cases. J Chemother 2017;29:126–129.

Available at: https://www.ncbi.nlm.nih.gov/pubmed/27454143.

Mantle Cell Lymphoma

Mantle cell lymphoma (MCL) comprises about 4% of all newly diagnosed non-Hodgkin lymphomas (NHL).1 MCL is a heterogenous subtype of B-cell NHL, thought to possess the unfavorable characteristics of both indolent and aggressive NHL owing to the incurability of disease with conventional chemoimmunotherapy and a typically more aggressive disease course

compared to indolent NHL.2

MCL is characterized by the reciprocal chromosomal translocation

t(11;14), juxtaposing the CCND1 gene locus with the IGHV gene locus,

resulting in the overexpression of cyclin D1; the diagnosis of MCL

generally requires the expression of cyclin D1.3 Cyclin D1-negative MCL with otherwise typical immunophenotype has also been reported, though rare (<5%).4,5 Rearrangements involving the CCND2 gene are present in 55% of cyclin D1-negative MCL and are associated with high expression of cyclin D2 mRNA.6

Gene expression profiling (GEP) and microRNA (miRNA) profiling showed that the genomic signatures of cyclin D1-negative MCL were similar to

those of cyclin D1-positive MCL.5-7 The pathologic features and clinical

characteristics of cyclin D1-negative MCL appear to be similar to those of cyclin D1-positive MCL.6,7 Thus, in the absence of data suggesting

otherwise, cyclin D1-negative MCL should not be managed differently than cyclin D1-positive MCL.

The 2022 WHO Classification of Hematolymphoid Tumors (WHO5) and

International Consensus Classification (ICC) reflect the heterogeneity of

this entity and recognize the three subtypes of MCL with different

clinicopathologic and molecular features: classical MCL (nodal or

extranodal); leukemic and non-nodal MCL; and in situ mantle cell

neoplasia (ISMCN).8,9

Classical MCL is SOX11-positive and IGHV unmutated with a generally

aggressive clinical course.10 The blastoid/pleomorphic variant is

characterized by different cytologic features resembling lymphoblasts or

large cell lymphomas, a more aggressive clinical course, and is often

associated with poor prognostic features such as TP53 mutations and high Ki-67 proliferation index.10,11

The leukemic and non-nodal subtype typically is SOX11-negative, IGHV

mutated, and has an indolent disease course. This variant most commonly presents with peripheral blood, bone marrow, and splenic involvement, as well as low tumor burden and a Ki-67 proliferation index <10%.10,12,13

However, there are some presentations with gastrointestinal (GI) or

blood/bone marrow involvement only, which may express SOX11.

ISMCN is characterized by the preservation of the lymph node architecture and presence of cyclin D1-positive B cells restricted to the mantle zones

with minimal expansion of the mantle zone (and with only minimal or no

spread of cyclin D1-positive cells in the interfollicular area).14,15 An unusual presentation with a scattering of cyclin D1-positive cells in the germinal

centers (but not the mantle zones) of a lymph node specimen

retrospectively evaluated several years prior to the diagnosis of

symptomatic MCL has also been reported.16

Development of overt MCL in patients with ISMCN has been reported,

although this appears to be very uncommon.15 The occurrence of ISMCN in studies of reactive lymph nodes from patients without a history of

lymphoma is very rare and the significance or potential for malignancy of ISMCN in patients without known MCL remains uncertain.15,17 These

instances appear to have a very indolent disease course with long-term

survival even without treatment intervention; it is therefore important to

distinguish ISMCN from overt MCL with a mantle zone pattern.15 In

patients with ISMCN in whom overt MCL can be excluded based on a

thorough evaluation (eg, biopsy of additional suspicious nodes, physical

This discussion corresponds to the NCCN Guidelines for B-Cell Lymphomas. Last updated: August 18, 2025.

examination, peripheral blood flow cytometry, CT scan of neck, chest,

abdomen, and pelvis), close follow-up may still be warranted.18 The WHO classification recommends that a diagnosis of MCL not be made in such instances when the suspected diagnosis is ISMCN.19

Literature Search Criteria

Prior to the update of this version of the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for B-Cell Lymphomas an electronic

search of the PubMed database was performed to obtain key literature in MCL published since the previous Guidelines update. The PubMed

database was chosen as it remains the most widely used resource for

medical literature and indexes peer-reviewed biomedical literature.20

The search results were narrowed by selecting studies in humans

published in English. Results were confined to the following article types: Clinical Trial, Phase II; Clinical Trial, Phase III; Clinical Trial, Phase IV;

Guideline; Randomized Controlled Trial; Meta-Analysis; Systematic

Reviews; and Validation Studies.

The data from key PubMed articles deemed as relevant to these

Guidelines and discussed by the Panel have been included in this version of the Discussion section (eg, e-publications ahead of print, meeting

abstracts). Recommendations for which high-level evidence is lacking are based on the Panel’s review of lower-level evidence and expert opinion.

Diagnosis

The diagnosis can be established by histologic examination in combination with adequate immunophenotyping with immunohistochemistry (IHC) or

flow cytometry. Typical immunophenotype of MCL is CD5+, CD10-/+,

CD20+, CD23-/+, CD43+, and cyclin D1+. Occasionally, MCL may be

CD5- or CD23+.

Currently available reagents for the evaluation of cyclin D1 by IHC are

robust and yield good staining. In the rare instances of MCL that is cyclin D1 and t(11;14) negative, overexpression of cyclin D2 or cyclin D3 may be observed.7,21 However, IHC for cyclin D2 or cyclin D3 is not helpful in

establishing the diagnosis of cyclin D1-negative MCL, as these proteins

are also expressed in other B-cell malignancies. SOX11 is positive in most patients with MCL, with the exception of the aforementioned indolent

subtype, regardless of cyclin D1 expression level. IHC for SOX11 or IGHV gene sequencing potentially aid in differentiating cyclin D1-negative MCL from other B-cell lymphomas.22-24

In certain circumstances, fluorescence in situ hybridization (FISH) for

CCND2 and CCND3 rearrangements or t(11;14) can be helpful for the

diagnosis of MCL that is cyclin D1-negative.6,25 FISH for t(14;18) and a

FISH panel for chronic lymphocytic leukemia (CLL) may also be useful to distinguish MCL that is cyclin D1-negative from CLL.

Ki-67 proliferation index is an independent predictor of outcome in

patients with advanced-stage MCL treated with chemoimmunotherapy, and Ki-67 proliferation index of <30% has been associated with a more

favorable prognosis.26-31 Ki-67 has also been integrated into the MCL

International Prognostic Index (MIPI) for the risk stratification of patients with advanced-stage disease in clinical trials evaluating

chemoimmunotherapy and high-dose therapy with autologous stem cell rescue (HDT/ASCR).32-35 Ki-67 should be included in the IHC panel for

initial diagnostic workup. However, this should not be used to guide

treatment decisions at this time.

Genetic aberrations involving the TP53 gene are associated with poor

prognosis. See the section on TP53-Mutated Classical MCL.

Workup

The initial workup should include a thorough physical examination with

attention to node-bearing areas, evaluation of performance status and

constitutional symptoms, and laboratory assessments (complete blood

count [CBC] with differential and a comprehensive metabolic panel, in

addition to measurements of serum lactate dehydrogenase [LDH]).

Patients with high tumor burden and elevated LDH should be assessed for spontaneous tumor lysis syndrome (TLS), including measurements of uric acid level. Measurement of serum beta-2-microglobulin levels may also be useful in some circumstances. Testing for hepatitis B virus (HBV) should be performed for all patients. HBV testing is indicated due to the risk of

viral reactivation in patients receiving chemoimmunotherapy. Testing for

hepatitis C virus (HCV) may be useful under certain circumstances.

MCL is a systemic disease with frequent involvement of the bone marrow, and evaluation with bone marrow biopsy with or without aspirate will be

useful in certain circumstances. PET/CT scan (preferred) or

chest/abdomen/pelvis CT with contrast of diagnostic quality are

recommended as part of initial diagnostic workup, if systemic therapy is planned. CT scan of the neck with contrast may be useful in selected

circumstances. In patients with the blastic variant or for patients presenting with central nervous system (CNS) symptoms, a lumbar puncture should be performed to evaluate the cerebral spinal fluid for potential disease

involvement. Multigated acquisition (MUGA) scan or echocardiogram is

recommended for patients being considered for treatment regimens

containing anthracyclines or anthracenediones.

GI involvement has been reported in 15% to 30% of patients with MCL. In two prospective studies, the frequency of GI tract involvement in patients with MCL was higher than that reported in the literature.36,37 In the study by Romaguera et al, MCL was histologically present in the lower and upper

GI tract in 88% and 43% of patients, respectively, and 26% of patients

presented with GI symptoms at the time of diagnosis.36 Despite the high

frequency of GI tract involvement (which was primarily observed at the

microscopic level), the use of endoscopy with biopsies led to changes in

clinical management in only 4% of patients.36 Salar et al reported upper or lower GI tract involvement in 38% and 54% of patients, respectively, at

diagnosis.30 The NCCN Guidelines Panel does not recommend endoscopy or colonoscopy as part of routine initial workup, but suggests that it may

be useful in certain circumstances. However, endoscopic or colonoscopic evaluation of the GI tract is necessary for confirmation of stage I–II

disease and for response assessment to initial therapy.

Treatment Options for Stage I–II MCL

Few patients present with localized MCL and the available published

literature on the management of localized disease is retrospective and

anecdotal. In a retrospective analysis of 26 patients with limited bulk,

early-stage (stage IA or IIA) MCL, radiation therapy (RT) with or without

chemotherapy was associated with significantly improved progression-free survival (PFS) at 5 years (68% vs. 11%; P = .002) and a trend towards

improved OS.38

Less aggressive chemoimmunotherapy with or without ISRT is included as an option for induction therapy. Involved-site RT (ISRT) (30–36 Gy)

alone is an appropriate treatment option for patients with stage I or

contiguous stage II, non-bulky disease. In highly selected patients with

asymptomatic disease (noncontiguous stage II, non-bulky), close

observation with deferred therapy is a reasonable option, especially for

those with good performance status and lower risk scores on standard

International Prognostic Index (IPI).39,40 These recommendations are

based on treatment principles in the absence of more definitive clinical

data.

No further treatment is necessary for patients achieving a complete

response (CR) to induction therapy. Clinical follow-up with a complete

history and physical exam and laboratory assessment is recommended

every 3 to 6 months for the first 5 years, and then annually (or as clinically indicated) thereafter. Surveillance imaging with CT scans can be

performed no more than every 6 months up to the first 2 years following completion of treatment, and then no more than annually thereafter in the absence of symptoms or clinical findings of concern.

Patients with a partial response (PR) or disease progression after less

aggressive chemoimmunotherapy with or without ISRT should be treated as described below for disease relapse. Patients with stage I or

contiguous stage II non-bulky disease achieving PR or disease

progression after prior ISRT alone should be treated as described for

stage II (noncontiguous, bulky) and stage III–IV disease.

Disease relapse after less aggressive chemoimmunotherapy with or

without ISRT should be treated as described for relapsed/refractory

disease. In selected patients, relapsed disease may be treated as

described below for advanced-stage disease.

Disease relapse after prior treatment with ISRT alone (for stage I or

contiguous stage II non-bulky disease) should be treated as described

below for advanced-stage disease.

Treatment Options for Stage II (noncontiguous, bulky) and Stage III–IV MCL

The majority of patients have advanced-stage disease, requiring systemic therapy. While some investigators have suggested that treatment with

less aggressive regimens could yield survival outcomes similar to that

achieved with more aggressive regimens, others have reported superior survival outcomes with more aggressive regimens.41,42 In a single-center cohort analysis of 111 patients with newly diagnosed MCL, among the 75

patients with available data on treatment regimens, the majority of

patients (70%) had received CHOP (cyclophosphamide, doxorubicin,

vincristine, and prednisone)-like regimen with or without rituximab and only 7% of patients had received rituximab in combination with

hyperCVAD (R-hyperCVAD; rituximab, cyclophosphamide, vincristine, doxorubicin, and dexamethasone) alternating with high-dose

methotrexate and cytarabine and/or HDT/ASCR.41 The median OS from diagnosis was 85 months, and the 5-year OS rate was 66%.

An analysis from the NCCN Oncology Outcomes Database (n = 167)

reported superior PFS outcomes with R-hyperCVAD alone or with

rituximab-containing regimens, RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) followed by HDT/ASCR,

compared with RCHOP alone, in the first-line setting for patients <65

years of age.42 However, the median PFS remained 3 to 4 years despite the use of aggressive regimens.

Among patients with indolent MCL with leukemic and non-nodal

presentation (as described earlier), observation is a reasonable option for patients with asymptomatic disease with no indications for

treatment.10,12,13 Patients with symptomatic disease requiring therapy

should be treated with chemoimmunotherapy regimens based on the

TP53 mutation status as described below.

Classical MCL (TP53 wild-type)

Aggressive induction therapy with cytarabine-based

chemoimmunotherapy followed by HDT/ASCR and rituximab

maintenance has been the standard treatment approach for patients who are eligible for transplant.43-45 Less aggressive induction therapy followed by rituximab maintenance is recommended for patients who are not

candidates for transplant.46

Alternating RCHOP + ibrutinib/RDHA (rituximab, dexamethasone and high-dose cytarabine) + platinum (carboplatin, cisplatin, or oxaliplatin) is included as an option for aggressive induction therapy, based on the

preliminary results of the TRIANGLE study.47,48

TP53-Mutated Classical MCL

In younger patients with classical MCL, TP53 mutation is associated with inferior responses to both induction chemoimmunotherapy and

HDT/ASCR.49-51 In an analysis that evaluated the prognostic effect of the most common genomic alterations in 183 younger patients treated in

Nordic MCL clinical trials, TP53 mutations were significantly associated

with Ki-67 >30%, blastoid morphology, and inferior responses to both

induction chemoimmunotherapy and HDT/ASCR.49

BTK inhibitor (BTKi) either as monotherapy or in combination regimens

has demonstrated activity in TP53-mutated classical MCL.47,48,52-54

The TRIANGLE study (discussed below) established the safety and

efficacy of using ibrutinib in combination with high-dose cytarabine-based chemoimmunotherapy (alternating RCHOP/RDHA + platinum [carboplatin, cisplatin, or oxaliplatin]) as induction therapy for TP53-mutated classical MCL in patients who were younger and eligible for transplant.47,48 The

subgroup analyses demonstrated a failure-free survival (FFS) benefit

with the addition of ibrutinib to induction and maintenance therapy in

patients with p53 overexpression, but the impact of ibrutinib in patients with TP53 mutation was not reported.

In a multicenter phase II trial of 25 patients with previously untreated

TP53 mutated classic MCL, zanubrutinib in combination with

obinutuzumab and venetoclax resulted in an ORR of 96% (88% CR).52

After a median follow-up of 28 months, the 2-year PFS and OS rates

were 72% and 76%, respectively. Undetectable minimal residual disease (uMRD) levels <10–5 (uMRD5) and uMRD levels <10–6 (uMRD6) were

observed in 95% and 84% of patients, respectively. Treatment was

discontinued after 24 cycles for patients achieving CR with uMRD,

suggesting that MRD-directed discontinuation of treatment may be an

effective treatment approach for patients with TP53-mutated MCL. Longterm follow-up is needed to confirm these findings.

The results of the SYMPATICO trial showed that ibrutinib + venetoclax resulted in higher response rates and PFS benefit in patients with

relapsed/refractory TP53-mutated MCL.53 In a subgroup analysis of 73 patients with TP53-mutated MCL enrolled this study, the ORR was 84% (57% CR) and the median PFS was 21 months.54

NCCN Recommendations

The NCCN Guidelines recommend TP53 sequencing as an essential

prognostic test to identify TP53-mutated classical MCL, and aids in the

selection of appropriate treatment, particularly if upfront HDT/ASCR is

anticipated.55 The European MCL Network has reported high TP53

expression as a strong predictor of shorter time-to-treatment failure (TTF) and overall survival (OS), independent of Ki-67 proliferation index.56

However, there are conflicting reports regarding the use of TP53

expression by IHC as a surrogate for TP53 mutation.57,58 TP53

sequencing is preferred; however, in the front-line setting, TP53

expression by IHC can be used as a surrogate for initial screening, but should be confirmed with sequencing.

Participation in clinical trials is strongly suggested for patients with TP53-mutated classical MCL. In the absence of a suitable clinical trial, the

following options can be considered.

• Zanubrutinib/obinutuzumab/venetoclax is an option for all patients

(regardless of their eligibility of aggressive therapy).52

• Alternating RCHOP + ibrutinib/RDHA + platinum (carboplatin, cisplatin,

or oxaliplatin) is included as an option for patients suitable for

aggressive induction therapy, based on the results of the TRIANGLE

study (discussed below).47,48

• Less aggressive induction therapy is recommended for patients who

are not suitable for aggressive induction therapy.

Induction Therapy

Historically, aggressive induction therapy (chemoimmunotherapy with

high-dose cytarabine-based regimens, and potential use of HDT/ASCR as consolidation) has been reserved for fit patients aged ≤65 years.

There are no prospective randomized studies comparing the various

aggressive regimens or for the addition of BTKi to

chemoimmunotherapy, although some randomized data exist for less

aggressive regimens.

The NCCN B-Cell Lymphomas Panel stratified the regimens for initial

induction therapy into three categories (based on the available evidence, efficacy, toxicity, preexisting comorbidities, and access to certain

agents): Preferred, Other Recommended, and Useful in Certain

Circumstances (as outlined on MS-5).

Aggressive Induction Therapy: Preferred Regimens

LYMA Regimen: RDHA and Platinum (carboplatin, cisplatin, or oxaliplatin)

In a phase III randomized LYMA trial that evaluated the role of rituximab maintenance after HDT/ASCR in patients <66 years of age, induction

chemoimmunotherapy with rituximab, dexamethasone, and cytarabine

RDHA + platinum (carboplatin, cisplatin, or oxaliplatin) (RDHAP) resulted in an overall response rate (ORR) of 89% (77% CR), and HDT/ASCR

following induction therapy was performed in 257 patients, resulting in a CR rate of 65%.44 The 4-year PFS rate was 83% for rituximab

maintenance following HDT/ASCR compared to 64% for observation (P = .001). The 4-year OS rates were 89% and 80% for rituximab maintenance

and observation group (P = .04), respectively. The 7-year follow-up data

confirmed that rituximab maintenance following HDT/ASCR is associated with long-term disease control without increase in relapse rate at the end of rituximab maintenance.59

In a subsequent analysis that evaluated the prognostic impact of

carboplatin, cisplatin, or oxaliplatin on survival outcomes, in the

intent-to-treat population (n = 298), the PFS and OS rates were better

with RDHA-oxaliplatin compared to RDHA-cisplatin and RDHAcarboplatin.60 The 4-year PFS rate was 87% for RDHA-oxaliplatin

compared to 65% for both RDHA-carboplatin and RDHA-cisplatin (P =

.02). The 4-year OS rates were 92% for RDHA-oxaliplatin versus 76% for both RDHA-cisplatin and RDHA-carboplatin. Low MIPI and treatment

with RDHA-oxaliplatin were independent favorable prognostic indicators for PFS.

LYMA-101 trial showed that obinutuzumab-based induction

chemoimmunotherapy (obinutuzumab + DHAP [dexamethasone, highdose cytarabine, and cisplatin] [ODHAP]) and obinutuzumab maintenance after HDT/ASCR in younger patients eligible for transplant (<66 years; n = 85) was also associated with prolonged PFS and OS.61 In the propensity

score matching analysis, the survival rates were comparable (without

excess toxicity) to those reported in the aforementioned LYMA trial for

rituximab-based induction chemoimmunotherapy (RDHAP) and rituximab maintenance after HDT/ASCR.60 The estimated 5-year PFS (83% vs.

67%; P = .029) and OS (86% vs. 71%; P = .039) rates were longer for

obinutuzumab-based induction chemoimmunotherapy.61

Based on the results of this trial, the Panel consensus supported the

substitution of obinutuzumab for rituximab (optional) across all lines of

therapy at the discretion of the treating physician.

Abstract

In the Nordic MCL2 study (n = 160), induction therapy with dose-intensified RCHOP (maxi-CHOP) alternating with high-dose cytarabine resulted in an ORR and CR rate of 96% and 54%, respectively, in patients ≤65 years of age with previously untreated MCL. 62 Patients with responding disease were eligible to proceed to HDT/ASCR. The ORR and 6-year PFS and OS rates were 96% (54% CR), 66%, and 70%, respectively, with no relapses occurring after a median follow-up of approximately 4 years (at the time of the initial report).

After a median follow-up of 15 years, the median PFS and OS were 9 years and 13 years, respectively, for all the intent-to-treat patient population. 63 The median OS was not reached and median PFS was 11 years for the 145 patients who proceeded to HDT/ASCR. The OS and PFS were significantly better for patients who had achieved CR to induction therapy than those who achieved PR (P = .0038 for OS; P < .0001 for PFS). However, a continuous pattern of relapse and an excess mortality were observed even after prolonged remission (late relapses were reported in 6 patients, who experienced disease relapse > 10 years after the end of therapy). 63 In the multivariate analysis, the MIPI and Ki-67 expression level were the only independent predictors of survival outcomes. 63 In this trial, patients were monitored by disease-specific primers for molecular relapse, and those with disease relapse received rituximab as re-induction but were not considered to have disease relapse unless there was morphologic evidence of disease relapse.

Bendamustine and Rituximab Followed by Rituximab and High-Dose Cytarabine

The results of a pooled analysis (n = 88) showed that induction therapy with BR (bendamustine and rituximab; 3 cycles) followed by rituximab and high-dose cytarabine (3 cycles) followed by HDT/ASCR resulted in high rates of durable remissions. 64 At the end-of-induction therapy, the ORR was 97% (90% CR) for the 87 patients in whom responses were evaluable. After a median follow-up of 33 months, the 3-year PFS and OS rates were 83% and 92%, respectively.

TRIANGLE Regimen: Alternating RCHOP + Ibrutinib/RDHA + Platinum (carboplatin, cisplatin, or oxaliplatin)

In the phase III randomized Intergroup trial conducted by the European-MCL Network, alternating RCHOP/RDHAP followed by HDT/ASCR was associated with significantly improved TTF compared to RCHOP followed by HDT/ASCR in younger patients with advanced-stage MCL. 65 The long-term follow-up data also showed an improvement in OS for the RDHAP arm (median OS was not reached vs. 11 years for the RCHOP arm). 66

This regimen formed the basis for the TRIANGLE study, a three-arm phase III randomized trial evaluating the addition of ibrutinib to induction and maintenance therapy in younger patients eligible for transplant. 47 ight hundred and seventy patients with previously untreated stage II-IV MCL who were < 66 years of age were randomized to three treatment arms (1:1:1): Arm A: alternating RCHOP/RDHAP followed by HDT/ASCR and observation (n = 288); Arm A + I: alternating RCHOP + ibrutinib/RDHAP followed by HDT/ASCR and 2-year maintenance therapy with ibrutinib (n = 292); and Arm I: alternating RCHOP + ibrutinib/RDHAP followed by maintenance therapy with ibrutinib (n = 290). Rituximab maintenance was included in all three arms following its incorporation into the European guidelines. The ORRs were 94% (36% CR) for arm A and 98% (45% CR) for the combined arms A + I/I. With a median follow-up of 31 months, the 3-year FFS rates were significantly higher for arm A + I (88%; P = .0008 for A + I vs. A) and arm I (86%; P = .9979 for I vs. A) than for arm A (72%), respectively). Disease progression was higher in group A (n = 67) than in A + I (n = 34) or I (n = NCCN 授权医脉通提供NCCN指南全文下载。wmlsyy于2025/12/23,21:20在医脉通平台下载，仅供个人使用，严禁分发。2025 美国国家综合癌症网络版权所有。

References

35), and the 3-year PFS rates were 73%, 88%, and 87% for A, A+I, and I, respectively. The median OS was not reached in all three arms and the 3-year OS rates were 91%, 92%, and 86% for A + I, I, and A,

respectively.

The safety profile of alternating RCHOP + ibrutinib/RDHAP was similar to that of alternating RCHOP/RDHAP, with anemia (61% vs. 59%),

neutropenia (49% vs. 47%), and thrombocytopenia (61% vs. 59%) being the most common grade 3–5 hematologic toxicities.

Based on the preliminary results of the TRIANGLE study, alternating

RCHOP + ibrutinib/RDHA + platinum (carboplatin, cisplatin, or oxaliplatin) is included as an option for aggressive induction therapy for patients with classical MCL, TP53-mutated MCL, and classical MCL, TP53 wild-type.

Longer-term follow-up data confirmed these findings. After a median

follow-up of 53 months, the 3-year FFS rate for treatment arm A (induction followed by HDT/ASCR) was not superior compared to treatment arms

containing ibrutinib: A + I or I (75%, 86%, and 75% respectively; P = .28

for A + I vs. I; P = .9942 for A vs. I; P = .0034 for A + I vs. A). There was

also a trend towards prolonged OS for treatment arms containing ibrutinib (A + I and I) compared to treatment arm A.48 The 3-year OS rates were

90%, 91%, and 85%, respectively (P = .0069 for A + I vs. A; P = .0041 for A vs. I).

Head-to-head clinical trials in other B-cell malignancies have

demonstrated a more favorable safety profile for acalabrutinib and

zanubrutinib (compared to ibrutinib without compromising efficacy).67,68 Therefore, the substitution of ibrutinib with another covalent BTKi

(acalabrutinib or zanubrutinib) in the induction phase of the TRIANGLE regimen is included with a category 2B recommendation. However,

acalabrutinib and zanubrutinib were not specifically evaluated in the

TRIANGLE study.

Aggressive Induction Therapy: Other Recommended Regimen

Rituximab + HyperCVAD Alternating With High-Dose Methotrexate and Cytarabine

R-hyperCVAD/high-dose methotrexate and cytarabine has resulted in

favorable PFS and OS outcomes in patients with previously untreated

MCL.69-72 In a phase II study of 97 patients with previously untreated MCL,R-hyperCVAD/high-dose methotrexate and cytarabine resulted in 3-year FFS and OS rates of 64% and 82%, respectively, with a median follow-up time of 40 months.69 After 10 years of follow-up, the median OS had not

been reached and the median TTF was 5 years for all patients, with similar results seen in confirmatory phase trials.72,73 However, this regimen has

substantial toxicity including myelotoxicity.

The use of ibrutinib + rituximab as induction therapy prior to the

administration of R-hyperCVAD has been shown to minimize the number of cycles of R-hyperCVAD and rituximab maintenance in young

patients.73 Based on the more favorable safety profile for acalabrutinib

and zanubrutinib (compared to ibrutinib without compromising efficacy), the Panel consensus supported the use of other covalent BTKis

(acalabrutinib or zanubrutinib) + rituximab as induction therapy prior to the administration of R-hyperCVAD.

RBAC500 (rituximab, bendamustine, and cytarabine)

The combination of BR with low-dose cytarabine (RBAC500) has been

shown to be an effective treatment option for patients with untreated MCL who are not suitable for aggressive induction therapy.74,75

In a multicenter retrospective analysis that compared the outcome of

newly diagnosed patients with MCL (median age, 72 years) treated with RBAC (n = 103) or BR (n = 53), the CR rate was 91% for RBAC and 60% for BR (P < .0001).74 At a median follow-up of 46 months, the 2-year PFS rates were 87 ± 3% and 64 ± 7% for RBAC and BR, respectively (P =

MS-89

Abstract

.001). The median OS was 121 months and 78 months for RBAC and BR, respectively. RBAC was also associated with significantly superior PFS (P = .01) among the subgroup of 127 patients > 65 years of age. In a multicenter phase II study (n =57), after a median follow-up of 86 months the 7-year PFS and OS rates were 55% and 63%, respectively for patients with previously untreated MCL. Blastoid/pleomorphic morphology was an adverse prognostic factor for PFS in the multivariate analysis. 75

Role of HDT/ASCR Consolidation

7] [78] [79] [80] [81] [82] [83] A phase III randomized trial of 269 patients showed a survival benefit for HDT/ASCR compared with interferon alfa maintenance (PFS: 39 vs. 17 months; P = .011; OS: 7.5 vs. 5 years; P = .019) in patients ≤65 years of age with advanced-stage MCL in remission after CHOP-like induction therapy with or without rituximab. 77, 78 However, HDT/ASCR appears less effective after highly effective induction therapy (based on results from the TRIANGLE study), 47 and may not benefit patients achieving deep remissions (CR with uMRD6) based on the results of the US trial (ECOG-ACRIN EA4151). 84 Thus, there is increasing uncertainty regarding the need for the routine incorporation of consolidation with HDT/ASCR in the treatment of newly diagnosed MCL in the modern era.

In the TRIANGLE study (discussed above), at a median follow-up of 31 months, induction therapy with alternating RCHOP + ibrutinib/RDHAP followed by maintenance therapy with ibrutinib + rituximab resulted in superior FFS compared to induction therapy with alternating RCHOP/RDHAP followed by HDT/ASCR. 47 Both of the ibrutinibcontaining arms (A + I and I) were associated with superior FFS compared to transplant alone. FFS rates were not significantly different between the two ibrutinib-containing arms (A + I vs. I). Grade 3-5 neutropenia was higher with A + I (44%) compared to ibrutinib (23%) or A alone (17%). However, this did not translate into higher rate of infections in the A + I arm. The results of the TRIANGLE study suggest that alternating RCHOP + ibrutinib/RDHAP followed by maintenance therapy with ibrutinib + rituximab is an effective induction therapy for patients < 66 years of age and consolidation therapy with HDT/ASCR could be avoided in this group of patients.

Initial results from the ECOG-ACRIN EA4151 phase 3 randomized trial demonstrated a lack of survival benefit for consolidation with HDT/ASCR in patients achieving CR with disease uMRD6 after induction therapy (n = 653; 73% of patients received aggressive induction therapy with highdose cytarabine-based regimens and 27% of patients received less aggressive induction therapy). 84 Five hundred sixteen patients achieving CR with uMRD6 following induction therapy were randomized to HDT/ASCR with maintenance rituximab (Arm A; n = 257) or maintenance rituximab alone (Arm B; n = 259), and the remaining patients with MRDpositive CR (Arm C; n = 49) or MRD-indeterminate CR (Arm D; n = 85) were randomized to HDT/ASCR + maintenance rituximab. A pre-planned interim analysis after a median follow-up of 3 years showed no significant differences in PFS or OS between Arm A and Arm B. The 3-year PFS rate was 77% for all randomized patients in both arm A and arm B. The corresponding 3-year OS rates were 82% and 83%, respectively. An exploratory analysis of patients randomized to Arm C (49 patients with MRD-positive CR) showed that survival rates were higher for patients who achieved CR with uMRD6 following HDT/ASCR (the 3-year PFS and OS rates were 100%) compared to those patients with detectable MRD (3-year PFS and OS rates were 49% and 64%, respectively), suggesting that patients achieving MRD-positive CR might benefit from HDT/ASCR. Thus, while HDT/ASCR as first-line consolidation has demonstrated promising outcomes in a number of studies, and is considered as an

References

MS-90

[78] [79] [80] [81] [82] Less Aggressive Induction Therapy: Preferred Regimens

Acalabrutinib (continuous) + Bendamustine + Rituximab

In the phase III randomized ECHO trial (598 patients randomized to receive acalabrutinib + BR [n = 299] and BR [n = 299] ), the addition of acalabrutinib to BR resulted in statistically improved PFS in patients with newly diagnosed MCL (≥ 65 years). 85 This trial allowed crossover to the acalabrutinib + BR arm for patients with disease progression on the control arm. The ORRs were 91% (67% CR) and 88% (54% CR) for acalabrutinib + BR and BR + placebo, respectively. After a median followup of 50 months, the median PFS was 66 months and 50 months for the two treatment arms, respectively. After censoring for deaths related to corona virus disease (COVID-19), the median PFS were not reached and 62 months, respectively, for the two treatment arms. There was no statistically significant difference in OS between the treatment arms (not reached in both arms; P = .2743).

Based on the results of this study, the combination of acalabrutinib with BR was FDA approved for the treatment of patients with previously untreated MCL who are not candidates for aggressive therapy including HDT/ASCR.

Bendamustine + Rituximab

The efficacy of BR as first-line therapy for MCL was established in two randomized phase III studies. 86, 87 e randomized phase III study of the StiL (Study Group Indolent Lymphomas) compared BR versus RCHOP as first-line therapy in patients with advanced follicular, indolent, and MCLs (514 evaluable patients; MCL histology comprised 18% of patients). 86 With a median follow-up time of 45 months, the BR regimen was associated with significantly longer median PFS (primary endpoint) compared with RCHOP (70 vs. 31 months; P < .0001). However, OS outcomes were not significantly different between treatment arms and ORR was similar in both arms (93% with BR vs. 91% with RCHOP), although the CR rate was significantly higher in the BR arm (40% vs. 30%; P = .021). Among the subgroup of patients with MCL, the median PFS was significantly higher with BR compared with RCHOP (35 vs. 22 months; P = .0044). 86 The BR regimen was associated with less frequent serious treatment-emergent adverse events (TEAEs; 19% vs. 29%) and less grade 3-4 hematologic TEAEs compared with RCHOP. Grade 3-4 neutropenia (29% vs. 69%), peripheral neuropathy (all grades; 7% vs. 29%), and infectious complications (all grades; 37% vs. 50%) were less frequent with BR compared with RCHOP. Fatal sepsis occurred in 1 patient in the BR arm and 5 patients in the RCHOP arm. Skin toxicities (all grades) including erythema (16% vs. 9%) and allergic reactions (15% vs. 6%) were more frequent with BR than with RCHOP. 86 Although this phase III randomized trial showed superior PFS outcomes with the BR regimen compared with RCHOP, there may be limitations given that data from more than half of the patients in this trial were censored prior to the minimum follow-up period.

Another randomized phase III study (BRIGHT) demonstrated that BR was noninferior to RCHOP or RCVP (in terms of PFS) as first-line treatment of patients with indolent lymphoma or MCL (224 patients were randomized to receive BR and 223 patients were randomized to receive RCHOP or RCVP). 87 At a median follow-up of 5 years, the corresponding 5-year PFS rates for the overall study population were 66% and 56% (P = .0025), respectively, for BR and RCHOP/RCVP. 87 The 5-year OS rate was not statistically different between the treatment groups and the incidences of

References

vomiting, drug hypersensitivity reactions, opportunistic infections, and

secondary malignancies were significantly higher with BR.

The randomized phase III SHINE study compared ibrutinib in

combination with BR and rituximab maintenance therapy (n = 261) and placebo with BR and rituximab maintenance therapy (n = 262) in patients >65 years of age with previously untreated MCL.88 At a median follow-up of 85 months, the median PFS was superior for ibrutinib + BR compared to BR + placebo (81 vs. 53 months; P = .01). Although this study met the primary endpoint of superior PFS in the ibrutinib arm, the OS was not

different in the two treatment arms, specifically due to more deaths

related to TEAEs in the ibrutinib group compared to the placebo group

(11% vs. 6%). Based on these results, the Panel consensus did not

support the inclusion of ibrutinib + BR as an option for less aggressive

induction therapy.

Bortezomib, Rituximab, Cyclophosphamide, Doxorubicin, and

Prednisone (VR-CAP)

A phase III randomized study evaluated the safety and efficacy of

VR-CAP (bortezomib in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone) versus RCHOP in patients with newly

diagnosed MCL who are not candidates for HDT/ASCR.89 In this study, 487 patients were randomly assigned to VR-CAP or RCHOP; 268 patients (140 patients in the VR-CAP group and 128 patients in the RCHOP group) were included in the final follow-up analysis. The majority of patients had stage IV disease (74%) and 54% of patients had an IPI ≥3. After median follow-up of 82, the median OS was significantly longer for patients in the VR-CAP group than in the RCHOP group (91 vs. 56 months; P =

.001). The incidences of grade ≥3 TEAEs, although slightly higher with

VR-CAP (93% compared to 84% with RCHOP), were manageable.

Lenalidomide + Rituximab

In a multicenter phase II study that evaluated lenalidomide plus rituximab as induction and maintenance therapy for patients with previously

untreated MCL (n = 38), at a median follow-up of 64 months,

lenalidomide plus rituximab resulted in an ORR of 92% (64% CR).90 The

3-year PFS and OS rates were 80% and 90%, respectively, with a 5-year estimated PFS and OS of 64% and 77%, respectively. High-risk MIPI

was a predictor of unfavorable OS, but Ki-67 proliferation index did not

have any impact on PFS or OS. Long-term follow-up data also confirmed

the efficacy of lenalidomide + rituximab.91 At a median follow-up of 103

months, the 9-year PFS and OS rates were 51% and 66%, respectively.

RCHOP

In the earlier studies, the addition of rituximab to CHOP resulted in higher response rates but did not translate to prolonged PFS or OS.92,93 The

development of modern regimens proven to be highly active (or superior) for first-line treatment of MCL (eg, BR, TRIANGLE, VR-CAP) has resulted in a diminishing role for RCHOP.

Less Aggressive Induction Therapy: Other Recommended Regimen

Acalabrutinib + Rituximab

In a phase II trial for patients who are older (≥65 years; n = 50; TP53

aberrations were present in 12 patients), acalabrutinib + rituximab as

induction therapy resulted in an ORR of 94% (90% CR).94 After a median follow-up of 28 months, the median PFS and OS were not reached. The 2-year PFS and OS rates were 94% and 96%, respectively.

Role of Rituximab Maintenance

Rituximab maintenance after HDT/ASCR or less aggressive therapy has been associated with improved event-free survival (EFS)/PFS and, in

some settings, an improvement in OS.43-46

In a phase III randomized trial, rituximab maintenance after HDT/ASCR

prolonged EFS, PFS, and OS compared to observation in patients <66

years of age.44 In this trial involving 299 patients, 279 patients received

induction chemoimmunotherapy with RDHA with a platinum agent

(carboplatin, cisplatin, or oxaliplatin) resulting in an ORR of 89% (77%

CR). HDT/ASCR was performed in 257 patients following induction

therapy. Among these 257 patients, 240 patients were randomized to

receive rituximab maintenance or observation after HDT/ASCR. After a

median follow-up of 50 months, the 4-year EFS, PFS, and OS rates were 79%, 83%, and 89%, respectively, for patients assigned to rituximab

maintenance. The corresponding survival rates were 61%, 64%, and 80%, respectively, for patients assigned to observation.

In an observational study, patients with newly diagnosed MCL treated with the Nordic MCL regimen followed by HDT/ASCR achieved survival benefit with rituximab maintenance.45 The estimated 5-year PFS and OS were

both 83% after rituximab maintenance compared to 63% and 79%,

respectively, after observation.

Rituximab maintenance is also associated with substantially prolonged

PFS and OS in older patients who are not candidates for HDT/ASCR.46 In the phase III randomized trial (n = 316), patients with disease

responding to induction therapy with RCHOP or R-FC (n = 316) underwent second randomization to receive maintenance therapy (given until

progression) with either rituximab or interferon. After a median follow-up of 8 years, the median PFS and OS were 5 years and 10 years,

respectively, for patients randomized to rituximab maintenance

(compared to 2 years and 7 years, respectively, for those randomized to interferon). The 5-year PFS rates were 50% and 22%, respectively (P < .0001), for patients randomized to rituximab maintenance and interferon. The corresponding 5-year OS rates were 75% and 58%, respectively (P = .0026).46 Grade 3–4 hematologic toxicities occurred more frequently with

interferon alfa and rituximab was associated with more frequent grade 1–2 infections. This study clearly confirms the benefit of rituximab maintenance after RCHOP induction therapy in patients with newly diagnosed MCL.46

Although one randomized phase II study showed no benefit with

rituximab maintenance after induction therapy with BR, the findings of

this study have limited impact due to the study’s relatively small sample

size.95 In contrast, a large observational study of 4126 patients with MCL treated in U.S. community settings found that rituximab maintenance after either BR or RCHOP was associated with a longer time to next treatment (TTNT), and OS.96 Another large observation study of 796 patients with

MCL treated in U.S. academic centers also confirmed that rituximab

maintenance after induction therapy with BR was associated with

improved EFS and OS.97 While rituximab maintenance has not been

formally evaluated after induction therapy with other regimens (such as

VR-CAP or RBAC), and poses infectious risks, it has emerged as an

important option in first-line therapy for MCL.

NCCN Recommendations

Maintenance After Aggressive Induction Therapy

Based on the preliminary results of the TRIANGLE study, the NCCN

Guidelines recommend maintenance therapy with ibrutinib + rituximab for

patients with a CR following aggressive induction therapy.47 It should be

noted that the TRIANGLE study confirmed the benefit of ibrutinib

maintenance after alternating RCHOP + ibrutinib/RDHAP, and the value of ibrutinib maintenance after other aggressive induction therapy regimens

has not been established. As with the induction phase, the substitution of ibrutinib with another covalent BTKi (acalabrutinib or zanubrutinib) in the

maintenance phase of the TRIANGLE regimen is included with a

category 2B recommendation.

HDT/ASCR followed by maintenance therapy with BTKi and rituximab

remains an option for first-line consolidation of CR, based on historical

data and practice of some NCCN Member Institutions.76-82 However, the scope of HDT/ASCR has become increasingly narrow in the context of

improved induction therapies and demonstration of subsets of patients

unlikely to benefit from first-line consolidation (eg, those achieving CR with uMRD6 after induction therapy), highlighting the need for careful patient

selection.

Covalent BTKi is the preferred treatment option for patients with a PR to aggressive induction therapy. Alternatively, additional treatment with

second-line chemoimmunotherapy regimens may be considered in an

effort to improve the quality of a response. Consolidation with HDT/ASCR may be considered for eligible patients in remission (CR or improved PR) following additional therapy.

Patients with stable or progressive disease following aggressive induction therapy should be treated as described for relapsed or refractory disease.

Maintenance After Less Aggressive Induction Therapy

Rituximab maintenance (every 8 weeks x 2–3 years) is recommended for patients who are not candidates for HDT/ASCR, and who are in remission

after induction therapy with less aggressive regimens (category 1 following RCHOP).46

Relapsed/Refractory Disease

Early treatment failure after induction therapy (disease relapse and

initiation of second-line therapy within 12 months after upfront autologous HCT) and progression of disease (POD) within 24 months of diagnosis are associated with a poor prognosis.98-102 Additionally, patients with disease progression after ≥2 lines of therapy are considered a high-risk group with a shortened median time to subsequent relapse.99

In the MANTLE-FIRST study that evaluated the clinical outcomes of

patients with relapsed/refractory MCL following cytarabine-based induction chemoimmunotherapy, ibrutinib was particularly effective for refractory

disease to induction chemoimmunotherapy or early POD and

bendamustine-based regimens had similar efficacy to ibrutinib for late

POD.103 However, longer follow-up is needed to confirm these findings

from this retrospective study.

The optimal approach to relapsed or refractory disease remains to be

defined. The NCCN B-Cell Lymphomas Panel has stratified second-line

and subsequent therapy regimens into three categories (Preferred, Other Recommended, and Useful in Certain Circumstances) based on the

evidence from clinical trials that have evaluated the safety and efficacy of the regimens.

Second-Line and Subsequent Therapy: Preferred Regimens

Covalent BTKis (acalabrutinib and zanubrutinib) and lenalidomide +

rituximab are the preferred treatment options for second-line therapy.104-107 Acalabrutinib and zanubrutinib are the two covalent BTKis that currently have an FDA-approved indication for treatment of relapsed or refractory MCL.

Acalabrutinib

In a phase II study of 124 patients with relapsed or refractory MCL, at a

median follow-up of 15 months, acalabrutinib resulted in an ORR of 81%

(40% CR).108 The 12-month PFS and OS rates were 67% and 87%,

respectively. Headache (38%), diarrhea (36%), fatigue (28%), cough

(22%), bleeding (22%), and myalgia (21%) were the most common grade

1 or 2 TEAEs. Anemia (10%), neutropenia (10%), pneumonia (6%), and infections (15%) were the most common grade 3 or 4 TEAEs.

Long-term follow-up also confirmed these initial findings and no new

TEAEs were reported with additional follow-up.104 At a median follow-up of

MS-94

Abstract

26 months, the estimated 24-month PFS and OS rates were 49% and 72%. The median PFS was 20 months, and the median OS was not reached. Higher ORRs were observed in patients with blastoid or pleomorphic MCL with a Ki-67 index ≥50%. The incidences of serious infections decreased with longer follow-up (2% grade ≥3).

Zanubrutinib

The efficacy of zanubrutinib in relapsed/refractory MCL was established in two multicenter single-arm clinical trials. 105, 109 In the phase II study (n = 86), the ORR was 84% (69% CR). After a median follow-up of 18 months, the median PFS was 22 months and the estimated 12-month PFS rate was 76%. 109 Neutropenia (20%) and lung infection/pneumonia (9%) were the most common grade ≥3 TEAEs. Major bleeding events were observed in 3 patients with no reports of atrial fibrillation. In the phase I/II study (n = 48; 37 patients with relapsed or refractory MCL), the ORR was 84% (25% CR). After a median follow-up of 19 months, the median PFS and the estimated 12-month EFS and OS rates were 21 months, 87%, and 83, respectively. 105 Infections (19%), anemia (13%), pneumonia (9%), and myalgia (9%) were the most common grade ≥3 TEAEs.

Lenalidomide + Rituximab

Lenalidomide in combination with rituximab has demonstrated efficacy in patients with relapsed or refractory MCL. 106, 107 a phase I/II study of 52 patients with relapsed or refractory MCL, lenalidomide in combination with rituximab resulted in an ORR of 57% (36% CR). 106 The median duration of response (DOR), PFS, and OS were 19 months, 11 months, and 24 months, respectively. The most common grade 3 or 4 toxicities included neutropenia (66%) and thrombocytopenia (23%). An observational study of 58 patients also showed that lenalidomide-based regimens have clinical activity in relapsed/refractory MCL after prior therapy with ibrutinib and the addition of rituximab to lenalidomide improved ORR (27% compared to 15% for lenalidomide monotherapy). 107 Fatigue (38%) and cough, dizziness, dyspnea, nausea, and peripheral edema (19% each) were the most common TEAEs associated with lenalidomide-based regimens.

Second-Line and Subsequent Therapy: Other Recommended Regimens

Ibrutinib ± Rituximab

[112] [113] In the multicenter phase II study of 111 patients with relapsed or refractory MCL after a median of 3 prior therapies, after a median follow-up of 27 months, ibrutinib monotherapy resulted in an ORR of 67% (23% CR) with a median DOR of 18 months. 111 The 24-month PFS and OS rates were 31% and 47%, respectively. In another phase II study of 50 patients with relapsed or refractory MCL after a median of 3 prior therapies, at a median follow-up of 47 months, ibrutinib in combination with rituximab resulted in a CR of 58% and the median PFS was 43 months. 112 Blastoid morphology, high-risk MIPI score, and high Ki-67 were associated with inferior survival.

In a phase III randomized trial (RAY) that compared ibrutinib (n = 139) and temsirolimus (n = 141) in patients with relapsed or refractory MCL, the ORR was significantly higher for ibrutinib (77% vs. 47% for temsirolimus; P < .0001). 113 After a median follow-up of 39 months, the median PFS was significantly longer with ibrutinib (16 vs. 6 months) and there was also a trend toward improved OS for ibrutinib (30 vs. 24 months; P = .06). Diarrhea (33%), fatigue (24%), and cough (23%) were the most common TEAEs of any grade in the ibrutinib group. Thrombocytopenia (56%), anemia (44%), and diarrhea (31%) were the most common TEAEs in the

References

temsirolimus group. The rate of grade ≥3 bleeding events (9% vs. 5%) and

atrial fibrillation (5% vs. 1%) were higher with ibrutinib.

Ibrutinib received accelerated approval for relapsed/refractory MCL in

November 2013 based on the ORR from the phase II clinical trial.110 In

April 2023, the accelerated approval status for ibrutinib for the treatment of relapsed/refractory MCL was withdrawn following the results of the

confirmatory phase III SHINE study (discussed earlier).88 While the Panel acknowledged the change in the regulatory status of ibrutinib, the

consensus of the Panel was to continue the listing of ibrutinib

monotherapy or ibrutinib in combination with rituximab as an option for

second-line and subsequent therapy based on the safety and efficacy

results from earlier phase II and phase III studies in relapsed or

refractory MCL.111-113

The Panel consensus was to move ibrutinib ± rituximab to other

recommended regimens based on the data from head-to-head clinical

trials in other B-cell malignancies that have demonstrated a more

favorable safety profile for acalabrutinib and zanubrutinib compared to

ibrutinib without compromising efficacy.67,68

Second-Line and Subsequent Therapy: Useful in Certain Circumstances

Venetoclax-based regimens (single agent or in combination with a BTKi or an anti-CD20 monoclonal antibody [mAb]) has demonstrated activity in

patients with relapsed or refractory MCL with high-risk features including Ki-67 >30%, blastoid/pleomorphic histology, complex karyotype, and TP53 aberrations.53,114-117

In the phase III randomized SYMPATICO study (n = 267), the

combination of ibrutinib + venetoclax (n = 134) resulted in statistically

improved PFS compared to ibrutinib + placebo (n = 133) in patients with relapsed or refractory MCL. Ibrutinib + venetoclax also resulted in higher CR rate (54% vs. 32%) and TTNT (median not reached vs. 35 months).53

After a median follow-up of 51 months, the median PFS was also

significantly longer for ibrutinib + venetoclax (32 months vs. 22 months for ibrutinib + placebo). The estimated 24-month PFS rates were 57%

and 45%, respectively, for the two treatment arms. There was no

statistically significant difference in OS between the 2 treatment arms.

The estimated 24-months OS rates were 66% and 61% for ibrutinib +

venetoclax and ibrutinib + placebo, respectively. Higher response rates and PFS benefit with ibrutinib + venetoclax were consistent across

prespecified patient subgroups including those withTP53-mutated MCL.54

Venetoclax ± rituximab and ibrutinib + venetoclax are included as options for second-line subsequent therapy.53,114-117 In addition, the following

regimens are also included as options for second-line and subsequent

therapy based on the available evidence mostly from phase II trials.

• Bortezomib ± rituximab118,119

• Bendamustine + rituximab (if not previously given)120,121

• GemOx (gemcitabine and oxaliplatin) + rituximab122,123

• RBAC500 (if not previously given)124

Patients with high tumor burden, particularly those with MCL treated with venetoclax, are at increased risk for TLS and may be best managed with a starting dose of 20 mg daily for 1 week and gradually escalating to a target dose of 400 mg daily over 5 weeks along with TLS prophylaxis based on risk assessment [disease burden and rate of disease progression] and

close monitoring to reduce the risk of TLS.125

Progressive Disease After Prior Covalent BTKi

Limited data from retrospective studies suggest that RBAC500 and

venetoclax monotherapy result in favorable response rates in patients with

relapsed/refractory MCL after BTKi therapy.114,115,124 Acalabrutinib and

zanubrutinib were shown to be effective in the treatment of patients with B-

cell malignancies with intolerance to ibrutinib.126-128 Acalabrutinib and

zanubrutinib have not been shown to be effective for ibrutinib-refractory MCL with BTK C481S mutations as the mechanisms of resistance to

acalabrutinib and zanubrutinib are similar to that of ibrutinib.

Prior to the approval of chimeric antigen receptor (CAR) T-cell therapy

(discussed below), the optimal treatment approach for relapsed/refractory MCL after BTKi therapy had not been established in prospective studies, with many of the studies reporting poor outcomes for relapsed/refractory MCL after prior BTKi therapy.129-131

CAR T-Cell Therapy

Brexucabtagene autoleucel was FDA-approved for the treatment of

relapsed/refractory MCL after chemoimmunotherapy and BTKi therapy

based on the results of the ZUMA-2 trial (74 patients with

relapsed/refractory MCL who had been treated with up to 5 prior lines of

therapy including anthracycline-based or bendamustine-based

chemotherapy, anti-CD20 mAb, and BTKi).132 The estimated 24-month

PFS and 30-month OS rates were 53% (72% for patients with CR) and

60% (76% for patients in CR), respectively. Brexucabtagene autoleucel

also resulted in favorable ORR, PFS, and OS among patients treated with prior BTKis. The ORRs were 92%, 80%, and 100%, respectively, among patients treated with prior ibrutinib (n = 52), acalabrutinib (n = 10), and

both (n = 6). The median PFS and OS were 26 months and 46 months,

respectively, for patients treated with prior ibrutinib. The corresponding

median survival times were 6 months and not reached for patients treated with acalabrutinib. Longer-term follow-up data also confirmed the efficacy of brexucabtagene autoleucel (higher ORR and OS benefit).133,134 After a median follow-up of 36 months, the ORR for all patients treated in the trial was 91% (68% CR) and the ORR was consistently higher among patients with poor prognostic features including pleomorphic or blastoid

morphology, TP53 mutation, or Ki-67 index ≥50.133 At a median follow-up

of 48 months, the median OS for the entire study population was 46

months and among patients who had achieved CR, the median OS was 69 months.134 Grade ≥3 cytopenias (94%) and infections (32%) were the most common TEAEs; grade ≥3 cytokine release syndrome (CRS) and

neurologic events occurred in 15% and 31% of patients, respectively, and no new TEAEs were reported with longer follow-up.132-134 Brexucabtagene autoleucel also resulted in high response rates (ORR, 91%; 73% CR) in patients with relapsed or refractory MCL who have not received prior BTKi therapy with a 12-month OS rate of 90%.135

A report from the US Lymphoma CAR-T Consortium (189 patients with

relapsed/refractory MCL) confirmed that the safety and efficacy of

brexucabtagene autoleucel in the standard-of-care setting was consistent with those reported in the ZUMA-2 trial.136 In the univariable analysis, highrisk simplified MIPI, high Ki-67, TP53 aberration, complex karyotype, and blastoid/pleomorphic variant were associated with shortened PFS.

Lisocabtagene maraleucel was FDA-approved for the treatment of

relapsed/refractory MCL after ≥2 prior lines of therapy including a BTKi

based on the results of the TRANSCEND NHL1 study (104 patients

underwent leukapheresis; 88 patients received lisocabtagene maraleucel; 30% had received ≥5 previous lines of therapy; 53% had disease

refractory to BTKi; and 23% had TP53 mutation).137 The ORR was 83%

(72% CR). The median DOR and median PFS were 16 months and 15

months, respectively. Neutropenia (56%), anemia (38%),

thrombocytopenia (25%), prolonged cytopenia (40%), and infections

(15%) were the most common grade ≥3 TEAEs. CRS and neurologic

events were reported in 61% and 31% of patients, respectively.

Brexucabtagene autoleucel and lisocabtagene maraleucel are

recommended as second-line or subsequent therapy for patients with

progressive disease on prior covalent BTKi.

NCCN Guidelines Version 1.2026 B-Cell Lymphomas

Pirtobrutinib (a highly selective non-covalent BTKi) received accelerated FDA approval for the treatment of relapsed or refractory MCL based on the results of the multicenter, single-arm phase I/II BRUIN trial that demonstrated the safety and efficacy of pirtobrutinib in patients with intolerance or disease that is refractory to prior covalent BTKis (152 patients with relapsed/refractory MCL after prior therapy with covalent BTKi). 138, 139 The ORR was 49% (16% CR) for patients with MCL previously treated with a covalent BTK inhibitor and 86% for those with MCL that is covalent BTK inhibitor naive. 139 At median follow-up of 24 months, DOR rate was 39% (median DOR was 22 months for patients with MCL previously treated with a covalent BTK inhibitor). 139 The median PFS and OS for with MCL previously treated with a covalent BTK inhibitor were 6 months and 24 months, respectively. High ORRs were observed in patients with progressive disease on prior covalent BTKi (43%; DOR, 15 months) and high-risk features including blastoid variant (40%; DOR, not reached), elevated Ki-67 (44%; DOR, 22 months), and TP53 mutation (43%; DOR, 18 months). 139 the cohort of patients with MCL, fatigue (32%), diarrhea (22%), and dyspnea (18%) were the most common TEAEs. Pirtobrutinib was also associated with low rates of hemorrhage (grade ≥3, 2%), and atrial fibrillation or flutter (all grades; 4%). 139 rtobrutinib is recommended as second-line or subsequent therapy for patients with progressive disease on prior covalent BTKi.

Bispecific Antibodies

The safety and efficacy of CD3 x CD20 bispecific antibody, glofitamab (fixed duration for 12 cycles; step-up dosing with a target dose of 16 mg or 30 mg), in patients with relapsed or refractory MCL (after 2 prior therapies including a BTKi) was evaluated in a phase I/II study (N = 61; 60 evaluable patients for safety and efficacy). 140 The ORR was 85% (78% CR) for the overall study population and the median duration of CR was 15 months. After a median follow-up of 20 months, the median PFS and OS were 17 months and 30 months, respectively. The 12-month PFS and OS rates were 57% and 74%, respectively. The ORR and CR rates were 74% and 71%, respectively, for patients with relapsed or refractory MCL previously treated with BTKi. The corresponding response rates were 97% and 86%, respectively, for patients with BTKi-naïve relapsed or refractory MCL. CRS (70%; grade 3 or 4, 12%), neutropenia (38%; grade 3 or 4, 23%), and pyrexia (32%) were the most common TEAEs. Nine of 60 patients required admission to the intensive care unit (ICU). In addition, serious infectious adverse events were reported in 33% of patients, with fatal infections including COVID-19 (8 patients) and pneumonia (5 patients). Pretreatment with obinutuzumab (1000 mg or 2000 mg) was given for all patients to mitigate CRS. Pretreatment with 2000 mg of obinutuzumab was associated with lower incidences of CRS (64% vs. 88%; grade ≥2, 23% vs. 63%), longer time to CRS onset, and shorter duration of CRS, compared to pretreatment with 1000 mg obinutuzumab. However, this trial was not designed to compare the pretreatment dose of obinutuzumab required for the effective mitigation of CRS.

Glofitamab is recommended as a second-line or subsequent therapy option (category 2B) for patients with progressive disease after CAR T-cell therapy and pirtobrutinib or for patients who are not candidates for CAR Tcell therapy. Loss of CD20 tumor antigen expressions has been suggested as a possible mechanism of resistance to treatment with mAbs targeting CD20 (including bispecific antibody therapy). 141 The activity of CD3 x CD20 bispecific antibody therapy is unclear in the setting of CD20negative lymphomas. Rebiopsy to confirm CD20 positivity is recommended prior to the initiation of CD-19-directed therapy or CD3 x CD20 bispecific antibody therapy.

References

Allogeneic HCT

Allogeneic hematopoietic cell transplant (HCT) is a potentially curative

option for eligible patients with relapsed/refractory disease that is in

remission following second-line therapy.142-145 Allogeneic HCT using

reduced-intensity conditioning (RIC) has been evaluated as a

consolidation strategy for patients in remission following treatment for

relapsed/refractory MCL and it has also been shown to be an effective

treatment for relapsed or refractory MCL with TP53 mutation.146-150

Remission duration after autologous HCT has been identified as the only significant predictor of outcome following allogeneic HCT in patients with relapsed MCL.98 Longer remission duration (>12 months) after autologous HCT was associated with significantly better outcomes compared to early relapse (within 1 year after autologous HCT) or primary refractory disease.

With the approval of CAR T-cell therapy (brexucabtagene autoleucel and lisocabtagene maraleucel) and pirtobrutinib for relapsed/refractory MCL, in most NCCN Member Institutions, allogeneic HCT has been deferred to relapsed/refractory disease after multiple prior therapies.

NCCN Recommendations

Continuation of covalent BTKi until disease progression or intolerance is recommended for patients with relapsed/refractory MCL responding to

second-line therapy with covalent BTKi-based regimens.

Brexucabtagene autoleucel, lisocabtagene maraleucel, and pirtobrutinib are included as options for patients with MCL that is refractory to or

progressing on second-line therapy (covalent BTKi-based regimens or

fixed-duration regimens) and also for patients achieving a PR to secondline therapy fixed-duration treatment regimens. Prior bendamustine

exposure (within 24 months before leukapheresis) was associated with

shorter PFS and OS. Bendamustine should be used with caution in

patients intended to receive CAR T-cell therapy, since it could impact the success of the patient's T-cell collection.

Glofitamab is recommended as second-line or subsequent therapy for

patients with progressive disease after CAR T-cell therapy and

pirtobrutinib or for patients who are not candidates for CAR T-cell therapy. As noted above, the glofitamab was associated with serious infectious

adverse events and a higher incidence of CRS (than that reported in

patients with DLBCL). Therefore, the benefits (fixed-duration treatment)

and risks (higher incidences of CRS) of using this regimen should be

carefully evaluated and retreatment with obinutuzumab (2000 mg) should be given to all patients prior to initiation of treatment with glofitamab.

Consolidation with allogeneic HCT is recommended in selected patients

with relapsed/refractory MCL that is in remission following second-line

therapy with fixed-duration regimens. Some of the Panel members also

felt that consolidation therapy with HDT/ASCR (if not previously received as part of induction therapy) is a reasonable treatment option for

selected patients with classical MCL that is TP53 wild-type, who have

achieved CR to second-line therapy with fixed-duration regimens.144

Allogeneic HCT is also included as an option for patients with MCL that is refractory to or progressing on second-line and subsequent therapy

(covalent BTKi-based regimens or fixed-duration regimens) and for

disease relapse or progressive disease following CAR T-cell therapy,

particularly if the disease is responsive to additional therapy (CR or PR to alternative second-line therapy). Data on the outcomes of allogeneic HCT following CAR T-cell therapy are not yet available.

References

Diffuse Large B-Cell Lymphomas

Diffuse large B-cell lymphomas (DLBCL) are the most common lymphoid neoplasms in adults, accounting for approximately 30% of non-Hodgkin

lymphomas (NHL) diagnosed annually.1 DLBCL, not otherwise specified (NOS) includes all nodal and extranodal large B-cell lymphomas (LBCL) that do not belong to a more specific diagnostic category.

Gene expression profiling (GEP) has identified distinct subtypes within

DLBCL, NOS based on cell of origin (COO): germinal center B-cell (GCB) subtype and activated B-cell (ABC) subtype.2,3 GCB DLBCL is associated with an improved outcome compared to ABC DLBCL. Molecular profiling has identified additional subtypes with distinct clinical characteristics.4-7 At the present time, the classification of DLBCL based on the COO is

retained in both the International Consensus Classification (ICC) and the updated WHO Classification of Hematolymphoid Tumors (WHO5).8,9

LBCL with IRF4 rearrangement is considered a definite entity in ICC and WHO5 and should be managed as DLBCL.8,9

In the 2017 WHO classification, a molecularly distinct subset of B-cell

lymphomas with morphologic and clinical features similar to Burkitt

lymphoma (BL), characterized by aberrations of 11q but lacking MYC

rearrangements, were included as a provisional entity (Burkitt-like

lymphoma with 11q aberration).10-13 This provisional entity has been

renamed as LBCL with 11q aberration in the ICC, whereas in the WHO5 this uncommon variant is referred to as high-grade B-cell lymphoma

(HGBL) with 11q aberration.8,9 These are now known to be genetically

distinct from BL. The optimum management of this rare subtype is

uncertain, as some evidence suggests it may not behave as aggressively as BL, though it is most often treated like BL. Distinction between BL and the LBCL/HGBL with 11q aberration may be difficult based on histologic

and immunophenotypic features. A recent study demonstrated that LEF1 is not expressed in LBCL/HGBL with 11q aberration but is uniformly

expressed in BL.14

EBV-positive DLBCL, NOS is an aggressive lymphoma associated with poor prognosis and can occur in any age group. Causes of underlying immune suppression must be excluded clinically.15,16 The expression of multiple pan-B-cell markers in >50% of the tumor cells and extranodal presentation help to differentiate Epstein-Barr virus (EBV)-positive

DLBCL, NOS from EBV-positive classic Hodgkin lymphoma (CHL).8

DLBCL presenting as isolated body-cavity effusions without solid masses represent an understudied group that occurs more often, but not

exclusively, in patients with underlying fluid-overload states. Both

classifications have introduced a new category (HHV8-negative, EBVnegative, primary effusion-based lymphoma [ICC], and fluid overloadassociated LBCL [WHO5]). The classifications differ with respect to

inclusion criteria, most notably with the ICC considering EBV-positive

cases to represent a spectrum of EBV-positive DLBCL rather than this

entity. Both groups require HHV8-negativity for inclusion. Optimal

treatment for these is uncertain, although some patients have an indolent disease course even without cytotoxic therapy.

Intravascular LBCL, DLBCL associated with chronic inflammation; fibrinassociated DLBCL; EBV-positive DLBCL, NOS; and T-cell/histiocyte-rich LBCL are also managed according to the DLBCL algorithms.

Literature Search Criteria

Prior to the update of this version of the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for B-Cell Lymphomas, an electronic

search of the PubMed database was performed to obtain key literature in DLBCL published since the previous Guidelines update, using the

following search terms: diffuse large B-cell lymphoma, aggressive B-cell

This discussion corresponds to the NCCN Guidelines for B-Cell Lymphomas. Last updated: August 18, 2025.

lymphoma, primary mediastinal B- cell lymphoma, gray zone lymphoma and HGBL. The PubMed database was chosen as it remains the most

widely used resource for medical literature and indexes peer-reviewed

biomedical literature.17

The search results were narrowed by selecting studies in humans

published in English. Results were confined to the following article types: Clinical Trial, Phase II; Clinical Trial, Phase III; Clinical Trial, Phase IV; Guideline; Randomized Controlled Trial; Meta-Analysis; Systematic

Reviews; and Validation Studies.

The data from key PubMed articles deemed relevant to these Guidelines and discussed by the Panel have been included in this version of the

Discussion section (eg, e-publications ahead of print, meeting abstracts). Recommendations for which high-level evidence is lacking are based on the Panel’s review of lower-level evidence and expert opinion.

Diagnosis

Adequate immunophenotyping is required to establish the diagnosis and COO (GCB vs. non-GCB). GEP is not routinely performed in the clinic and remains utilized only in the context of clinical trials. Immunohistochemistry (IHC) algorithms have been developed as surrogates for GEP to assign

COO in clinical practice and can generally assign tumors as GCB or nonGCB. The term “non-GCB” is used when classified by IHC because

specific IHC markers for ABCs are not routinely available, and thus the

non-GCB category is more heterogeneous than true ABC DLBCL when

assigned by GEP.

The most commonly used IHC algorithms include CD10, BCL6, and

IRF4/MUM1 to classify DLBCL into GCB (CD10+; or BCL6+, IRF4/MUM1-) and non-GCB (CD10-, IRF4/MUM1+; or BCL6-, IRF4/MUM1-).18 IHC

algorithms including GCET1, FOXP1, and LMO2 in addition to CD10,

BCL6, and IRF4/MUM1 have been proposed.19-21 Presently, the upfront

treatment remains the same for both GCB and non-GCB subtypes.

Results from randomized clinical trials have shown that targeted agents such as ibrutinib and lenalidomide are effective treatment options for

relapsed/refractory DLBCL, non-GCB subtype.22-24

The IHC panel should include CD20, CD3, CD5, CD10, CD45, BCL2,

BCL6, Ki-67, IRF4/MUM1, and MYC. Additional markers such as CD138, CD30, cyclin D1, ALK1, SOX11, HHV-8, and EBV in situ hybridization

(EBV-ISH) may be useful under certain circumstances to establish the

subtype. SOX11 positivity may be useful in differentiating cyclin D1-

negative pleomorphic or blastoid mantle cell lymphoma (MCL) from CD5-positive DLBCL.25,26

MYC rearrangements (reported in approximately 10% of patients with

DLBCL) often correlate with GCB phenotype. Prognostic impact of MYC rearrangement alone remains debated in the literature.27-33 The negative prognostic impact of MYC rearrangement is correlated in some studies to the MYC partner gene (IG vs. non-IG) in patients with DLBCL treated with chemoimmunotherapy and the adverse prognostic impact was evident

within 2 years after diagnosis in patients with a concurrent BCL2 and/or BCL6 rearrangement with an IG partner gene.30,33

Fluorescence in situ hybridization (FISH) for MYC rearrangement is

recommended as an essential diagnostic test. If MYC rearrangement is present, FISH should be done for the detection of BCL2 and BCL6 gene rearrangements.

Workup

The initial workup for newly diagnosed patients with DLBCL should include a thorough physical examination with attention to node-bearing areas, and evaluation of performance status (PS) and constitutional symptoms.

Laboratory assessments should include standard blood work including

complete blood count (CBC) with differential, a comprehensive metabolic

panel, and measurements of serum lactate dehydrogenase (LDH).

Patients with high tumor burden and elevated LDH should be assessed for spontaneous tumor lysis syndrome (TLS), including measurements of uric acid, potassium, phosphorous, calcium, and renal function. Hepatitis B

virus (HBV) testing prior to initiation of treatment is recommended for all

patients who will receive anti-CD20 monoclonal antibody (mAb)–based

regimens due to increased risk of HBV reactivation. Human

immunodeficiency virus (HIV) testing, hepatitis C virus (HCV) testing, and measurement of serum beta-2-microglobulin levels would be useful in

selected patients.

Fluorodeoxyglucose (FDG)-PET/CT scans are essential for the initial

staging of DLBCL where upstaging resulting in altered therapy occurs

about 9% of the time, and for response assessment after treatment

because they can distinguish residual fibrotic masses from masses

containing viable tumor.34 Whole body FDG-PET/CT scan ±

chest/abdomen/pelvis CT with contrast of diagnostic quality is

recommended for initial workup. FDG-PET/CT has also been reported to be accurate and complementary to bone marrow biopsy for the detection of bone marrow involvement in patients with newly diagnosed DLBCL.35,36 Bone marrow biopsy may not be needed if there is clearly positive marrow uptake by FDG-PET/CT. Bone marrow biopsy may also be omitted in the absence of any skeletal uptake on the staging FDG-PET/CT scan, unless finding another lymphoma subtype (discordant low-grade lymphoma)

would be considered important for treatment decisions.

The staging workup is designed to identify all sites of known disease and determine prognosis with known clinical risk factors. International

Prognostic Index (IPI) and the revised IPI (R-IPI) identify specific groups of patients who are more or less likely to be cured with standard therapy.37,38 IPI scores are based on patient’s age, stage of disease, serum LDH level,

ECOG PS, and the number of extranodal sites. In patients who are ≤60

years, an age-adjusted IPI uses the prognostic factors of stage, ECOG

PS, and serum LDH level.20

An NCCN-IPI has also been developed based on the outcome data from NCCN Member Institutions, and can stratify patients with newly diagnosed DLBCL into four different risk groups (low, low-intermediate, highintermediate, and high) based on quantification of age, LDH, sites of

involvement, Ann Arbor stage, and ECOG PS.39 This analysis included

1650 patients identified in the NCCN database who were diagnosed with DLBCL between 2000 and 2010 and treated with rituximab-based therapy. The NCCN-IPI defined the prognosis for patients in the low- and high-risk subgroups better (5-year overall survival [OS] rate 96% vs. 33%) than the IPI (5-year OS rate 90% vs. 54%). The NCCN-IPI was also validated using an independent cohort of 1138 patients from the British Columbia Cancer Agency.39 While the IPI, R-IPI, and NCCN-IPI predict clinical outcome with high accuracy, R-IPI and NCCN-IPI could also identify a specific subgroup of patients with very good prognosis (3-year progression-free survival

[PFS] and OS of 100%).40

Stage I–II

In the SWOG 0014 study that evaluated 3 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) followed by involved-field radiation therapy (IFRT) in patients with at least one adverse factor (non-bulky stage II disease, age >60 years, ECOG PS 2, or

elevated serum LDH) as defined by the stage-modified IPI (smIPI) (n =

60), the 4-year PFS rate was 88%, after a median follow-up of 5 years; the corresponding 4-year OS rate was 92%.41 In historical comparison, these results were favorable relative to the survival rates for regimens without

rituximab (4-year PFS and OS rates were 78% and 88%, respectively).

The phase III MabThera International Trial (MInT) found a benefit to

rituximab-based CHOP-like chemotherapy with a 6-year OS rate of 90%

MS-113

Abstract

versus 80% (P = .0004) in patients < 60 years of age and had 0-1 IPI risk factors. 42 Three quarters of patients had limited-stage disease, and radiation therapy (RT) was included for all extranodal sites of disease or any site > 7.5 cm. The 6-year event-free survival (EFS) rate (74% vs. 56%; P < .0001) and PFS rate (80% vs. 64%; P < .0001) were also significantly higher for patients assigned to chemotherapy plus rituximab compared to chemotherapy alone. 42

R-CHOP (3 cycles) with RT was also associated with reduced short-term toxicity (significantly lower risk of second-line therapy and lower incidences of neutropenia including those requiring hospitalization) compared to 6 to 8 cycles of R-CHOP alone in a large cohort of older patients with stage I-II DLBCL, while both treatment options had similar OS. 43 e results of the prospective randomized trial conducted by LYSA/GOELAMS showed that RT could be omitted in patients with nonbulky, defined by a tumor < 7 cm in diameter, limited-stage DLBCL who achieve FDG-PET-negative complete response (CR) with R-CHOP-14 (4 or 6 cycles), thus avoiding toxicity related to RT. 44 In this trial, 334 patients were randomized to receive R-CHOP-14 (n = 165) or R-CHOP-14 plus RT (n = 169). Patients with 0 IPI risk factors received 4 cycles, while patients with ≥1 risk factor received 6. After a median follow-up of 64 months, the 5-year EFS (89% and 92%, respectively; P = .18) and OS (92% and 96%, respectively) were not statistically significantly different between the two treatment arms.

The FLYER trial demonstrated that in younger patients with non-bulky, defined by a tumor < 7.5 cm in diameter, limited-stage DLBCL with a favorable prognosis (normal serum LDH levels, ECOG PS 0-1), R-CHOP (4 cycles plus two doses of rituximab) is non-inferior to R-CHOP (6 cycles) in terms of efficacy and was also associated with reduced toxicity. 45 Five hundred ninety-two patients were randomized to receive 6 cycles of R-CHOP (n = 295) or 4 cycles of R-CHOP plus two doses of rituximab (n = 297). After a median follow-up of 66 months, the 3-year PFS rate was 96% for R-CHOP (4 cycles plus two doses of rituximab) and 93% for R-CHOP (6 cycles). The incidences of hematologic (294 vs. 426) and non-hematologic treatment-emergent adverse events (TEAEs; 1036 vs. 1280) were also significantly lower with R-CHOP (4 cycles plus two doses of rituximab).

The feasibility of an FDG-PET-directed treatment approach for patients with limited-stage DLBCL was also evaluated in two other studies, both of which concluded that the majority of patients with limited-stage disease and a negative FDG-PET scan after R-CHOP (3 cycles) require only one additional cycle of R-CHOP to complete the treatment, without exposure to RT. 46, 47 RT is recommended only for the minority of patients with positive interim FDG-PET scan.

Stage III-IV

[50] [51] [52] Two randomized trials that have compared R-CHOP-21 with R-CHOP-14 showed that while both treatment options are associated with similar OS and PFS, R-CHOP-14 was associated with significantly higher rates of grade 3 or 4 neutropenia. 51, 52 In the phase III randomized trial of 1080 patients with newly diagnosed DLBCL, at a median follow-up of 46 months, the 2-year OS rates were 83% and 81%, respectively, for R-CHOP-14 and R-CHOP-21 (P = .38). The corresponding 2-year PFS rates were 75% for both treatment arms (P = .59). Notably, there was no difference in outcome between GCB-like and non-GCB-like DLBCL by IHC in this large prospective study. TEAEs were similar, except for a lower rate of grade 3 or 4 neutropenia in the R-CHOP-14 arm (31% vs. 60%), reflecting the fact that all patients in the R-CHOP-14 arm received primary

References

MS-114

Abstract

growth factor prophylaxis with granulocyte colony-stimulating factor (G-CSF), whereas no primary prophylaxis was given with R-CHOP-21. In the phase III LNH03-6B GELA study that compared R-CHOP-14 (8 cycles) with R-CHOP-21 in 602 older patients (age 60-80 years) with untreated DLBCL, after a median follow-up of 56 months, no significant differences were observed in terms of 3-year EFS (56% vs. 60%; P = .76), PFS (60% vs. 62%), or OS rates (69% vs. 72%) between R-CHOP-14 and R-CHOP-21. Grade 3 or 4 neutropenia was more frequent in the R-CHOP-14 arm (74% compared to 64% in the R-CHOP-21 arm) despite a higher proportion of patients having received G-CSF (90%) compared with patients in the R-CHOP-21 arm (66%).

Abstract

DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) has shown significant activity in patients with untreated DLBCL with 5-year and 1-year OS rates of 84% and 64%, respectively, in a phase II trial. 53,54 In a phase III randomized trial (CALGB 50303), 524 patients were randomly assigned to 6 cycles of R-CHOP (n = 223) or DA-EPOCH-R (n = 232). 55 The overall response rate (ORR) was 88% and 87%, for R-CHOP and DA-EPOCH-R, respectively. After a median follow-up of 5 years, there were no statistically significant differences in PFS (2-year PFS rate: 76% vs. 79%; P = .65) or OS (2-year OS rate: 86% and 87%; P = .64) between R-CHOP and DA-EPOCH-R. In addition, R-CHOP also had a more favorable safety and tolerability profile. DA-EPOCH-R was associated with a significantly increased risk of cytopenias and neuropathy.

Collectively, available data from clinical trials discussed above suggest that R-CHOP administered on a 21-day schedule remains the standard treatment regimen for the majority of patients with newly diagnosed DLBCL. [58] [59] Polatuzumab vedotin, an anti-CD79b antibody drug conjugate, in combination with R-CHP (rituximab, cyclophosphamide, doxorubicin, and prednisone), a modified R-CHOP regimen, was approved for first-line therapy for patients with previously untreated DLCBL, based on the results of the POLARIX trial. 60 In this trial, 879 patients with previously untreated DLBCL (ECOG PS 0-2; IPI score 2-5; adequate organ function; regardless of COO) were randomized to receive polatuzumab vedotin-R-CHP (pola-R-CHP; n = 440; 47 patients with stage I-II; 393 patients with stage III-IV) and R-CHOP (n = 439; 52 patients with stage I-II; 387 patients with stage III-IV). After a median follow-up of 61 months, the estimated PFS at 5 years was significantly higher with pola-R-CHP (64%) compared to 59% for R-CHOP. The 5-year OS rate was not significantly different (82% and 79%, respectively). 61 Although the trial was not designed or powered for subgroup analysis, point estimates suggested benefit in patients > 60 years of age, with an IPI score 3-5, and with ABC subtype of DLBCL. 60 Neutropenia (28% vs. 31% for RCHOP), febrile neutropenia (14% vs. 8% for RCHOP), and anemia (12% vs. 8% for R-CHOP) were the most common TEAEs, and the incidences of peripheral neuropathy were not different between the treatment arms (53% vs. 54% for R-CHOP). 60 Although the incidence of febrile neutropenia was higher with pola-R-CHP, the incidences of grade 3 or 4 infections were similar in both treatment arms (15% and 13%, respectively).

NCCN Recommendations

Stage I-II (excluding stage II with extensive mesenteric disease) R-CHOP (3 cycles) followed by interim restaging with FDG-PET/CT is recommended for patients with non-bulky ( < 7.5 cm; smIPI 0-1) disease, based on the results of the FLYER trial. 45 R-CHOP (6 cycles) with or without involved-site RT (ISRT) is recommended for patients with bulky disease (≥7.5 cm; smIPI 0-1). Pola-R-CHP is recommended for patients with smIPI > 1 based on the results of the POLARIX trial.

References

R-mini-CHOP (decreased dose of CHOP with a conventional dose of

rituximab) may be substituted for patients who are very frail and >80 years of age with comorbidities to improve tolerability.62-64

ISRT alone for DLBCL is associated with a high rate of relapse and is only recommended for patients who are not candidates for any

chemoimmunotherapy.

Stage II with Extensive Mesenteric Disease or Stage III, IV

R-CHOP (6 cycles) and pola-R-CHP (for patients with IPI ≥2) are included as preferred regimens (both with category 1 recommendation).51,52,60

DA-EPOCH-R is included as an option under other recommended

regimens. DA-EPOCH-R may be preferred for patients with primary

mediastinal large B-cell lymphoma (PMBL) or with HGBLs with

translocations of MYC and BCL2 (double-hit/triple-hit lymphomas;

DHL/THL). There is no evidence to suggest that an intensified regimen is better in patients with DLBCL and IHC expression of MYC and BCL2

without chromosomal rearrangements (double-expressing lymphomas;

DEL), for whom standard R-CHOP remains preferred.

R-mini-CHOP may be substituted for patients who are very frail and >80 years of age with comorbidities to improve tolerability.62-64

In patients with bulky disease or impaired renal function, initial therapy

should include monitoring and prophylaxis for TLS.

Results from the RICOVER-noRTh trial (an amendment to the RICOVER60 trial) showed a significant advantage to adding ISRT following CR

(evaluated by CT criteria) to initial bulky sites ≥7.5 cm or extranodal

involvement.65 In this study, 164 patients with stage III–IV disease were treated with 6 cycles of R-CHOP-14 and RT to bulky sites or extranodal involvement was omitted. The 3-year PFS and OS rates were significantly

inferior, compared to the corresponding survival rates in patients from the

RICOVER-60 trial treated with the same chemoimmunotherapy with RT to bulky sites.65 The study was therefore discontinued. Similarly, subgroup

analyses of the MInT and RICOVER-60 trials showed that patients with

skeletal involvement significantly benefited from RT to sites of skeletal

involvement.66 Although retrospective subgroup analyses may be

subjected to selection biases, the benefit of RT held up on multivariate

analysis in both studies. In selected cases, RT to initially bulky sites of

disease may be beneficial (category 2B).

Multiple randomized trials (RICOVER 60, NHL-B2, MInT, and the

MegaCHOEP trials) have demonstrated superior outcomes in females

relative to males, particularly in older adults, with older females benefiting more from the addition of rituximab than males.67 This could be explained

by a slower clearance rate of rituximab in older females. A prospective

non-randomized trial evaluated R-CHOP with rituximab dose of 500 mg/m2

in males >60 years with DLBCL.68 Rituximab 500 mg/m2 was associated

with better serum levels and improved OS rates in male patients

compared to historical data in older males treated with rituximab 375

mg/m2. In a planned subgroup analysis, rituximab 500 mg/m2 was

associated with improved PFS (P = .039) with a trend toward better OS

(P = .076) but was also not more toxic than 375 mg/m2 rituximab in older male patients. Based on these data, a rituximab dose of 500 mg/m2 may

be considered in male patients >60 years of age treated with R-CHOP. A randomized clinical trial is ongoing.

Response Assessment

Interim restaging is performed to identify patients whose disease has not responded to or has progressed on induction therapy. A negative FDGPET scan after 2 to 4 cycles of induction therapy has been associated with significantly higher EFS and OS rates in several studies.69-72 However,

interim FDG-PET scans can produce false-positive results and

chemoimmunotherapy is associated with a favorable long-term outcome

despite a positive interim FDG-PET scan.73,74 In one prospective study, the PFS in patients with a positive interim FDG-PET scan and negative biopsy (after 4 cycles of accelerated R-CHOP) was identical to that in patients

with a negative interim FDG-PET scan.73 A retrospective analysis also

reported only a minor difference in the 2-year PFS rates between patients with a positive interim FDG-PET scan and a negative interim FDG-PET

scan after treatment with 6 to 8 cycles of R-CHOP (72% and 85%,

respectively; P = .0475).74 Conversely, FDG-PET scan at the end of

treatment (EOT) was highly predictive of PFS; the 2-year PFS rate was

64% for patients with a final positive FDG-PET scan compared to 83% for those with a final negative FDG-PET scan (P < .001).

The limited prognostic value of interim FDG-PET scans in patients with

DLBCL treated with R-CHOP has also been confirmed in other reports.75-78 In a prospective study that evaluated the predictive value of interim FDGPET scans after 2 cycles of R-CHOP in 138 evaluable patients, the 2-year EFS rate was significantly shorter for patients with a positive interim FDGPET scan compared to those with a negative interim FDG-PET scan (48% vs. 74%; P = .004); however, the 2-year OS was not significantly different between the two groups (88% vs. 91%; P = .46).77 The results of the FDGPETAL trial showed that a positive interim FDG-PET scan (change in

SUVmax of <66%) was associated with significantly inferior EFS and OS, although FDG-PET–based treatment intensification did not improve

outcome in patients with DLBCL treated with R-CHOP.79

An FDG-PET–guided treatment approach is helpful to minimize the use of RT in selected patients with limited-stage DLBCL.45-47 If treatment

modifications are considered based on interim FDG-PET scan results, a

repeat biopsy of residual masses should be strongly considered to confirm FDG-PET positivity prior to additional therapy. EOT restaging is performed upon completion of treatment. The optimal time for EOT restaging is not

known. However, the Panel recommends waiting for 6 to 8 weeks after

completion of therapy before repeating FDG-PET scans.

Response assessment by FDG-PET/CT should be done according to the 5-point scale (5-PS).35,80 The 5-PS is based on the visual assessment of FDG uptake in the involved sites relative to that of the mediastinum and

the liver.81-83 A score of 1 denotes no abnormal FDG avidity, while a score of 2 represents uptake less than the mediastinum. A score of 3 denotes

uptake greater than the mediastinum but less than the liver, while scores of 4 and 5 denote uptake greater than the liver, and greater than the liver with new sites of disease, respectively. Different clinical trials have

considered scores of either 1 to 2 or 1 to 3 to be FDG-PET negative, but a score of 1 to 3 is now widely considered to be FDG-PET negative. Scores of 4 to 5 are universally considered FDG-PET positive. A score of 4 on an interim or EOT restaging scan may be consistent with a partial response(PR) if the FDG avidity has declined from initial staging, while a score of 5 denotes persistent or progressive disease.

Circulating tumor DNA (ctDNA) is being evaluated in clinical trials as a

biomarker for response assessment and determination of measurable

residual disease (MRD; also referred to as minimal residual disease) at

the EOT after first-line therapy as well as second-line therapy for

relapsed/refractory disease.84-86 In a phase II trial that evaluated

chemoimmunotherapy (DA-EPOCH-R or RCHOP) with or without

acalabrutinib as first-line therapy (n = 55), FDG-PET/CT at the EOT was positive in 26% of patients (n = 14) and 50% of these patients had

undetectable ctDNA without any disease progression.87 These preliminary findings confirm the feasibility and utility of ctDNA assay as an adjunct to FDG-PET/CT to determine the extent of MRD at the EOT after first-line

therapy. ctDNA assays have variable limits of detection (LOD) for MRD

and the results of another trial demonstrated that an LOD of at least 1 in

106 is essential for the efficient detection of MRD at the EOT.88 Additional larger clinical trials are needed to confirm these findings.

Repeat biopsy is recommended for patients with FDG-PET–positive

disease prior to the initiation of additional treatment. Based on the

preliminary findings (discussed above), if a biopsy is not feasible, the

guidelines recommend consideration of ctDNA assay (using a test with a detection limit of <1 part per million) for the detection of MRD prior to the initiation of additional therapy (category 2B).

Stage I–II Disease (excluding stage II with extensive mesenteric disease)

Interm restaging with FDG-PET/CT after 3 cycles of RCHOP is

recommended for patients with non-bulky disease (smIPI 0–1). ISRT or

one additional cycle of RCHOP (total of 4 cycles) is recommended if

interim restaging demonstrates CR (FDG-PET negative; 5-PS 1–3).45 If

the interim restaging demonstrates a PR (FDG-PET positive; 5-PS 4),

ISRT or additional cycles of RCHOP (1–3 cycles; total of 4–6 cycles) with or without ISRT followed by EOT restaging is recommended. Patients with progressive disease (FDG-PET positive; 5-PS 5) are treated as described for relapsed or refractory disease. Repeat biopsy is recommended prior to initiation of treatment for patients with a PR or progressive disease.

Interim restaging after 3 to 4 cycles of chemoimmunotherapy is

recommended for patients with bulky disease (smIPI 0–1). Additional

cycles of chemoimmunotherapy (2–3 cycles; total of 6 cycles) with or

without ISRT are recommended, if interim restaging demonstrates CR

(FDG-PET negative; 5-PS 1–3). Additional chemoimmunotherapy (2–3

cycles; total of 6 cycles) with or without ISRT followed by EOT restaging is recommended if interim restaging demonstrates PR (FDG-PET positive; 5-PS 4). Higher dose ISRT may be needed for patients with a PR (FDG-PET positive; 5-PS 4). Patients with progressive disease (FDG-PET positive; 5-PS 5) are treated as described for relapsed or refractory disease. Repeat

biopsy is recommended prior to initiation of treatment for patients with a PR or progressive disease.

Stage II with Extensive Mesenteric Disease or Stage III–IV

Interim staging (after 2–4 cycles) is recommended. Continuation of firstline therapy to a total of 6 cycles followed by EOT restaging is

recommended if the interim restaging demonstrates a CR (FDG-PET

negative; 5-PS 1–3) or PR (FDG-PET positive; 5-PS 4/5). No response or

progressive disease (after 2–4 cycles of first-line therapy) should be

managed as described below for relapsed or refractory disease. However,

FDG-PET/CT scan at interim restaging can lead to increased false

positives and should be carefully considered in select cases. If FDGPET/CT scan is performed and positive, rebiopsy is recommended before changing course of treatment.

After EOT restaging, active surveillance is preferred for patients with a CR. ISRT to initially bulky disease or isolated skeletal sites can be

considered.65,66 Patients with a PR (after completion of initial therapy) and those with progressive disease are treated as described below for

relapsed or refractory disease.

Studies that have evaluated high-dose therapy (HDT)/autologous stem

cell rescue (ASCR) as consolidation therapy for patients in first CR after

induction therapy found no benefit to upfront HDT/ASCR, except in

patients with high-risk IPI.89-91 However, this remains controversial since

this finding emerged only on a retrospective subset analysis involving a small number of patients and, notably, in this study a third of the patients

did not receive rituximab as part of their induction regimen.91 HDT/ASCR is therefore not recommended as first-line consolidation.

Follow-up

After EOT restaging, clinical follow-up at regular intervals (every 3–6

months for 5 years and then annually or as clinically indicated thereafter)

is recommended. Considerable debate remains regarding the routine use of imaging for surveillance in patients who achieve a CR after completion of first-line therapy. Although positive scans can help to identify patients

with early asymptomatic disease relapse, false-positive results are

common and problematic, and may lead to unnecessary radiation

exposure and invasive procedures for patients, as well as increased health care costs.

While a few studies have reported that surveillance FDG-PET scans may be useful for detecting early relapse and to identify patients with more

limited disease at the time of relapse, the use FDG-PET or CT scans for

routine surveillance has not been shown to improve clinical outcome.92-94 Data from several retrospective studies also suggest that routine

surveillance with FDG-PET or CT scans is of limited utility in the detection of relapse in the majority of patients with DLBCL.95-99

In a multiinstitutional retrospective analysis of two independent

prospectively enrolled cohorts of patients with DLBCL (767 patients with

newly diagnosed DLBCL treated with anthracycline-based

chemoimmunotherapy enrolled onto the Molecular Epidemiology

Resource [MER] or North Central Cancer Treatment Group NCCTGN0489 and 820 patients from a GELA LNH2003B program and the

hospital-based registry in France), patients who achieved EFS at 24

months (EFS24) had an OS equivalent to that of the general population (P = .25).100 These results suggest that EFS24 should be useful for

developing strategies for post-therapy surveillance, patient counseling,

and as an end point in clinical studies for patients with DLBCL.

In the absence of evidence demonstrating an improved outcome favoring routine surveillance imaging for the detection of relapse, the NCCN

Guidelines® do not recommend imaging for routine surveillance for

patients who have achieved a CR to initial therapy. When surveillance

imaging is performed, CT scan is preferred over FDG-PET/CT for the

majority of patients. FDG-PET/CT may be preferable for patients with

primarily osseous presentations, with the caveat that bone remodeling

may also be FDG-avid, so a biopsy is recommended for PE-positive sites prior to instituting second-line therapy. The NCCN Guidelines recommend CT scans with contrast no more than once every 6 months for up to 2

years after completion of treatment, with no ongoing routine surveillance imaging after that time, unless it is clinically indicated.

Prediction and Management of CNS Disease

The German High-Grade Non-Hodgkin Lymphoma Study Group

(DSHNHL) has proposed a prognostic model (CNS-IPI) to predict the risk

of CNS relapse incorporating the six clinical factors (age >60 years, LDH > normal, ECOG PS >1, stage III or IV disease, extranodal involvement >1,

and involvement of the kidney and/or adrenal gland).101,102 The CNS-IPI

separated patients into three risk groups based on the rate of developing

CNS disease at 2 years: low-risk (0 or 1 risk factor; rate of CNS disease

0.6%), intermediate-risk (2 or 3 risk factors; rate of CNS disease 3%), and

high-risk group (4 to 6 risk factors; rate of CNS disease at 10%).101 In the multivariate analysis, age >60 years, elevated LDH, ECOG PS >1, and

stage III or IV disease were identified as the most significant predictors of CNS relapse. Although involvement of >1 extranodal site was not a

significant predictor of CNS relapse, it was retained in the final CNS-IPI for the ease of application. Among the specific extranodal sites, only the

involvement of the kidney or adrenal gland were significantly associated

with CNS relapse or progression. In another international multicenter

retrospective analysis of 1532 patients with DLBCL treated with

chemoimmunotherapy, there was a strong correlation between absolute

number of extranodal sites and risk of CNS relapse. The 3-year

cumulative incidence of CNS relapse was 15% for patients with >2

extranodal sites compared with 3% for those with ≤2 extranodal sites

(P < .001).103

Stage IE primary DLBCL of the breast has also been identified as a

potential risk factor for CNS relapse.104,105 Primary testicular DLBCL is also associated with an increased risk of CNS and contralateral scrotal

recurrence, even when presenting with stage I disease. Inclusion of

methotrexate for CNS prophylaxis as well as scrotal RT (25–30 Gy) after completion of chemoimmunotherapy is therefore recommended.106

Intrathecal methotrexate given once per systemic treatment cycle has

been used for many years for CNS prophylaxis. Some retrospective

studies have suggested that high

‐

dose IV methotrexate-based prophylaxis may be associated with a lower incidence of CNS relapses.107-111

However, other reports suggest that CNS prophylaxis is insufficient to

prevent CNS relapse.112-116

The role of CNS prophylaxis remains controversial, but it can be

considered for patients with high-risk disease (4–6 risk factors according to CNS-IPI; kidney or adrenal gland involvement; testicular lymphoma;

primary cutaneous DLBCL, leg type or stage IE DLBCL of the breast).

Lumbar puncture should be considered for these patients, particularly if

neurologic symptoms are present. The diagnostic yield is improved if flow cytometric analysis of cerebrospinal fluid is undertaken. The following

options are included in the NCCN Guidelines for CNS prophylaxis if used: systemic high-dose methotrexate (3–3.5 g/m2 for 2–4 cycles) and/or

intrathecal methotrexate and/or cytarabine (4–8 doses) during or after the course of treatment.

Systemic methotrexate (≥3 g/m2) should be given with the R-CHOP cycle that has been supported by growth factors for concurrent presentation of CNS disease with parenchymal involvement. Different schedules have

been used for the integration of high-dose methotrexate with

RCHOP.107,117 However, the Panel prefers Day 15 of a 21-day cycle.

Adequate hydration and alkalinization of the urine is recommended prior to the administration of high-dose methotrexate, and leucovorin rescue

should be started beginning 24 hours after the initiation of methotrexate infusion. Renal and hepatic function as well as methotrexate clearance must be monitored. Adequate recovery of blood counts should be

confirmed prior to initiating the next cycle of R-CHOP. Intrathecal

methotrexate/cytarabine and/or systemic methotrexate (3–3.5 g/m2)

should be incorporated as part of the treatment plan and Ommaya

reservoir placement should be considered for patients with concurrent presentation of CNS disease with leptomeningeal involvement.

Treatment Options for Relapsed or Refractory Disease

The efficacy of second-line therapy is predicted by the second-line ageadjusted IPI, and the outcomes of relapsed/refractory DLBCL differ based on the response to initial therapy, timing of relapse, and opportunity to

undergo HDT/ASCR.118-120 In a population-based study of 1039 patients

with relapsed/refractory DLBCL treated with anthracycline-based

chemoimmunotherapy, 244 patients (23%) had relapsed disease that was subsequently re-treated.120 Across all therapies, the 4-year OS rate was

28% and 51% for patients who underwent HDT/ASCR. The 4-year OS rate was 47% for patients with disease relapse after 12 months from initial

diagnosis, whereas the 4-year OS rate was 13% for those with a transient or no response to initial therapy. Pre-transplant FDG-PET scans have

been identified as predictive factors in patients undergoing HDT/ASCR,

with positive FDG-PET scans following second-line therapy predicting

poor outcomes following HDT/ASCR.121-123

HDT/ASCR

The role of HDT/ASCR in patients with relapsed or refractory disease was demonstrated in an international randomized phase III trial (Parma study)

in the pre-rituximab era.124 In a retrospective analysis based on data from the EBMT registry that evaluated the role of HDT/ASCR in patients

achieving a second CR after second-line therapy (n = 470; 25% of patients had received rituximab-based therapy prior to ASCR), the 5-year DFS and

OS rates after ASCR were 48% and 63%, respectively, for all patients.125 The median disease-free survival (DFS) after ASCR was 51 months,

which was significantly longer than the duration of first CR (11 months; P <.001). The longer DFS with ASCR compared with first CR was also

significant in the subgroup of patients previously treated with rituximab (median not reached vs. 10 months; P < .001) and the subgroup who

relapsed within 1 year of first-line therapy (median 47 months vs. 6

months; P < .001). The results from other studies suggest that

HDT/ASCR should also be considered for patients with disease that is chemotherapy sensitive at relapse (ie, disease with a good PR to

second-line therapy).126-130

CAR T-Cell Therapy

CD19-directed chimeric antigen receptor (CAR) T-cell therapies

(axicabtagene ciloleucel, lisocabtagene maraleucel, and tisagenlecleucel) are FDA-approved for relapsed/refractory DLBCL (after ≥2 prior systemic therapy regimens).131-133 Lisocabtagene maraleucel is also an option for second-line therapy for relapsed/refractory DLBCL in patients who are not eligible for transplant but are eligible for CAR T-cell therapy.134,135

Axicabtagene ciloleucel and lisocabtagene maraleucel are also approved as second-line therapy for patients with primary refractory disease or

relapsed disease within 12 months after first-line therapy.136,137

Axicabtagene ciloleucel, tisagenlecleucel, and lisocabtagene maraleucel result in responses across all subgroups, including DHL/THL, GCB, and non-GCB subtypes. CD19 expression levels did not correlate with

response.

Axicabtagene Ciloleucel

The multicenter phase II study (ZUMA-1) evaluated axicabtagene

ciloleucel in patients with refractory DLBCL (n = 81), transformed follicular lymphoma (TFL; n = 30), or PMBL (n = 8).131 Eligible patients had an

absolute neutrophil count >1,000 cells/µL, an absolute lymphocyte count

>100 cells/µL, a platelet count >75,000 cells/µL, adequate organ function,

no central CNS involvement, and no active infection. The primary analysis included 101 patients (78 patients with disease refractory to ≥2 lines of

prior therapy and 21 patients with disease relapse after HDT/ASCR) who were evaluated 6 months after the infusion of axicabtagene ciloleucel.

After a median follow-up of 15 months, the ORR was 83% (58% CR). The median OS was 26 months. The estimated 5-year OS and diseasespecific survival (DSS; excluding deaths unrelated to disease progression)rates were 43% and 51%, respectively.

The results of the ZUMA-7, international, randomized, phase III trial

showed that axicabtagene ciloleucel was superior to second-line

chemoimmunotherapy followed by HDT/ASCR (in terms of EFS rates

and response rates) in patients with primary refractory disease or early relapse (≤12 months after completion of first-line

chemoimmunotherapy).136 In this study, 180 patients were randomized to axicabtagene ciloleucel and 179 patients were randomized to

investigator-selected second-line chemoimmunotherapy followed by

consolidation with HDT/ASCR for patients with disease responding to

second-line chemoimmunotherapy. At a median follow-up of 25 months, the ORRs were 83% (65% CR) and 50% (32% CR), respectively, for

patients randomized to axicabtagene ciloleucel and second-line therapy followed by consolidation with HDT/ASCR. The median EFS (8 months vs. 2 months) and the estimated 24-month EFS rates (41% vs. 16%)

were higher with axicabtagene ciloleucel compared to second-line

therapy followed by consolidation with HDT/ASCR. There were no

statistically significant differences in the estimated 2-year OS rates

between the 2 groups (61% and 52%, respectively). Grade ≥3 TEAEs

were reported in 91% of patients in the axicabtagene ciloleucel group

and occurred in 83% of patients in the HDT/ASCR group.

Lisocabtagene Maraleucel

The TRASCEND NHL 001 study evaluated lisocabtagene maraleucel in

344 patients with relapsed or refractory LBCLs including DLBCL, HGBL

with rearrangements of MYC and BCL2 and/or BCL6 rearrangements,

DLBCL transformed from any indolent lymphoma, PMBL, and FL grade

3B.132 Among 256 patients evaluable for efficacy, lisocabtagene

maraleucel resulted in an ORR of 73% (53% CR) and responses rates

were similar across all patient subgroups. With a median follow-up of 19

months, the PFS and OS rates at 1 year were 44% and 58%, respectively.

In the PILOT study, lisocabtagene maraleucel resulted in an ORR of 80% (54% CR) for relapsed/ refractory DLBCL in patients who are not

candidates for HDT/ASCR (61 patients; 33 patients had refractory

disease; 13 patients had relapsed disease within 12 months of first-line

therapy, and 15 patients had relapsed disease after 12 months of first-line therapy).134 At a median follow-up of 16 months, for patients who had

achieved a CR, the median PFS was 23 months and median OS was not reached. The final analysis of the study confirmed the durability of

responses with lisocabtagene maraleucel.135 After the median follow-up of 23 months, the median duration of response (DOR) was 23 months for all patients, and it was not reached for those with a CR. The median PFS was 9 months, and the median OS was not reached.

In the phase 3 randomized TRANSFORM study, lisocabtagene maraleucel also resulted in significantly improved CR rates, EFS, and PFS rates

compared to second-line therapy followed by HDT/ASCR in patients with primary refractory disease or early disease relapse (≤12 months after

completion of first-line chemoimmunotherapy).137 One hundred eighty-four patients were randomly assigned to lisocabtagene maraleucel or platinumbased chemoimmunotherapy followed by consolidation with HDT/ASCR in patients with disease responding to second-line chemoimmunotherapy. At a median follow-up of 18 months, the median EFS was not reached for

patients randomized to lisocabtagene maraleucel and 2 months for those randomized to chemoimmunotherapy followed by consolidation with

HDT/ASCR. The CR rate (74% vs. 43%; P < .0001) and the median PFS (not reached vs. 6 months; P < .0001) were also significantly higher for

lisocabtagene maraleucel. The median OS was not reached for patients in the lisocabtagene maraleucel group and was 30 months for those in the

HDT/ASCR group. After adjusting for crossover from the HDT/ASCR

group to lisocabtagene maraleucel, the estimated 18-month OS rates were 73% and 54%, respectively.

Tisagenlecleucel

The multicenter phase II study (JULIET) evaluated tisagenlecleucel in

patients with relapsed/refractory DLBCL (after at least two lines of therapy, including rituximab and an anthracycline) and TFL.133 Patients who had

been previously treated with CD19-directed CAR T-cell therapy or an

allogeneic hematopoietic cell transplant (HCT), and those with PMBL or

active CNS involvement were excluded. In this study, 115 patients

received infusion with tisagenlecleucel. After a median follow-up of 40

months, the best ORR was 53% (39% CR). The median PFS and OS

were 3 months and 11 months, respectively. Among the patients who had achieved a CR at 3 months and 6 months, the median PFS and OS were not reached.

The BELINDA trial, however, showed that tisagenlecleucel was not

superior to second-line therapy followed by HDT/ASCR in a similar patient population.138

Bispecific Antibodies

CD3 x CD20 bispecific antibodies have shown promising efficacy for the

treatment of heavily pretreated DLBCL, including disease relapse following

CAR T-cell therapy. Epcoritamab and glofitamab are FDA-approved for

relapsed/refractory DLBCL (after ≥2 systemic therapy regimens).139-142

MS-122

Results from clinical trials (discussed below) suggest that the addition of bispecific antibodies to chemoimmunotherapy results in improved outcomes in patients with relapsed or refractory DLBCL after ≥1 systemic therapy options including those with primary refractory disease. 143, 144 ofitamab ± Gemcitabine and Oxaliplatin Glofitamab (intravenous; fixed-duration treatment for 12 cycles) was evaluated in a phase II study for patients (n = 154) with relapsed or refractory DLBCL (including transformed FL, HGBL, or PMBL) after ≥2 lines of therapy (including an anti-CD20 mAb-based or an anthracyclinebased regimen, prior failure of HDT/ASCR, or CAR T-cell therapy). 141 Pretreatment with one dose of obinutuzumab was given for all patients to mitigate CRS. At a median follow-up of 13 months, 52% of patients had an objective response (39% CR) as assessed by the independent review committee (IRC). The median PFS was 5 months. The estimated 12month PFS and OS rates were 37% and 50%, respectively. In the prespecified subgroup analysis, there was a trend towards higher CR rate among patients with relapsed disease compared to those with disease that is refractory to the patient's last line of therapy. The CR rate was 35% for patients who had received prior CAR T-cell therapy and 42% for those who had not received CAR T-cell therapy. Long-term follow-up data confirmed the durability of responses (the median duration of CR was 30 months). 142 The estimated 24-month PFS and OS rates were 57% and 77%, respectively, in patients with a CR at EOT. The CR rate was 37% with a median DOR of 22 months in patients who had received prior CAR T-cell therapy.

In the phase III randomized STARGLO trial, glofitamab + GemOx, for patients with relapsed/refractory DLBCL who are not candidates for transplant, resulted in significant OS survival benefit compared to GemOX + rituximab. 144 In this trial, 274 patients were randomly assigned to glofitamab + GemOx (n = 183; primary refractory disease, n = 106) or GemOX + rituximab (n = 91; primary refractory disease, n = 47). Glofitamab (step-up dosing to 30 mg) was administered as a fixedduration treatment for a total of 12 cycles. After a median follow-up of 21 months, the OS was significantly improved in patients treated with glofitamab + GemOX (median OS was 26 months) compared to 13 months for patients treated with GemOX + rituximab. It should, however, be noted that the majority of the patients enrolled in the study were from Asia and the subgroup analyses (not adequately powered) showed potential inconsistencies in OS and PFS benefit based on geographical origin and race. Glofitamab monotherapy for relapsed/refractory DLBCL has shown consistent efficacy across race and region in the earlier phase I/II study. 141

Epcoritamab ± Gemcitabine and Oxaliplatin

The EPCORE NHL-1 trial evaluated epcoritamab (subcutaneous) in patients (n = 157) with relapsed or refractory DLBCL (including transformed indolent lymphomas, HGBLs, or PMBLs) after ≥2 lines of therapy (including an anti-CD20 mAb-based regimen, prior failure and ineligibility for HDT/ASCR, and prior CAR T-cell therapy [≥30 days since last treatment]). 139 At the median follow-up of 37 months, the ORR (assessed by the investigators) was 59% (41% CR). 140 The median PFS was 4 months (37 months in patients who achieved CR) and the 36-month PFS rate was 63%. The median OS was 19 months (not reached in patients who achieved CR). Among the prespecified subgroups, the ORR was 55% (30% CR) for patients with primary refractory disease and 54% (34% CR) for patients who had received prior CAR T-cell therapy. 139 The ORR was higher in the subgroup of patients who had not received prior CAR T-cell therapy (69%; 42% CR). Epcoritamab is given as continuous treatment until disease progresses, and further studies are needed to determine the optimal duration of treatment in patients achieving CR.

References

The results of the phase IB/II EPCORE-NHL-2 trial (n = 103; patients with

relapsed/refractory disease after ≥2 prior therapies, 62%; patients with

primary refractory disease, 52%) showed that epcoritamab in combination with GemOx (gemcitabine and oxaliplatin) results in durable long-term

responses in patients with relapsed/refractory DLBCL who are not

candidates for transplant.143 Epcoritamab was administered indefinitely

until disease progression or development of unacceptable toxicity. After a median follow-up of 13 months, the combination of epcoritamab and

GemOx resulted in an ORR of 85% (61% CR). The median duration of CR was 24 months, and the median OS was 22 months. The CR rates were higher in patients with relapsed or refractory DLBCL after one prior

therapy (73% compared to 53% in patients who had received ≥2 prior

therapies). These are significantly improved outcomes in historical

comparison with the CR rates (30%–44%) reported in the clinical trials that have evaluated GemOx + rituximab.145,146

Mosunetuzumab + Polatuzumab Vedotin

Mosunetuzumab is a CD3 x CD20 bispecific antibody approved for

relapsed/refractory FL, with a favorable safety profile enabling outpatient administration.147

Mosunetuzumab (21-day cycles; step-up dosing) in combination with

polatuzumab vedotin demonstrated efficacy for relapsed or refractory

DLBCL in patients who are not candidates for transplant in a phase II trial (n = 120; primary refractory disease, n = 69), resulting in an ORR of 59% (45% CR).148 Mosunetuzumab was given as fixed-duration treatment (8

cycles if CR was achieved and 17 cycles for patients achieving a PR). This study enrolled an older population with a median age of 68 years. ORR

and CR rates were preserved in older patients, with observed ORR and

CR rates of 59% and 44% in patients <75 years and 61% and 50% in

patients ≥75 years. After a median follow-up of 24 months, the median

duration of CR was not reached. The median PFS and OS were 11

months and 23 months, respectively. This combination resulted in higher response rates in patients with non-GCB DLBCL (55%) compared to GCB DLBCL (36%). Peripheral neuropathy, reported in 31% of patients, was

primarily grade 1–2 (28%) and among the patients experiencing peripheral neuropathy, 30% had improvement by the time of data cut-off.

This study, however, did not include patients who received prior treatment with polatuzumab vedotin and additional data are needed to determine the efficacy of this combination in this group of patients. This issue regarding the activity of this regimen in patients with prior polatuzumab vedotin

exposure is particularly relevant given the increasing use of Pola-R-CHP (rituximab, polatuzumab vedotin, cyclophosphamide, doxorubicin, and

prednisone) as first-line therapy for DLBCL based on results of the

POLARIX study.61

CD19-Directed Monoclonal Antibody

Tafasitamab + Lenalidomide

The single-arm phase II trial (L-MIND) established the safety and efficacy of tafasitamab in combination with lenalidomide (12 cycles followed by

tafasitamab monotherapy for patients with stable disease given until

disease progression) in patients with relapsed/refractory DLBCL after at

least one prior systemic therapy (but no more than 3 lines of prior therapy) and ineligible for transplant (n = 156).149 At a median follow-up of 46

months, the ORR was 58% (41% CR) and it was higher in patients who

received tafasitamab plus lenalidomide as second-line treatment (68%;

53% CR) compared to those who received tafasitamab plus lenalidomide as third-line or subsequent therapy (48%; 30% CR).150 The median PFS

and OS were 12 months and 34 months, respectively. The median PFS

(24 months vs. 8 months) and OS (not reached vs. 16 months) were also longer in patients who received tafasitamab plus lenalidomide as secondline treatment compared to those who received tafasitamab plus

lenalidomide as third-line or subsequent therapy. The median OS was also

higher (not reached) in patients who achieved a CR or PR, whereas the

median OS was 19 months in patients who achieved only a PR as the best response.

Tafasitamab + lenalidomide also resulted in promising response rates in

patients with GCB DLBCL, suggesting activity for this combination that

was irrespective of the COO. However, a more definitive interpretation

was not possible, as 27% of patients had undetermined COO or the geneexpression profiling results were unevaluable in 60% of patients.

Neutropenia (49%), thrombocytopenia (17%), and febrile neutropenia

(12%) were the most common grade ≥3 hematologic toxicities. The

majority of non-hematologic TEAEs were grade 1–2 with diarrhea,

asthenia, cough, peripheral edema, pyrexia, and decreased appetite being the most common non-hematologic toxicities occurring in >20% of

patients. The incidence and severity of TEAEs decreased upon

discontinuation of lenalidomide after 12 cycles as per study protocol.

Tafasitamab in combination with lenalidomide is FDA-approved for the

treatment of relapsed/refractory DLBCL in patients who are not candidates for transplant. Loss of CD19/CD20 expression has been suggested as a possible mechanism of resistance to CD19 and CD20-directed mAb

therapy and may also have an impact on response to CD19-directed CAR T-cell therapy.151-153 The potential risk of loss of CD19 expression in

patients with relapsed or refractory disease should be considered. At the

present time, it is unclear whether CD19-directed mAb therapy would have a negative impact on the efficacy of subsequent CD19-directed CAR T-cell therapy. Rebiopsy to confirm CD19 positivity is recommended prior to the initiation of CD19-directed CAR T-cell therapy.

Antibody Drug Conjugates

Polatuzumab vedotin (CD79b-directed) in combination with BR

(bendamustine and rituximab) and loncastuximab tesirine (CD19-directed)

are FDA-approved for relapsed/refractory DLBCL after ≥2 prior lines of therapies.154,155 Brentuximab vedotin (BV; CD30-directed antibody drug conjugate) has demonstrated activity in CD30-positive DLBCL (across variable CD30 expression levels).156

Polatuzumab Vedotin

In the phase II randomized trial that evaluated polatuzumab vedotin + BR (n = 40) versus BR (n = 40) in patients with relapsed or refractory DLBCL ineligible for HDT/ASCR, at a median follow-up of 27 months, the CR rates were significantly higher for polatuzumab vedotin + BR compared with BR alone (40% vs. 18%; P = .026).154 The median PFS (10 months vs. 4

months; P < .0001) and OS (12 months vs. 5 months; P = .0023) were

also significantly longer for polatuzumab vedotin + BR compared with BR. Polatuzumab vedotin + BR was also associated with survival benefit

regardless of COO (GCB vs. non-GCB) and double expressor status

(MYC and BCL2 overexpression), although the biomarker sample sizes

were small. In patients with non-GCB subtype (14 patients in the

polatuzumab vedotin + BR arm; 16 patients in the BR arm), the median

PFS and OS were 11 months and 14 months, respectively, for

polatuzumab vedotin + BR. The corresponding median PFS and OS were 3 months and 4 months, respectively, for BR. In patients with MYC and

BCL2 overexpression (9 patients in the polatuzumab vedotin + BR arm; 6 patients in the BR arm), the median PFS and OS were 7 months and 13

months, respectively, for polatuzumab vedotin + BR. The corresponding

median PFS and OS were <1 month and 4 months for BR.

Loncastuximab Tesirine

In a multicenter, single-arm, phase II trial (LOTIS-2) of 145 patients with

relapsed/refractory DLBCL after ≥2 multiagent systemic therapy regimens (including HGBCL with MYC and BCL2 and/or BCL6 rearrangements and primary mediastinal B-cell lymphoma), loncastuximab tesirine resulted in an ORR of 48% (24% CR).155 After a median follow-up of 8 months, the

MS-125

Abstract

median PFS and OS for the overall study population were 5 months and 10 months, respectively. Among patients who achieved a CR, the corresponding median survival rates were not reached and the 24-month PFS and OS rates were 73% and 68%, respectively. Neutropenia (26%) and thrombocytopenia (18%) were the most common grade ≥3 hematologic toxicities. The majority of non-hematologic TEAEs were grade 1-2 with fatigue (26%), nausea (23%), cough (21%), and peripheral edema (19%) being the most common non-hematologic toxicities. Elevated levels of gamma-glutamyl transferase (24%), alkaline phosphatase (19%), aspartate aminotransferase (15%), and alanine aminotransferase (13%) were the most common grade 1-2 biochemical TEAEs with elevated gamma-glutamyl transferase being the most common treatment-related adverse event leading to treatment discontinuation in 10% of patients.

A real-world retrospective analysis (n = 187) also confirmed the efficacy of loncastuximab tesirine in patients with heavily pretreated DLBCL. 157 entuximab Vedotin + Lenalidomide + Rituximab BV (anti-CD30 antibody drug conjugate) has demonstrated activity in CD30-positive DLBCL (across variable CD30 expression levels). 156 The ECHELON-3 (phase III) trial evaluated BV in combination with lenalidomide and rituximab in patients with relapsed or refractory DLBCL (after ≥2 lines of therapy; regardless of CD30 expression) who are not candidates for transplant or CAR T-cell therapy or bispecific antibodies (N = 230; BV + lenalidomide + rituximab, n = 112; lenalidomide + rituximab + placebo, n = 118). 158 After a median follow-up of 16 months, BV in combination with lenalidomide and rituximab resulted in a higher ORR (64% vs. 42%; P < .001), longer median PFS (4 months vs. 2 months; P < .001), and higher OS (14 months vs. 9 months; P = .009) compared to lenalidomide and rituximab. Favorable outcomes were seen across all subgroups of patients (including those who had received prior CAR T-cell therapy) regardless of CD30 expression and COO (this is in contrast to the previous studies, which reported favorable efficacy of lenalidomide in patients in non-GCB subtype). 159

Selective Small Molecule Inhibitor of XPO1-Mediated Nuclear Export

Selinexor

Selinexor was evaluated in a multicenter, randomized, phase IIb study (SADAL) of patients with heavily pretreated relapsed/refractory DLBCL (2-5 lines of previous therapies and progression of disease after autologous HCT or patients who were not candidates for autologous HCT), resulting in an ORR of 29% (12% CR; 17% PR). 160 In this study, 267 patients were randomly assigned to a 60-mg group (n = 175) or 100mg group (n = 92), which was discontinued due to the improved therapeutic window observed with 60 mg in a prespecified interim analysis (which included highly selected patients with refractory DLBCL who had to be off treatment at least for 3 months since the end of their last therapy). The primary analysis included 127 patients from the 60-mg group. The median follow-up was 11 months. The median OS for all patients was 9 months (median OS not reached in patients with a PR or better and 18 months in patients with stable disease). In a subgroup analysis, selinexor resulted in an ORR of 34% (14% CR) in GCB DLBCL compared to an ORR of 21% (10% CR) in non-GCB DLBCL. Thrombocytopenia (46%), neutropenia (25%), anemia (22%), fatigue (11%), hyponatremia (8%), and nausea (6%) were the most common grade 3-4 TEAEs.

Second-Line Therapy for Relapsed Disease < 12 Months or Primary Refractory Disease: Candidates for CAR T-Cell Therapy

Prior to the approval of CAR T-cell therapies, the optimal treatment approach had not been established in prospective studies. Retrospective studies reported extremely poor outcomes (to conventional second-line therapies) for primary refractory disease or relapsed disease < 12 months after completion of first-line therapy. 161, 162 CN 授权医脉通提供NCCN指南全文下载。wmlsyy于2025/12/23,21:20在医脉通平台下载，仅供个人使用，严禁分发。2025 美国国家综合癌症网络版权所有。

References

The results of the ZUMA-7 and TRANSFORM trials (discussed above) have confirmed that axicabtagene ciloleucel and lisocabtagene maraleucel are effective treatment options for patients with primary disease or relapsed disease after < 12 months (after completion of primary treatment). The NCCN Guidelines have included these as options (category 1) for patients who are eligible for CAR T-cell therapy. 136, 137 The guidelines recommend bridging therapy (as needed) until CAR T-cell product is available; if bridging therapy results in a CR or very good PR, proceeding with HDT/ASCR is an appropriate alternative. ISRT can be used for bridging therapy either as monotherapy or sequentially with systemic therapy. 163

Second-Line Therapy for Relapsed Disease > 12 Months: Intention to Proceed to Transplant R-ICE (rituximab, ifosfamide, carboplatin, and etoposide), 164-166 R-DHA (rituximab, dexamethasone, and cytarabine) + platinum (cisplatin or oxaliplatin), [166] [167] [168] [169] or R-GDP (rituximab, gemcitabine, dexamethasone, carboplatin, cisplatin, or oxaliplatin) are effective second-line regimens for patients who are candidates for HDT/ASCR. 170, 171 the international randomized intergroup study (CORAL study) that evaluated second-line chemoimmunotherapy (R-ICE vs. R-DHAP) followed by ASCR in 469 patients with chemosensitive relapsed or refractory DLBCL, no significant difference in outcome was found between treatment arms. 166 The ORRs were 63% after R-ICE and 64% after R-DHAP. After a median follow-up of 44 months, the 4-year EFS rate was 26% with R-ICE compared with 34% with R-DHAP (P = .20), and the 4year OS rate was 43% and 51% for R-ICE and RDHAP, respectively (P = .30). 166 Notably, patients relapsing < 1 year after initial R-CHOP therapy had a particularly poor outcome with a 3-year PFS of 23%. The CORAL study also showed that there was no benefit for rituximab maintenance (every 2 months for 1 year) compared with observation following ASCR.

A subgroup analysis from the CORAL study (Bio-CORAL) showed that for patients with a GCB phenotype (based on Hans algorithm), R-DHAP resulted in improved PFS (3-year PFS 52% vs. 31% with R-ICE). 172 This difference was not observed among patients with non-GCB phenotype (3year PFS of 32% with R-DHAP vs. 27% with R-ICE). 172 Moreover, the subgroup of patients with MYC gene rearrangement (with or without concurrent BCL2 and/or BCL6 gene rearrangements) had poor outcomes regardless of treatment arm. 173 The 4-year PFS was 18% among patients with MYC gene rearrangements compared with 42% in those without (P = .032); 4-year OS was 29% and 62%, respectively (P = .011). Among patients with MYC gene rearrangements, the 4-year PFS was 17% with R-DHAP and 19% with R-ICE; OS was 26% and 31%, respectively. 173 a randomized study of 619 patients with relapsed/refractory aggressive lymphoma (419 patients with relapsed/refractory DLBCL randomized to receive GDP [gemcitabine, dexamethasone, and cisplatin] or DHAP), GDP was non-inferior to DHAP in terms of ORR (45% vs. 44%) and transplantation rate (52% vs. 49). 171 GDP was also associated with fewer TEAEs (P < .001). After a median follow-up of 53 months, no differences were detected in EFS (P = .95) or OS (P = .78) between GDP and DHAP.

Second-line combination chemotherapy is recommended for patients with an intention to proceed to transplant. Rituximab should be included if there is disease relapse after a reasonable remission period ( > 6 months) and biopsy demonstrates continued CD20 expression; however; rituximab can be omitted in patients with primary refractory disease. 5] [126] [127] [128] [129] [130] ISRT before HDT/ASCR has been shown to result in good local disease control and improved outcome. 174 Additional RT can be given to limited sites with prior positive disease before or after HDT/ASCR.

References

CAR T-cell therapy (axicabtagene ciloleucel or tisagenlecleucel or

lisocabtagene maraleucel) is also an appropriate option for patients

achieving a PR following second-line therapy.131-133 Allogeneic HCT should be considered in selected patients with mobilization failures and persistent bone marrow involvement or lack of adequate response to second-line

therapy, though patients should be in CR or near CR at the time of

transplant.

Second-Line Therapy for Relapsed Disease <12 Months or Primary Refractory Disease (Non-candidates for CAR T-Cell Therapy) or

Relapsed Disease >12 Months (No Intention to Proceed to

Transplant)

Optimal treatment for relapsed or refractory disease in patients who are

not candidates for transplant or CAR T-cell therapy are not established

and therefore, clinical trial is preferred for these patients.

Lisocabtagene maraleucel is an option for patients who are not eligible for transplant but are eligible for CAR T-cell therapy.134,135 Bendamustine

should be avoided (prior to leukapheresis) in patients potentially eligible

for CAR T-cell therapy.

GemOx + glofitamab or epcoritamab (category 1 for GemOx + glofitamab for relapsed disease >12 months) and mosunetuzumab + polatuzumab vedotin are included as preferred second-line therapy options for

relapsed disease >12 months in patients who are not candidates for

transplant or for relapsed disease <12 months or primary refractory

disease in patients who are not candidates for CAR T-cell therapy

(including patients who do not have access to CAR T-cell

therapy).143,144,148,154 As noted earlier, the activity of CD20 x CD3

bispecific antibodies in CD20-negative lymphomas is unclear. Therefore, rebiopsy to confirm CD20 positivity is recommended prior to the initiation of CD3 x CD20 bispecific antibody therapy.

In the L-MIND trial (discussed earlier, which also included 15 patients with primary refractory disease), the 30-month PFS rate for tafasitamab +

lenalidomide was lower in this patient population (34%) compared to 42% in patients who did not have primary refractory disease.149,150 Tafasitamab

+ lenalidomide is included as a preferred treatment for patients with

relapsed or refractory DLBCL (excluding primary refractory disease).

GemOx with or without rituximab is an appropriate option for patients

unable to receive epcoritamab or glofitamab.145,146,175 Lenalidomide (with or without rituximab) and ibrutinib are also appropriate treatment options for patients who are not eligible for transplant or CAR T-cell therapy

(particularly for patients with non-GCB DLBCL).22,159

In patients with relapsed disease for <12 months or primary refractory

disease who do not have access to CAR T-cell therapy or bispecific

antibodies, optional consolidation with HDT/ASCR can be considered if

CR is achieved after second-line chemoimmunotherapy regimens.

Patients with a PR to second-line therapy or those with progressive or

refractory disease to second-line therapy (regardless of transplant

eligibility) or those with disease relapse following HDT/ASCR or allogeneic HCT should receive third-line systemic therapy, palliative ISRT, or best

supportive care. Repeat biopsy should be strongly considered prior to

additional therapy for patients achieving FDG-PET–positive PR to secondline therapy, because FDG-PET positivity may represent post-treatment

inflammation.

Third-Line Therapy

Second-line systemic therapy options that were not previously used

could be considered for patients with relapsed/refractory disease

following second-line therapy. Patients with progressive disease after ≥2 prior lines of systemic therapy regimens are unlikely to derive additional benefit from currently available systemic therapy options, except for

patients who have experienced a long disease-free interval.176 Novel

chemotherapy-free regimens (discussed below) should be considered for patients with progressive disease after ≥2 prior lines of therapy.

CAR T-cell therapy (axicabtagene ciloleucel or tisagenlecleucel or

lisocabtagene maraleucel), if not previously used, is an option for those

with disease relapse after achieving a CR to second-line therapy or for

progressive disease on second-line therapy.131-133

Loncastuximab tesirine and selinexor are included an options for thirdline subsequent therapy for relapsed/refractory DLBCL.155,158,160 Loss of CD19 and CD20 tumor antigen expressions have been reported in

patients with relapsed or refractory lymphomas and have also been

suggested as a possible mechanism of resistance to treatment with mAbs targeting CD19 and CD20 (including bispecific antibody therapy).151-153 In the LOTIS-2 trial (discussed above), a subgroup of patients (10%)

achieved an ORR of 47% (40% CR) to subsequent CD19-directed CAR Tcell therapy and the results of another small study also showed that CD19 antigen loss after loncastuximab tesirine is not common.177 These findings suggest that the use of loncastuximab tesirine does not preclude

subsequent responses to CD19-directed CAR T-cell therapy. However,

these preliminary results need to be confirmed in a larger cohort of

patients, and at this time it is unclear if loncastuximab tesirine or any other CD-19–directed therapy (eg, tafasitamab) would have a negative impact

on the efficacy of subsequent CD19-directed CAR T-cell therapy. The

activity of CD3 x CD20 bispecific antibody therapy is unclear in the setting of CD20-negative lymphomas. Rebiopsy to confirm CD19 and CD20

positivity is recommended prior to the initiation of CD19-directed CAR Tcell therapy or CD3 x CD20 bispecific antibody therapy.

Despite the availability of novel treatment options, relapse following CAR T-cell therapy occurs in about 60% of patients and treatment options are

very limited for this group of patients.178,179 Epcoritamab and glofitamab

are recommended as options for third-line therapy for patients with

relapsed/refractory DLBCL including those with disease progression after transplant or CAR T-cell therapy. Selinexor is also an appropriate

treatment as a third-line and subsequent therapy option for

relapsed/refractory DLBCL in patients with disease progression after

transplant or CAR T-cell therapy. BV, lenalidomide, and rituximab is

included as an option for third-line therapy (other recommended

regimens) and would be appropriate for patients with relapsed/refractory DLBCL who are not candidates or who do not have access to CAR T-cell therapy or bispecific antibodies.158

Management of Toxicities Associated with T-Cell Engager Therapy

CAR T-Cell Therapy

Cytokine-release syndrome (CRS) and immune effector cell-associated

neurotoxicity syndrome (ICANS) (previously referred to as CAR T-cell–

related encephalopathy syndrome [CRES]) are the most common adverse events of special interest (AESI) associated with CAR T-cell therapy.180

CD19-directed CAR T-cell therapies should only be dispensed and

administered in health care facilities that are enrolled in and comply with the Risk Evaluation and Mitigation Strategies (REMS) requirements.

Different toxicity scales were used for the grading of CRS in the ZUMA-1 and JULIET trials (grade 3 CRS in JULIET was similar to grade 2 in

ZUMA-1), so while rates of any CRS can be compared, the rates

specifically of severe (grade 3 or 4) CRS cannot be directly compared with accuracy.

In the ZUMA-1 trial, CRS and neurologic toxicity of any grade were

reported in 93% (Grade ≥3: 11%) and 64% (Grade ≥3: 30%) of patients,

respectively.131 The median time from infusion to onset of symptoms was 2 days and 5 days, respectively, with the median duration of 8 days and 17 days, respectively. Pyrexia (11%), hypoxia (9%), and hypotension (9%)

were the most common symptoms of grade ≥3 CRS. The median time to CRS onset was 2 days after infusion and the median time until resolution was 8 days. Encephalopathy (21%), confusional state (9%), aphasia (7%), and somnolence (7%) were the most common grade ≥3 neurologic events. In the ZUMA-7 trial, among patients randomized to axicabtagene

ciloleucel, grade ≥3 CRS and neurologic events were reported in 6% and 21% of patients, respectively.136

In the TRASCNED NHL 001 study, CRS and neurologic toxicity of any

grade were reported in 42% and 30% of patients, respectively. Grade ≥3 CRS and neurologic events occurred in 2% and 10% of patients,

respectively.132 In the TRANSFORM study, lisocabtagene maraleucel was associated with lower rates of grade ≥3 CRS and neurologic events,

reported in 1% and 4% of patients, respectively.137

In the JULIET trial, CRS and neurologic toxicity of any grade were

reported in 57% and 20% of patients, respectively.133 Grade ≥3 CRS and neurologic events occurred in 23% and 11% of patients, respectively. The median time from infusion to onset of symptoms was 2 days and 6 days, respectively, with the median duration of 7 days and 14 days, respectively.

The anti-interleukin-6 (IL-6) receptor mAb tocilizumab is highly effective for the management of CRS, inducing rapid reversal of symptoms in

most patients.180 Tocilizumab is approved for the treatment of CRS

occurring after CAR T-cell therapy, and its use has not been shown to

have any impact on the efficacy of CAR T-cell therapy in terms of

response rates or DOR. Corticosteroids are also an important adjunctive treatment for CRS, in concert with tocilizumab. Corticosteroids are

preferred for the management of neurologic toxicity if not associated with CRS, whereas tocilizumab in combination with corticosteroids is

recommended for management of CRS occurring in tandem with

neurologic toxicity.180 Anakinra (interleukin-1 [IL-1] receptor antagonist)

has also shown promising results in the management of CRS and/or

steroid-refractory ICANs.181-184

The use of corticosteroids for the management of toxicities associated with CAR T-cell therapy did not impact the efficacy of CAR T-cell

therapy, although their use has been shown to impair T-cell function.

CRS and neurologic toxicity should be managed based on the toxicity

grade as outlined in the Management of CAR T-Cell–Related Toxicities section of the NCCN Guidelines for the Management of ImmunotherapyRelated Toxicities.

In addition to CRS and ICANS, severe and prolonged cytopenias are very common TEAEs of CAR T-cell therapy, which may be associated with the use of bridging chemotherapy (that is required for disease control in the majority of patients for better efficacy and minimizes the TEAEs of CAR Tcell therapy) or with the use of lymphodepleting chemotherapy prior to

CAR T-cell administration, or it may be an immune-mediated effect of the CARs.180,185 The presence of rapidly progressing disease and lack of

access to a certified CAR T-cell therapy center will also limit the use of

CAR T-cell therapy in many patients.

Bispecific Antibodies

CRS (mostly grade 1–2) was the most common AESI associated with all

three bispecific antibodies and ICANS were less common.186 CRS and

ICANS were graded using the American Society for Transplantation and Cellular Therapy (ASTCT) criteria.187

In the EPCORE NHL-1 trial, CRS (any grade) was reported in 50% of

patients (grade ≥3, 3%). CRS occurred after the administration of the first

full dose of epcoritamab, and prophylactic high-dose steroids were given to mitigate CRS during the initial 4 weeks of step-up dosing. Tocilizumab

was used for the management of CRS in 28% of patients.139 ICANS (any grade) was reported in 6% of patients (grade ≥3, 3%). Pyrexia (24%),

fatigue (23%), neutropenia (22%), diarrhea (20%), and nausea (20%)

were the other common TEAEs of any grade. In the EPCORE NHL-2 trial,

ICANS (any grade) was reported in 3% of patients (grade ≥3, 1%) with

CRS (52%, any grade), thrombocytopenia (73%), neutropenia (65%),

anemia (59%), and infections (72%) being the other most common

TEAEs.143 This safety profile for hematologic TEAEs and infections

reported in the EPCORE NHL-2 was consistent with the safety profile

reported for chemoimmunotherapy regimens used for the treatment of

DLBCL.

In the phase II study that evaluated glofitamab, CRS (any grade) was

reported in 63% of patients, and most of the CRS events were associated

with the first three doses during the step-up cycle.141 Obinutuzumab was given prior to the infusion of glofitamab for all patients to mitigate CRS,

and symptoms of CRS occurring after the infusion of glofitamab were

mainly controlled with corticosteroids and tocilizumab. ICANS (any grade)

was reported in 8% of patients (grade ≥3, 3%). All events associated with ICANS (dysphonia, confusional state, and disorientation) were mainly

grade 1–2. Infections (38%), neutropenia (38%), anemia (31%), and

thrombocytopenia (25%) were the other common TEAEs of any grade.

The safety profile for glofitamab + GemOx reported in the STARGLO trial

was also consistent with that reported in the clinical trials that evaluated

these agents individually, and growth factor support was administered to

all patients in the glofitamab + GemOx group.144 ICANS (any grade) was reported in 2% of patients. CRS (44%, any grade), neutropenia (42%),

anemia (41%), and infections (26%) were the other most common TEAEs reported in the STARGLO trial.

In the phase I/II study that evaluated mosunetuzumab + polatuzumab

vedotin, CRS (any grade) and ICANS were reported in 17% and 5% of

patients, respectively.148 Peripheral neuropathy (31%), neutropenia (35%), and infections (39%) were the other most common TEAEs.

Bispecific antibodies are “off-the-shelf” immunotherapies (more readily

available than CAR T cells), thus obviating the need for bridging

chemotherapy. Available data as discussed above suggest that the overall safety profile of bispecific antibodies is better than that of CAR T-cell

therapies. However, step-up-dosing schedule (over a period of time before reaching the effective target dose) to mitigate the risk of CRS is required for all three bispecific antibodies, which can be challenging in patients with rapidly progressing disease.186 Additional clinical trials to optimize the

step-up-dosing and long-term follow-up data from ongoing clinical trials

are needed to confirm the preliminary findings regarding the safety and

efficacy of bispecific antibodies.

ALK-Positive Large B-Cell Lymphomas

ALK-positive LBCL are mature aggressive B-cell lymphomas

characterized by large cells with plasmablastic differentiation and

cytoplasmic expression of ALK, and lacking CD20 expression.8,9

Cytoplasmic ALK expression helps differentiate this entity from other

aggressive CD20-negative LBCL with plasmacytic differentiation such as plasmablastic lymphoma, primary effusion lymphoma (PEL), and HHV8-

positive DLBCL. Cytogenetic/FISH analysis most commonly demonstrates the t(2;17)(p23;q23), denoting the CLTC (clathrin heavy chain)/ALK

fusion.188,189 EBV and HHV8 are negative in ALK-positive LBCL, and there is no association with immune deficiency.

The median age at diagnosis is approximately 40 years and there is a

strong male predominance, with most patients presenting with rapidly

progressive disease at an advanced stage.190,191 Age <40 years and earlystage disease are associated with a more favorable long-term

survival.192,193

Initial Therapy

Clinical trial is recommended, if available. These are most often CD20

negative, and rituximab is not necessary. While the optimal systemic

treatment approach is not established, the following induction regimens

have been used:

DA-EPOCH

CHOEP

CHOP may be associated with a suboptimal outcome. CHOP can be

considered for patients with early-stage disease receiving combined

modality therapy.

Mini-CHOP may be considered for patients who are frail or older

R-hyperCVAD (alternating with high-dose methotrexate and cytarabine) or R-CODOX-M/R-IVAC (based on PS and the presence of comorbidities

since these are potentially toxic regimens)

Consolidative ISRT is preferred for localized disease due to historically poor outcomes with chemotherapy alone.

Relapsed/Refractory Disease

Clinical trial is recommended, if available. Second-line platinum-based

chemotherapy followed by HDT/ASCR should be considered for

candidates for transplant with chemosensitive disease.

Responses have been observed for next-generation ALK inhibitors such

as alectinib and lorlatinib, which should be favored over the firstgeneration inhibitor crizotinib.194,195 Patients with a CR to a next-generation ALK inhibitor should be considered for allogeneic HCT.

Mediastinal Gray Zone Lymphomas

In the 2017 WHO classification, lymphomas with overlapping pathologic features between CHL and PMBL with a poorer clinical outcome than either CHL or PMBL (gray zone lymphomas) were termed as B-cell

lymphomas unclassifiable with features intermediate between DLBCL and CHL.3 These are now termed mediastinal gray zone lymphomas (MGZL) in both the ICC and the WHO5.8,9

MGZL are more commonly seen in young adult males between the ages of 20 to 40 years and are characterized by the presence of a large anterior mediastinal mass with or without supraclavicular lymph node

involvement.196-201 Non-mediastinal lymphomas are biologically and

clinically distinct and should not be considered in this category.8,9,202-204

MGZL show either morphology closely resembling CHL but with strong

expression of at least two B-cell antigens by IHC (CD20 expression and

other B-cell markers) or with morphology more closely resembling PMBL but with a downregulated B-cell antigen profile and strong expression of

CD30 and CD15.8 EBV is negative in the vast majority of cases, and

positivity should raise consideration for immune suppression or a

diagnosis of EBV-positive DLBCL, NOS.

The treatment of patients with MGZL poses a challenge, as these

lymphomas appear to be associated with a worse prognosis compared

with PMBL or CHL.196,199,205 In a multicenter retrospective analysis of gray zone lymphoma (that did not have central pathology review), patients with gray zone lymphomas treated with CHOP-like regimens with or without

rituximab had superior outcomes compared to patients with gray zone

lymphomas treated with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine), with 2-year PFS rates of 52% and 22%, respectively.202

DA-EPOCH-R has also been associated with improved clinical

outcomes.206,207 In a prospective study that evaluated 6 to 8 cycles of

DA-EPOCH-R in a small group of patients with MGZL (n = 24), the EFS

and OS were 62% and 74%, respectively, at the median follow-up of 59

months.206 With a median follow-up of 5 years, the EFS (62% vs. 93%; P = .0005) and OS (74% vs. 97%; P = .001) were significantly lower for

patients with MGZL compared to patients with PMBL (n = 51) enrolled in the same study.

There is no optimal treatment approach for the management of MGZL,

although multiagent chemotherapy regimens used for patients with DLBCL are typically used for the treatment of MGZL. Patients with MGZL should receive treatment in cancer centers with experience in treating this type of lymphoma. Clinical trial is the preferred treatment option for patients with MGZL. In the absence of suitable clinical trials, RCHOP-21 or

DA-EPOCH-R should be considered for initial therapy. Given the apparent inferior outcomes among MGZL treated with traditional

chemoimmunotherapy regimens, consolidative RT should be strongly

considered for patients with limited-stage disease amenable to RT.

References

Primary Mediastinal Large B-Cell Lymphoma

Primary mediastinal large B-cell lymphoma (PMBL) is a distinct subtype of non-Hodgkin lymphoma (NHL) that tends to occur in young adults with a median age of 35 years with a slight female predominance.1 PMBL arises from thymic B cells with initial locoregional spread to cervical,

supraclavicular, hilar nodes and into the mediastinum and lung.1

Widespread extranodal disease is uncommon at initial diagnosis, present in approximately one quarter of patients, but can be more common at

recurrence. Clinical symptoms that may be related to rapid growth of a

mediastinal mass include superior vena cava (SVC) syndrome, pericardial effusions, and pleural effusions.

PMBL overlaps with mediastinal grey zone lymphomas (MGZL) that have intermediate features between classic Hodgkin lymphoma (CHL) and

PMBL.2 Gene expression profiling (GEP) studies have indicated that

PMBL is distinct from diffuse large B-cell lymphoma (DLBCL) and the

pattern of gene expression in PMBL is more similar to CHL.2-4 PMBL

expresses B-cell antigens and lacks surface immunoglobulin. PMBL is

CD19+, CD20+, CD22+, CD21-, IRF4/MUM1+, and CD23+ with a variable expression of BCL2 and BCL6. CD30 is weakly and heterogeneously

expressed in >80% of patients. Cytogenetic abnormalities that are

common in PMBL include gains in chromosome 9p24 (involving the JAK2 in 50%–75% of patients) and chromosome 2p15 (involving the c-REL,

encoding a member of the NF-κB family of transcription factors) and loss in chromosomes 1p, 3p, 13q, 15q, and 17p.5,6 High programmed deathligand (PDL1 and PDL2) expression has been reported as an independent prognostic factor for inferior survival outcomes.7

International prognostic index (IPI) and age-adjusted IPI are of limited

value in determining the prognosis of PMBL at diagnosis.1,8,9 In a

retrospective analysis of 141 patients, ≥2 extranodal sites and the type of

initial therapy were predictors of outcome for event-free survival (EFS),

whereas only the initial therapy was a predictor for OS.8 In a new

prognostic index (based on the presence of extranodal involvement or

stage IV disease, bulky disease and elevated lactate dehydrogenase

[LDH]) defined high-risk subgroups better than IPI and age-adjusted IPI.10 In a multivariate analysis, extranodal involvement and elevated LDH (≥2 times upper limit of normal) were significantly associated with freedom

from progression; whereas extranodal involvement and bulky disease

were associated with lymphoma-specific survival.

Literature Search Criteria

Prior to the update of this version of the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for B-Cell Lymphomas an electronic

search of the PubMed database was performed to obtain key literature in PMBL published since the previous Guidelines update. The PubMed

database was chosen as it remains the most widely used resource for

medical literature and indexes peer-reviewed biomedical literature.11

The search results were narrowed by selecting studies in humans

published in English. Results were confined to the following article types: Clinical Trial, Phase II; Clinical Trial, Phase III; Clinical Trial, Phase IV;

Guideline; Randomized Controlled Trial; Meta-Analysis; Systematic

Reviews; and Validation Studies.

The data from key PubMed articles as well as articles from additional

sources deemed as relevant to these Guidelines as discussed by the

expert opinion.

This discussion corresponds to the NCCN Guidelines for B-Cell Lymphomas. Last updated: August 18, 2025.

Abstract

In retrospective analyses from the pre-rituximab era, intensive chemotherapy regimens have been more effective than CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), and the addition of involved-field radiation therapy (IFRT) has been associated with improved PFS. 9,[12][13] [14][15]

7] [18] In a subgroup analysis of 87 patients with PMBL from the MInT study, the addition of rituximab significantly improved the complete response (CR) rate (80% vs. 54% without rituximab; P = .015) and 3-year EFS rate (78% vs. 52%; P = .012), but not the overall survival (OS) rate (89% vs. 78%; P = .158). 17 The MInT study, however, only included young patients with lowrisk disease and IPI scores 0-1. In a retrospective analysis that evaluated the outcome of 80 patients with PMBL treated with a CHOP-based regimen with and without rituximab, the 5-year progression-free survival (PFS; 95% vs. 67%; P = .001) and OS (92% vs. 72%; P = .001) rates were significantly higher in the rituximab arm. 18 In a multivariate analysis, only the addition of rituximab to induction chemotherapy and CR after first-line therapy had a beneficial effect on both PFS and OS. 0] [21] A prospective phase II study from the National Cancer Institute (NCI) showed that DA-EPOCH-R is a highly effective regimen in patients with PMBL and obviates the need for RT in the large majority of patients. 19 In this study DA-EPOCH-R for 6 cycles and filgrastim, without RT, was evaluated in 51 patients with previously untreated PMBL (stage IV disease was present in 29% of patients). At a median follow-up of 63 months, EFS and OS rates were 93% and 97%, respectively. Grade 4 neutropenia and thrombocytopenia occurred in 50% and 6% of treatment cycles, respectively. Hospitalization for febrile neutropenia occurred in 13% of cycles.

3] [24] [25] [26] A multicenter cohort analysis (132 patients; 56 patients were treated with R-CHOP and 76 patients were treated with DA-EPOCH-R) reported excellent 2-year OS rates for both R-CHOP and DA-EPOCH-R (89% and 91%, respectively). 24 DA-EPOCH-R also resulted in higher CR rates than R-CHOP. In a retrospective analysis of 313 patients with PMBL treated with anthracycline-based chemoimmunotherapy regimens, RCHOP-14, RCHOP-21, and RACVBP (rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone) resulted in end-of treatment response rates of 87%, 77%, and 86%, respectively. 27 After a median follow-up of 44 months, the estimated 3-year PFS rates were superior for RACVBP and RCHOP-14, each 89%, compared with RCHOP-21, which was 75%. Febrile neutropenia and mucositis were higher with RACVBP. Another retrospective analysis of 63 patients with PMBL treated with RCHOP-21 reported a 21% rate of primary induction failure, with adverse predictors of outcome being advanced stage and high-risk IPI scores, suggesting that RCHOP may not be the optimal chemotherapy backbone in PMBL, particularly for patients with high-risk disease. 28 Additionally, the LYSA group performed a pooled analysis of 290 patients with PMBL included in prospective studies and found that patients treated with RCHOP-14 or RACVBP had significantly improved PFS and OS compared with RCHOP-21. 26 Sequential dose-dense RCHOP followed by consolidation with ICE (ifosfamide, carboplatin, and etoposide) without radiation therapy (RT) was also highly effective in patients with PMBL, resulting in survival outcomes similar to DA-EPOCH-R. 29, 30 In a retrospective analysis (n = 56), at a NCCN 授权医脉通提供NCCN指南全文下载。wmlsyy于2025/12/23,21:20在医脉通平台下载，仅供个人使用，严禁分发。2025 美国国家综合癌症网络版权所有。

References

median follow-up of 2 years, the median PFS was 1.7 years for sequential dose-dense RCHOP followed by ICE compared to 1.6 years for DAEPOCH-R and the 2-year OS rates were 88% and 83%, respectively.29

Similar findings were also reported in another retrospective analysis that included 226 patients with PMBL treated with RCHOP/RICE (rituximab,

ifosfamide, carboplatin, and etoposide) (n = 111; median follow-up: 7

years) and DA-EPOCH-R (n = 115; median follow-up: 4 years ).30 After a median follow-up of 6 years for the entire cohort, the estimated 5-year

PFS and OS rates were 86% and 94%, respectively, for patients in the

RCHOP/RICE cohort. The corresponding survival rates were 89% and

96% for patients in the DA-EPOCH-R cohort. Given the comparable

survival outcomes for the 2 treatment groups, the authors concluded that RCHOP/RICE may be an appropriate first-line alternative to DA-EPOCH-R since this is associated with reduced hospitalizations rates.

With numerous studies evaluating different induction regimens for PMBL (some of which with small sample sizes and heterogeneous populations), a large meta-analysis evaluated the impact of dose-intensive regimens

such as DA-EPOCH-R, RACVBP, and RCHOP-14, compared to

conventional RCHOP-21.31 This meta-analysis, which included >4000

patients with PMBL from 11 prospective and 41 retrospective studies,

reported an improved PFS and OS favoring the intensified regimens

compared to RCHOP-21, as well as lower use of RT.

NCCN Recommendations

In the absence of randomized trials, optimal first-line treatment for patients with PMBL is more controversial than other subtypes of NHL. However,

based on the available data, DA-EPOCH-R (6 cycles) or RCHOP-21 (6

cycles) or RCHOP-14 (4 or 6 cycles) are included as options for first-line therapy. Given some studies suggesting inferior outcomes with RCHOP21, intensified regimens such as DA-EPOCH-R or RCHOP-14 are

preferred at most NCCN institutions for eligible patients. Although patients

with PMBL treated with DA-EPOCH-R experience more short-term

treatment-related toxicities, they can be spared long-term risks associated with mediastinal RT, thus restricting RT only to the minority of patients with PET-positive disease at the end-of treatment restaging (5-point scale [5-

PS] 4 with high uptake above liver and 5-PS 5).32

Residual mediastinal masses are common and post-treatment PET/CT is considered essential. Interim and end-of-treatment PET can help to limit

the use of RT only for patients with a positive PET scan and can also

identify patients with a high risk of progression requiring additional

therapy.33-37

Active surveillance is appropriate for patients achieving CR (PET/CT is

negative at the end of treatment; 5-PS 1–3) after 6 cycles of DA-EPOCHR or RCHOP-14. Active surveillance or consolidation with involved-site RT (ISRT) are options for patients achieving CR after 6 cycles of RCHOP-21. Consolidation with ICE (3 cycles) with or without rituximab is

recommended (category 2B) for patients achieving CR after 4 cycles of

RCHOP-14.29,30

In patients achieving a PR (PET/CT is positive at the end of treatment; 5-PS 4) or progressive disease (5-PS 5), biopsy is recommended before

additional treatment (ie, treatment as described below for relapsed or

refractory disease) is contemplated. ISRT is recommended for patients

achieving a PR (5-PS 4) after first-line therapy.

Relapsed or Refractory Disease

Chimeric antigen receptor (CAR) T-cell therapy (axicabtagene ciloleucel and lisocabtagene maraleucel) is approved as second-line therapy for patients with primary refractory disease or relapsed disease within 12

months after first-line therapy (based on the results of ZUMA-7 and

TRANSFORM trials, respectively), which applies to the vast majority of patients with relapsed or refractory PMBL after first-line therapy.38,39

Axicabtagene ciloleucel and lisocabtagene maraleucel, along with the PD1 inhibitor pembrolizumab, are also approved for relapsed or refractory

PMBL after ≥2 prior systemic therapy regimens.40-43

The TRANSFORM trial (lisocabtagene maraleucel for early relapse or

primary refractory disease), ZUMA-1 trial (axicabtagene ciloleucel), and

TRANSCEND NHL 001 trial (lisocabtagene maraleucel) included 17 (9%), 8 (8%), and 15 (6%) patients with relapsed/refractory PMBL, respectively, and CAR T-cell therapies resulted in favorable clinical outcomes across all subgroups of patients.39-41 In the TRANSCEND NHL 001 trial,

lisocabtagene maraleucel resulted in an ORR of 79% (50% CR) among

patients with relapsed/refractory PMBL. In the Italian prospective

observational CART-SIE study that included 70 patients with

relapsed/refractory PMBL, axicabtagene ciloleucel resulted in an ORR of 41%.42 After a median follow-up of 12 months, the 12-month PFS and OS rates were 62% and 86%, respectively.

In the KEYNOTE-170 study of patients with relapsed/refractory PMBL (n = 53), after a median follow-up of 49 months, pembrolizumab resulted in an ORR of 42% (21% CR).43 The median PFS and OS rates were 4 months and 22 months, respectively. The 4-year PFS and OS rates were 33% and 45%, respectively.

In the phase II CheckMate 436 study of 30 patients with relapsed or

refractory PMBL, nivolumab in combination with brentuximab vedotin (BV) resulted in an ORR of 73% (40% CR).44 After a median follow-up of 40

months, the median PFS was 26 months, and the median OS was not

reached. The PFS and OS rates at 24 months were 56% and 76%,

respectively. The efficacy of nivolumab + BV in patients with

relapsed/refractory PMBL was also demonstrated in a small cohort study that reported an ORR of 60% and the estimated 3-year PFS rate was

64%.45

NCCN Recommendations

Relapsed or refractory PMBL should be treated as described for

relapsed/refractory DLBCL based on transplant eligibility.

Axicabtagene ciloleucel and lisocabtagene maraleucel are preferred for

relapsed/refractory disease in patients who are candidates for CAR T-cell therapy. Pembrolizumab and nivolumab with or without BV (category 2B) are also included as third-line or subsequent therapy options for

relapsed/refractory PMBL.

The outcomes of second-line therapy followed by HDT/ASCR remain

poorly defined in patients with relapsed or refractory PMBL and

retrospective analyses have reported inferior survival outcomes following HDT/ASCR for patients with relapsed/refractory PMBL compared to

released/refractory DLBCL.46-48 However, survival outcomes are better for patients with relapsed/refractory PMBL that is chemosensitive prior to

HDT/ASCR.46,47 In a multivariate analysis, incomplete response to initial

therapy, advanced Ann Arbor stage at disease progression, and inability to achieve a greater than or equal to PR after second-line therapy were

independently associated with inferior EFS and OS.48 In CheckMate 436 study (described above), consolidative hematopoietic cell transplant (HCT) was received by 12 patients, with a 100-day post-transplant CR of 100%, suggesting that nivolumab in combination with BV could potentially be

considered as a bridging therapy to transplant in patients with

relapsed/refractory PMBL.44

Allogeneic HCT has also been reported to result in durable remissions in patients with relapsed/refractory PMBL that is sensitive to second-line

therapy prior to HCT and can be considered as an option for patients with relapse following HDT/ASCR.49,50

References

Abstract

ICE and dose-adjusted EPOCH-R are both appropriate frontline treatments for newly diagnosed primary mediastinal B-cell lymphoma: Results of a retrospective analysis

References

analysis of KEYNOTE-170. Blood 2023;142:141–145. Available at:

https://www.ncbi.nlm.nih.gov/pubmed/37130017.

44. Zinzani PL, Santoro A, Gritti G, et al. Nivolumab combined with

brentuximab vedotin for R/R primary mediastinal large B-cell lymphoma: a 3-year follow-up. Blood Adv 2023;7:5272–5280. Available at:

https://www.ncbi.nlm.nih.gov/pubmed/37352266.

45. Renaud L, Wencel J, Pages A, et al. Nivolumab combined with

brentuximab vedotin with or without mediastinal radiotherapy for

relapsed/refractory primary mediastinal large B-cell lymphoma.

Haematologica 2024. Available at:

https://www.ncbi.nlm.nih.gov/pubmed/38695142.

46. Kuruvilla J, Pintilie M, Tsang R, et al. Salvage chemotherapy and

autologous stem cell transplantation are inferior for relapsed or refractory primary mediastinal large B-cell lymphoma compared with diffuse large Bcell lymphoma. Leuk Lymphoma 2008;49:1329–1336. Available at:

https://www.ncbi.nlm.nih.gov/pubmed/18604722.

47. Aoki T, Shimada K, Suzuki R, et al. High-dose chemotherapy followed by autologous stem cell transplantation for relapsed/refractory primary

mediastinal large B-cell lymphoma. Blood Cancer J 2015;5:e372.

Available at: https://www.ncbi.nlm.nih.gov/pubmed/26636287.

48. Vardhana S, Hamlin PA, Yang J, et al. Outcomes of relapsed and

refractory primary mediastinal (thymic) large B-cell lymphoma treated with second-line therapy and intent to transplant. Biol Blood Marrow Transplant 2018;24:2133–2138. Available at:

https://www.ncbi.nlm.nih.gov/pubmed/29909154.

49. Herrera AF, Chen L, Khajavian S, et al. Allogeneic stem cell

transplantation provides durable remission in patients with primary

mediastinal large b cell lymphoma. Biol Blood Marrow Transplant

2019;25:2383–2387. Available at:

https://www.ncbi.nlm.nih.gov/pubmed/31394277.

50. Kondo E, Shimizu-Koresawa R, Chihara D, et al. Allogeneic

haematopoietic stem cell transplantation for primary mediastinal large Bcell lymphoma patients relapsing after high dose chemotherapy with autologous stem cell transplantation: data from the Japan Society for Haematopoietic Cell Transplantation registry. Br J Haematol

2019;186:e219–e223. Available at:

https://www.ncbi.nlm.nih.gov/pubmed/31355916.

Histologic Transformation of Indolent Lymphomas to DLBCL

Histologic transformation of indolent lymphomas (follicular lymphoma [FL] or marginal zone lymphoma [MZL]) to diffuse large B-cell lymphoma

(DLBCL) is recognized as an entity in the updated 2022 WHO

classification of hematolymphoid tumors (WHO5), whereas it is not

included in the International Consensus Classification (ICC).1,2

Histologic transformation of FL to either DLBCL or high-grade B-cell

lymphomas (HGBL) with translocations of MYC with either BCL2 or BCL6 rearrangement (double-hit cytogenetics) occurs at an estimated annual

rate of 2% to 3% and is generally associated with a poor clinical

outcome.3-6 Histologic transformation to HGBL with double-hit cytogenetics is associated with an inferior survival compared to transformed FL (TFL)

without double-hit cytogenetics (2-year survival rates of 50% and 73%,

respectively).7

In a pooled analysis of French and U.S. cohorts of patients with newly

diagnosed FL, histologically TFL after diagnosis was the leading cause of death (77 of 140 deaths).8 Advanced-stage FL, high-risk Follicular

Lymphoma International Prognostic Index (FLIPI) and International

Prognostic Index (IPI) scores at diagnosis, elevated lactate

dehydrogenase (LDH), and B symptoms at diagnosis have been reported as risk factors for histologic transformation of FL to DLBCL.3-5,9-11 Recent studies that have evaluated the outcomes of patients with TFL in the

rituximab era have reported improved survival in a subset of patients (eg, histologic transformation after early-stage FL and patients with no

previous exposure to chemotherapy or rituximab prior to histologic

transformation).5,11,12

Early initiation of treatment at diagnosis relative to Active surveillance has been suggested to decrease the risk of transformation in some

studies.5,9,11 However, in the randomized phase III intergroup trial that

evaluated the role of immediate treatment with rituximab versus active

surveillance in patients with advanced-stage, asymptomatic, low-tumorburden FL, the trial also addressed whether early intensive rituximab

therapy would change the risk of histologic transformation. No difference in time to transformation or incidence of histologic transformation was

detected between the three groups, after a median follow-up of almost 4 years.13

The incidence of histologic transformation of MZL to DLBCL is lower than that of FL and may occur across all subtypes; however, higher incidences have been reported in nodal MZL and splenic MZL.14,15 It is generally

associated with a poor clinical outcome. Nodal MZL subtype, high-risk IPI scores, elevated LDH, and B symptoms; disease involvement in multiple mucosal sites and greater than 4 nodal sites at the time of diagnosis of

MZL; and inability to achieve complete response (CR) after initial

treatment have been reported as risk factors for histologic transformation to DLBCL.14-20

Literature Search Criteria

Prior to the update of this version of the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for B-Cell Lymphomas an electronic

search of the PubMed database was performed to obtain key literature in histologic transformation of indolent lymphomas published since the

previous Guidelines update. The PubMed database was chosen as it

remains the most widely used resource for medical literature and indexes peer-reviewed biomedical literature.21

The data from key PubMed articles as well as articles from additional

sources deemed as relevant to these Guidelines as discussed by the

This discussion corresponds to the NCCN Guidelines for B-Cell Lymphomas. Last updated: August 18, 2025.

expert opinion.

Diagnosis

The diagnosis of histologic transformation to DLBCL should be confirmed by excisional lymph node biopsy (if lymph node is accessible) from a site with a maximum standardized uptake value (SUVmax) >5.1 As with the

diagnosis of other B-cell lymphomas, fine-needle aspiration (FNA) biopsy alone is not generally suitable for the initial diagnosis. In certain

circumstances, when a lymph node is not easily accessible for excisional or incisional biopsy, a combination of core needle biopsy (multiple biopsies preferred) and FNA biopsies in conjunction with appropriate ancillary

techniques may be acceptable to confirm the diagnosis of histologic

transformation.1

The presence of sites of disease with discordantly high SUVmax on PET scan (baseline SUVmax >10 or >20) should raise the suspicion of

histologic transformation to DLBCL, and can be used to direct the optimal site of biopsy for histologic confirmation.22-24 However, a retrospective

analysis of the GALLIUM study that assessed the relationship between

SUVmax at baseline PET scans and the risk of histologic transformation

showed that higher baseline SUVmax was not associated with subsequent histologic transformation.25 Therefore, PET scan findings alone are not

sufficient for the diagnosis of transformation. Histologic confirmation and evaluation of clinical features are necessary to determine the presence of histologic transformation.

Treatment Options

There are no data from randomized studies to support the optimal

treatment for patients with transformed indolent lymphomas (FL or MZL)

since earlier clinical trials often excluded this group of patients and most of the recommendations were extrapolated from the management of

relapsed/refractory DLBCL.

Results from retrospective cohort studies suggest that rituximab

monotherapy or in combination with anthracycline-based chemotherapy is associated with improved overall survival (OS) in patients with TFL.5,10,11 In a series that reported the outcomes of 60 patients with biopsy-proven TFL, RCHOP was the most common treatment for TFL (n = 35; 59%)

associated with a median OS of 50 months.5 At a median follow-up of 60 months, the 5-year OS rate was 66% for patients with TFL treated with

RCHOP, which was similar to the outcome of patients with de novo

DLBCL treated with RCHOP in the validation cohort (5-year OS rate of

73%).

In the National LymphoCare Study that included patients with TFL (147

patients with pathologically confirmed TFL and 232 patients with clinically suspected TFL), the majority of patients were treated with rituximab-based therapy (26% of patients received rituximab monotherapy and 35%

received chemotherapy with rituximab).11 At a median follow-up of 7 years, the median progression-free survival (PFS) and OS were 12 months and 60 months, respectively, for patients with biopsy-proven histologic

transformation to DLBCL.

In another study that evaluated the outcomes of patients with FL who had histologic transformation after response to first-line chemoimmunotherapy in the PRIMA trial, the majority of patients with TFL received

chemoimmunotherapy regimens recommended for DLBCL with a 5-year OS rate of 48% to 50%.10

High-dose therapy followed by autologous stem cell rescue (HDT/ASCR) as consolidation therapy has been evaluated only in retrospective

studies26-33 with some series reporting survival benefit for patients who

proceeded to transplant.29,31,33 Allogeneic HCT has been shown to benefit selected patients with disease relapse following HDT/ASCR, but is also

associated with significant transplant-related mortality (TRM).29,30,32,34

However, it should be noted that the efficacy of HDT/ASCR or allogeneic HCT in patients with TFL has not been confirmed in prospective controlled studies.

The management of transformed indolent lymphomas has evolved in

recent years with the inclusion of patients with transformed indolent

lymphomas in clinical trials evaluating novel treatment options for

relapsed/refractory DLBCL.

Loncastuximab tesirine, selinexor, and tafasitamab in combination with

lenalidomide are also FDA-approved for the treatment of

relapsed/refractory DLBCL including DLBCL arising from transformation of indolent lymphomas. Loncastuximab tesirine (anti-CD19 antibody drug

conjugate) and selinexor (selective small molecule inhibitor of XPO1-

mediated nuclear export) resulted in an ORR of 45% (24% CR) and 39%, respectively, among patients with transformed indolent lymphomas

included in the LOTIS-2 trial (29 patients) and SADAL trial (31

patients).35,36 L-MIND study (anti-CD19 antibody tafasitamab in

combination with lenalidomide for relapsed/refractory DLBCL) included

only eight patients with transformed indolent lymphoma, with three

patients achieving a CR and four patients achieving a PR.

T-cell Engager Therapy

Chimeric antigen receptor (CAR) T-cell therapy (axicabtagene ciloleucel lisocabtagene maraleucel and tisagenlecleucel) is U.S. Food and Drug

Administration (FDA)-approved for transformed indolent lymphomas after ≥2 systemic therapy regimens. Axicabtagene ciloleucel and

tisagenlecleucel are approved for TFL, whereas lisocabtagene maraleucel is approved for TFL and MZL.

ZUMA-1 (axicabtagene ciloleucel) and JULIET (tisagenlecleucel) trials

included 16% (n = 16) and 18% (n = 21) of patients with TFL, respectively, with the CAR T-cell therapies resulting in favorable clinical outcomes

across all subgroups of patients.37,38 The TRANSCEND NHL 001

(lisocabtagene maraleucel) trial included 60 patients with TFL and 18

patients with transformed indolent lymphomas other than FL (transformed indolent non-Hodgkin lymphoma [iNHL]; 10 patients had transformed

MZL).39 The overall response rate (ORR) was 84% and 61% for patients with TFL and transformed iNHL, respectively. The median PFS and OS

were not reached for patients with TFL. The median PFS and OS were 3 months and 7 months, respectively, for patients with transformed iNHL.

ZUMA-7 (axicabtagene ciloleucel vs. chemoimmunotherapy followed by

HDT/ASCR) and TRANSFORM (lisocabtagene maraleucel vs.

chemoimmunotherapy followed by HDT/ASCR) trials included 13% of

patients with TFL (n = 46; 19 patients were randomized to axicabtagene

ciloleucel) and 8% of patients with transformed indolent lymphomas (n = 15; 7 patients randomized to lisocabtagene maraleucel), respectively.40,41 In both these trials, CAR T-cell therapy resulted in significantly improved

ORR and EFS across all subgroups. In the ZUMA-7 trial, ORR was 89% for patients with TFL randomized to axicabtagene ciloleucel compared to

56% for those randomized to chemoimmunotherapy followed by

HDT/ASCR.40

Results from retrospective analyses have also shown that CAR T-cell

therapy results in favorable outcomes in patients with transformed indolent

lymphomas.42-46 A real-world retrospective analysis that evaluated the

safety and efficacy of axicabtagene ciloleucel in patients with

relapsed/refractory large B-cell lymphomas (n = 298; 76 patients had TFL) reported a 62% CR at 12 months as the best response rate for patients

with TFL.42 The 12-month PFS and OS rates were 51% and 70%,

respectively, for patients with TFL. A real-world multicenter retrospective

analysis confirmed that CAR T-cell therapy resulted in comparable

outcomes in patients with transformed indolent lymphoma and

relapsed/refractory de novo DLBCL.44 In this analysis that included 212

patients with transformed indolent lymphoma (TFL, n = 192; transformed MZL, n = 14) and 576 patients with relapsed/refractory de novo DLBCL,

the ORR was 78% (63% CR) for patients in the transformed indolent

lymphoma cohort which was comparable to the ORR of 77% (55% CR) for patients in the de novo DLBCL cohort. At a median overall follow-up of 13 months, the median PFS and OS were 11 months and 42 months,

respectively for patients in the transformed indolent lymphoma cohort

(corresponding median PFS and OS were 8 months and 30 months,

respectively for patients in the de novo DLBCL cohort).The 24-month PFS and OS rates were 39% and 66%, respectively for patients in the

transformed indolent lymphoma cohort (the corresponding PFS and OS

rates were 40% and 53%, respectively for patients in the de novo DLBCL cohort).

Epcoritamab is FDA-approved for TFL and MZL (after ≥2 systemic therapy regimens), whereas glofitamab is FDA-approved for TFL (after ≥2

systemic therapy regimens). In the EPCORE NHL-1 trial that included 40 patients with transformed indolent lymphomas (without identification of the source of the transformation), epcoritamab resulted in an ORR of 68%

(45% CR) in patients with transformed indolent lymphomas.47 In a phase II study of glofitamab for patients with relapsed or refractory DLBCL

(including 27 patients with TFL), the CR rate was 50% for patients with

TFL.48

Histologic Transformation After Minimal or No Prior Therapy

Anthracycline-based chemoimmunotherapy (with regimens recommended for first-line therapy for DLBCL, unless contraindicated) with or without

involved-site radiation therapy (ISRT) is recommended for histologic

transformation of FL to either DLBCL or HGBL with MYC and BCL6

rearrangements and transformed MZL.10,11 Histologic transformation of FL to HGBL with MYC and BCL2 rearrangements should be managed with

more aggressive chemoimmunotherapy regimens as recommended for

HGBL with translocations of MYC and BCL6 with or without BCL2.

Active surveillance or enrollment in a clinical trial are included as treatment options for patients achieving CR to initial treatment.29,31,33 Disease

relapse should be treated as described below for Histologic

Transformation After Multiple Lines Of Prior Therapies. Repeat biopsy

should be strongly considered if PET-positive prior to additional therapy,

because PET positivity may represent post-treatment inflammation. If

transformation is coexisting with extensive FL, rituximab maintenance

should be considered for patients achieving CR.49,50

CAR T-cell therapy (if eligible) is recommended for patients achieving PR or those with progressive or non-responsive disease. For patients who are not candidates for CAR T-cell therapy, second-line and additional therapy options are same as the systemic therapy options as described below for

Histologic Transformation After Multiple Lines Of Prior Therapies.

Histologic Transformation After Multiple Lines of Prior Therapies

Enrollment in an appropriate clinical trial is the preferred option. In the

absence of a suitable clinical trial, systemic therapy with or without ISRT, ISRT, or best supportive care are included as treatment options.10

RCHOP (if not previously used; rituximab, cyclophosphamide,

doxorubicin, vincristine, and prednisone), cytarabine-based, or

gemcitabine-based chemotherapy (with or without rituximab) and T-cell engager therapy (CD-19 directed CAR T-cell therapy [axicabtagene

ciloleucel tisagenlecleucel and lisocabtagene maraleucel] and bispecific antibodies [epcoritamab and glofitamab]) are included as options,

regardless of transplant eligibility.

Tafasitamab in combination with lenalidomide, loncastuximab tesirine,

selinexor, epcoritamab or glofitamab, and polatuzumab vedotin (with or

without bendamustine or rituximab) are appropriate options for patients

with no intention to proceed to transplant. Selinexor is included as a

treatment option for TFL only after at least two lines of systemic therapy, including patients with disease progression after transplant or CAR T-cell therapy. However, it should be noted that patients with transformed

lymphoma were excluded from the clinical trial that evaluated polatuzumab vedotin for relapsed/refractory DLBCL, and its inclusion is based on the

extrapolation of data for polatuzumab vedotin for relapsed/refractory

DLBCL.51

Consolidation therapy with HDT/ASCR with or without ISRT (if not

previously given) or active surveillance are included as treatment options for patients achieving CR.29,31,33 Allogeneic HCT should be considered

only in selected patients.

Active surveillance, allogeneic HCT with or without ISRT, CAR T-cell

therapy (if not previously given), or ISRT for localized residual disease

and/or residual fluorodeoxyglucose (FDG)-avid disease not previously

irradiated are included as second-line therapy options for patients

achieving partial response (PR) to initial therapy. If proceeding to

transplant, additional systemic therapy ± ISRT should be considered to

induce CR prior to transplant. However, it should be noted that data on the efficacy of transplant in patients who have received CAR T-cell therapy

are not available. HDT/ASCR is not recommended after CAR T-cell

therapy. Allogeneic HCT could be considered but remains investigational.

Patients with non-responsive or progressive disease can be treated with any of the treatment options (not received previously) if they are

candidates for additional therapy. Repeat biopsy should be strongly

considered prior to additional therapy, because PET positivity may

represent post-treatment inflammation.

References

表 1
GELF $CRITERIA^{a,b}$
• Involvement of ≥3 nodal sites, each with a diameter of ≥3 cm • Any nodal or extranodal tumor mass with a diameter of ≥7 cm • B symptoms • Splenomegaly • Pleural effusions or peritoneal ascites • Cytopenias (leukocytes <1.0 x 10$^{9}$/L and/or platelets <100 x 10$^{9}$/L) • Leukemia (>5.0 x 10$^{9}$/L malignant cells)

表 2
FLIPI - 1 CRITERIA$^{a,c}$
RISK FACTORS	RISK FACTORS	RISK GROUPS	RISK GROUPS
• Age	≥60 y		Number of factors
• Ann Arbor Stage	III-IV	Low	0-1
• Hemoglobin level	<12 g/dL	Intermediate	2
• Serum LDH level	>ULN	High	≥3
• Number of nodal $sites^{d}$	≥5

表 3
FIRST-LINE THERAPY	FIRST-LINE THERAPY
Preferred, high tumor burden (in alphabetical order)
Bendamustine$^{d}$ + Obinutuzumab$^{e,f}$ or Rituximab
CHOP (Cyclophosphamide/Doxorubicin/Vincristine/Prednisone) + Obinutuzumab$^{e,f}$ or Rituximab
CVP (Cyclophosphamide/Vincristine/Prednisone) + Obinutuzumab$^{e,f}$ or Rituximab
Lenalidomide + Rituximab
Preferred, low tumor burden
Rituximab (375 mg/m$^{2}$ weekly for 4 doses)$^{g}$
Other recommended	Other recommended
Lenalidomide + Obinutuzumab (category 2B)

表 4
Lugano Staging System for Gastrointestinal Lymphomas	Lugano Modification of Ann Arbor Staging System	TNM Staging System Adapted for Gastric Lymphoma	Tumor Extension
Stage I	Confined to Gl $tract^{a}$
Stage I	$I_{1}$ = mucosa, submucosa	$I_{E}$	T1 N0 M0	Mucosa, submucosa
Stage I	$I_{2}$ = muscularis propria, serosa	$I_{E}$	T2 N0 M0	Muscularis propria
Stage I	$I_{2}$ = muscularis propria, serosa	$I_{E}$	T3 N0 M0	Serosa
Stage II	Extending into abdomen
Stage II	$II_{1}$ = local nodal involvement	$II_{E}$	T1-3 N1 M0	Perigastric lymph nodes
Stage II	$II_{2}$ = distant nodal involvement	$II_{E}$	T1-3 N2 M0	More distant regional lymph nodes
Stage IIE	Penetration of serosa to involve adjacent organs or tissues	$II_{E}$	T4 N0 M0	Invasion of adjacent structures
Stage $IV^{b}$	Disseminated extranodal involvement or concomitant supradiaphragmatic nodal involvement		T1-4 N3 M0	Lymph nodes on both sides of the diaphragm/distant metastases (eg, bone marrow or additional extranodal sites)
Stage $IV^{b}$	Disseminated extranodal involvement or concomitant supradiaphragmatic nodal involvement	IV	T1-4 N0-3 M1	Lymph nodes on both sides of the diaphragm/distant metastases (eg, bone marrow or additional extranodal sites)

表 5
FIRST-LINE THERAPYd
Preferred (in alphabetical order)
● NMZL
▶ Bendamustine + Rituximab
▶ CHOP + Rituximab
▶ CVP + Rituximab
▶ Rituximab (375 mg/m² weekly for 4 doses) for low tumor burden
● SMZL
▶ Rituximab (375 mg/m² weekly for 4 doses)
Other recommended
● Lenalidomide + Rituximab for NMZL
● Rituximab (375 mg/m² weekly for 4 doses) for EMZL (multifocal)

表 6
FIRST-LINE THERAPY FOR OLDER OR INFIRM (if none of the above are expected to be tolerable in the opinion of treating physician)
Preferred
• Rituximab (375 mg/m² weekly for 4 doses)
• ISRT for local disease
Other recommended
• Cyclophosphamide ± Rituximab

表 7
FIRST-LINE EXTENDED THERAPY (optional)$^{d}$
• Rituximab maintenance 375 mg/m$^{2}$ one dose every 8–12 weeks for up to 2 years

表 8
INDUCTION THERAPY	INDUCTION THERAPY	INDUCTION THERAPY
Stage I or Stage II nonbulky (contiguous or noncontiguous)$^{c}$ or Classical TP53 wildtype: Stage II bulky and/or noncontiguous; Stage III, IV	Classical TP53 wildtype: Stage II bulky and/or noncontiguous; Stage III, IV	Classical TP53 mutated: Stage II bulky and/or noncontiguous; Stage III, IV
Less Aggressive Induction Therapy Preferred • Acalabrutinib$^{d,e}$ (continuous)/ Bendamustine$^{f}$ + Rituximab followed by Rituximab maintenance (2 y) • Acalabrutinib$^{d,e}$ (continuous) + Rituximab • Bendamustine$^{f}$ + Rituximab$^{g}$ Other recommended • CHOP$^{h}$ + Rituximab followed by Rituximab maintenance • Ibrutinib (continuous) + Rituximab followed by Rituximab maintenance (2 y) • Lenalidomide (continuous) + Rituximab • VR-CAP (Bortezomib/ Cyclophosphamide/Doxorubicin/ Prednisone) + Rituximab	Aggressive Induction Therapy Preferred (in alphabetical order) • Bendamustine$^{f}$ + Rituximab followed by high-dose Cytarabine + Rituximab • LyMA regimen: DHA (Dexamethasone/Cytarabine) + platinum (Carboplatin, Cisplatin, or Oxaliplatin) + Rituximab x 4 cycles followed by CHOP + Rituximab for non-PET CR • NORDIC regimen: Dose-intensified induction immunochemotherapy with maxi-CHOP (Cyclophosphamide/Doxorubicin/Vincristine/Prednisone) + Rituximab alternating with high-dose Cytarabine + Rituximab • TRIANGLE regimen (fixed duration): CHOP/covalent BTKi (Acalabrutinib, Ibrutinib, or Zanubrutinib)$^{d}$ + Rituximab alternating with DHA (Dexamethasone/Cytarabine) + platinum (Carboplatin, Cisplatin, or Oxaliplatin) + Rituximab • Hadiabutinib$^{d,e}$ (continuous) + Rituximab Other recommended • RBAC500 (Bendamustine$^{f}$/Low-dose Cytarabine) + Rituximab	Suitable for all patients • Venetoclax/Zanubrutinib + Obinutuzumab Suitable for aggressive induction therapy: • TRIANGLE regimen (fixed duration): CHOP/ covalent BTKi (Acalabrutinib, Ibrutinib, or Zanubrutinib)$^{d}$ + Rituximab alternating with DHA (Dexamethasone/Cytarabine) + platinum (Carboplatin, Cisplatin, or Oxaliplatin) + Rituximab followed by maintenance with Rituximab + covalent BTKi Not suitable for aggressive induction therapy: • Acalabrutinib$^{d,e}$ (continuous) + Rituximab

表 9
GENE	CLINICAL ASSOCIATION
ACTB, BCL2,$^{b}$ BCL6, CARD11, CD79B, CREBBP, EZH2, KMT2D, MYC,$^{c}$ MYD88, MEF2B, SOCS1	Diagnostic significance
BTK, CARD11, CD79B, MYD88	Associated with non-GCB DLBCL
NOTCH2	BN2 molecular subclassification
EZH2, SMARCB1	Treatment significance (EZH2 inhibitors)
PLCG2	Richter transformation; DLBCL arising from BTKi treated CLL/SLL
$TP53^{c}$	Mutations are frequent in DLBCL associated with chronic inflammation; TP53 mutations in conjunction with MYC rearrangement are associated with worse prognosis
ID3, TCF3, SMARCA4, CCND3	Mutations are more frequent in BL
B2M, CREBBP, EZH2, MYD88 L265P, SOCS1, TNFRSF14	Mutations favor other aggressive B-cell lymphoma subtypes other than BL
KMT2D, TP53	Mutations are more frequent in dark zone gene expression signature + LBCL with MYC and BCL2 or BCL6 rearrangements (double-hit lymphomas)
JAK/STAT, MAPK/ERK, NOTCH1 or NOTCH2	Mutations are frequent in plasmablastic lymphoma
MYD88, CD79B, PDL1, PDL2	Mutations are frequent in intravascular LBCL, primary cutaneous DLBCL, leg type, primary LBCL of immune-privileged sites
IL4R, ITPKB, NFKBIE, SOCS1, STAT6, XPO1	Mutations are characteristic of PMBL
CD79B, CREBBP, KMT2D, MYD88, PIM1	Often mutated in DLBCL, NOS, but not altered in PMBL
ATM, BIRC3, NSD2, UBR5	Mutations support the diagnosis of MCL

表 10
INTERNATIONAL PROGNOSTIC $INDEX^{a}$
ALL PATIENTS:	INTERNATIONAL INDEX, ALL PATIENTS:
• Age >60 years	• Low 0 or 1
• Serum LDH > normal	• Low-intermediate 2
• Performance status 2-4	• High-intermediate 3
• Stage III or IV	• High 4 or 5
• Extranodal involvement >1 site

表 11
AGE-ADJUSTED INTERNATIONAL PROGNOSTIC $INDEX^{a}$
PATIENTS ≤60 YEARS:	INTERNATIONAL INDEX, PATIENTS ≤60 YEARS:
• Stage III or IV	• Low
• Serum LDH > normal	• Low-intermediate
• Performance status 2-4	• High-intermediate
	• High

表 12
STAGE-MODIFIED INTERNATIONAL PROGNOSTIC INDEX (smIPI)$^{b}$
STAGE I OR II PATIENTS:	INTERNATIONAL INDEX, STAGE I OR II PATIENTS:
• Age >60 years	• Low 0 or 1
• Serum LDH > normal	• High 2-4
• Performance status 2-4
• Stage II or IIE

表 13
NCCN-IP1c	NCCN-IP1c	NCCN-IP1c	NCCN-IP1c
		RISK GROUP	RISK GROUP
Age, years	Age, years
>40 to ≤60	1	• Low	0-1
>60 to <75	2	• Low-intermediate	2-3
≥75	3	• High-intermediate	4-5
LDH, normalized	LDH, normalized	• High	≥6
>1 to ≤3	1
>3	2
Ann Arbor stage III-IV	1
Extranodal disease*	1	*Disease in bone marrow, CNS, liver/GI tract, or lung.
Performance status ≥2	1

表 14
PROGNOSTIC MODEL TO ASSESS THE RISK OF CNS DISEASE$^{d}$
RISK FACTORS	RISK GROUPS	RISK GROUPS
• Age >60 years	• Low risk	0–1
• Serum LDH > normal	• Intermediate-risk	2–3
• Performance status >1	• High-risk	4–6 or kidney or adrenal gland involvement
• Stage III or IV
• Extranodal involvement >1 site
• Kidney or adrenal gland involvement

表 15
ALK-POSITIVE LARGE B-CELL LYMPHOMAS (ALK+ LBCL)a
Definition	• ALK-positive LBCL is a mature aggressive B-cell lymphoma characterized by large cells with plasmablastic differentiation and cytoplasmic expression of ALK, and lacking CD20 expression. • Cytoplasmic ALK expression helps differentiate this entity from other aggressive CD20-negative LBCL with plasmacytic differentiation such as plasmablastic lymphoma, primary effusion lymphoma (PEL), and HHV8-positive DLBCL. • EBV and HHV8 are negative in ALK-positive LBCL, and there is no association with immune deficiency. • Cy�ogenetic/FISH analysis most commonly demonstrates the t(2;17)(p23;q23), denoting the CLTC (clathrin heavy chain):ALK fusion.
Clinical presentation	• The median age at diagnosis is approximately 40 years and there is a strong male predominance. • Most patients present with rapidly progressive disease at advanced stage, and both nodal and extranodal involvement are common.
Treatment	Initial therapy • Clinical trial is recommended, if available • Consolidative ISRT is preferred for localized $disease^{b}$ • These are most often CD20 negative and rituximab is not necessary. • While the optimal systemic treatment approach is not established, the following induction regimens have been used: • DA-EPOCH • CHOEP • CHOP may be associated with a suboptimal outcome. CHOP can be considered for patients with early-stage disease receiving combined modality therapy. • Mini-CHOP may be considered for patients who are frail or older • Potentially toxic regimens; performance status and comorbidities should be considered: ◇ HyperCVAD ◇ CODOX-M alternating with IVAC

表 16
MEDIASTINAL GRAY ZONE LYMPHOMA (MGZL)$^{a}$ (overlapping features between PMBL and CHL)
Clinical presentation$^{b}$	Present with large anterior mediastinal mass with or without supraclavicular lymph nodes. More common in males, presenting between 20-40 y
Morphology	Expert hematopathology review is essential. Diagnosis should not be made on a core needle biopsy. Large pleomorphic cells in a diffusely fibrous stroma. Typically larger and more pleomorphic than in PMBL, sometimes resembling lacunar or Hodgkin-like cells. Necrosis without neutrophilic infiltrate is frequent.
Immunophenotype	Atypical immunophenotype, often showing transitional features between PMBL and CHL. Typical immunophenotype: CD45+, PAX5+, BOB.1+, OCT-2+, CD15+, CD20+, CD30+, and CD79a+; CD10- and ALK-; BCL6 is variably expressed and EBV is usually negative.If the morphology more closely resembles PMBL: CD20 dim/-; CD30+ and CD15+ would be suggestive of gray zone lymphoma.If the morphology more closely resembles CHL: Strong uniform CD20+ (and/or other B-cell markers) and CD15- would be suggestive of MGZL.
Prognosis and Treatment	A worse prognosis than either CHL or PMBL has been suggested. While there is no consensus on the treatment, aggressive LBCL regimens are preferred.If the tumor cells are CD20+, the addition of rituximal to chemotherapy should be considered.CData suggest that the use of anthracycline-based chemioimmunotherapy as recommended for DLBCL (BCEL-C)$^{d}$ is helpful.If localized disease, then consolidative ISRT is preferred.

表 17
FIRST-LINE THERAPY	FIRST-LINE THERAPY	FIRST-LINE THERAPY	FIRST-LINE THERAPY
Stage I-II (excluding stage II with extensive mesenteric disease)	Stage II (with extensive mesenteric disease) or Stage III-IV	Patients with Poor Left Ventricular $Function^{e,f,g}$ (all stages)	Patients Who are Very Frail and Patients >80 Years of Age with Comorbidities$^{f,g}$ (all stages)
• CHOP + Rituximab^{c}$ • Pola-R-CHP (CHP [Cyclophosphamide/ Doxorubicin/Prednisone] + Polatuzumab vedotin-piq + Rituximab) (smIPI >1)$^{d}$ (category 1)	Preferred • CHOP + Rituximab^{c} (category 1) • Pola-R-CHP (IPI ≥2)$^{d}$ (category 1) Other recommended • Dose-adjusted EPOCH (Etoposide/Prednisone/Vincristine/ Cyclophosphamide/Doxorubicin) + Rituximab	Other recommended (in alphabetical order by category) • D-EPOCH^{h}$ + Rituximab • CDOP (Cyclophosphamide/Liposomal Doxorubicin/Vincristine/Prednisone) + Rituximab • CEOP (Cyclophosphamide/Etoposide/Vincristine/Prednisone) + Rituximab • GCVP (Gemcitabine/Cyclophosphamide/Vincristine/Prednisone) + Rituximab	Other recommended (in alphabetical order by category) • CDOP + Rituximab • Mini-CHOP + Rituximab • GCVP + Rituximab

表 18
CONCURRENT PRESENTATION WITH CNS DISEASE$^{1}$
• Parenchymal: systemic high-dose Methotrexate (≥3 g/m² given with anthracycline-based chemoimmunotherapy cycle that has been supported by growth factors). Different schedules have been used for the integration of high-dose Methotrexate with anthracycline-based chemoimmunotherapy; however, the Panel prefers day 15 of a 21-day cycle. • Leptomeningeal: IT Cytarabine/Methotrexate/Hydrocortisone, consider Ommaya reservoir placement. Systemic high-dose Methotrexate (3-3.5 g/m²) can be given in combination with anthracycline-based chemoimmunotherapy or as consolidation after anthracycline-based chemoimmunotherapy + IT Cytarabine/Methotrexate/Hydrocortisone • Consider consolidation with HDT/ASCR

表 19
SECOND-LINE THERAPY^{e,j,k} (relapsed disease <12 mo or primary refractory disease)
Candidates for CAR T-Cell Therapy	Non-Candidates for CAR T-Cell Therapy
CAR T-cell therapy^{l} ▲ Axicabtagene ciloleucel (CD19-directed) (category 1) ▲ Lisocabtagene maraleucel (CD19-directed) (category 1) Holding Therapy (prepheresis) Options DHA + platinum (Carboplatin, Cisplatin, or Oxaliplatin) ± Rituximab • GDP (Gemcitabine/Dexamethasone/Carboplatin or Cisplatin) ± Rituximab • GEMOX ± Rituximab • ICE (Ifosfamide/Carboplatin/Etoposide) ± Rituximab • Polatuzumab vedotin-piiq + Rituximab • ISRT (can be used as monotherapy or sequentially with systemic therapy) (NHODG-D 3 of 4) Bridging Therapy (postpheresis) Options (≥1 cycles as needed until CAR T-cell product is available) • DHA + platinum (Carboplatin, Cisplatin, or Oxaliplatin) ± Rituximab • GDP (Gemcitabine/Dexamethasone/Carboplatin or Cisplatin) ± Rituximab • GEMOX ± Rituximab • ICE (Ifosfamide/Carboplatin/Etoposide) ± Rituximab • Polatuzumab vedotin-piiq ± Rituximab ± Bendamustine^{m} ▲ Bisrot (can be used as monotherapy or sequentially with systemic therapy) (NHODG-D 3 of 4)	Preferred (in alphabetical order) • GEMOX^{n} + Epcoritamab-bysp^{o} ▲ GEMOX^{n} + Glofitamab-gxbm^{o} ▲ GEMOX^{n} + Polatuzumab vedotin-piiq + Rituximab • Lenalidomide + Tafasitamab-cxix^{p} (excluding primary refractory disease) • Polatuzumab vedotin-piiq ± Bendamustine^{m} ± Rituximab • Mosunetuzumab-axgb^{n,0} + Polatuzumab vedotin-piiq ▲ Other recommended (in alphabetical order) • CEOP ± Rituximab • DHA (Dexamethasone/Cytarabine) + platinum (Carboplatin, Cisplatin, or Oxaliplatin) ± Rituximab • ESHAP (Etoposide/Methylprednisolone/Cytarabine/Cisplatin) ± Rituximab • GDP ± Rituximab • GEMOX ± Rituximab (if unable to receive Epcoritamab-bysp, Glofitamab-gxbm, or Polatuzumab vedotin-piiq ▲ ICE ± Rituximab Useful in certain circumstances • Brentuximab vedotin • Ibrutinib^{n} (non-GCB DLBCL) • Lenalidomide ± Rituximab (non-GCB DLBCL)

表 20
SECOND-LINE THERAPY^{e,j,k}(relapsed disease >12 mo)
Intention to Proceed to Transplant	No Intention to Proceed to Transplant
Preferred (in alphabetical order)DHA + platinum (Carboplatin, Cisplatin, or Oxaliplatin) ± RituximabGDP ± RituximabICE ± RituximabOther recommended (in alphabetical order)ESHAP ± RituximabGEMOX ± Rituximab	Preferred (in alphabetical order)CAR T-cell therapy (CD19-directed) (with pre/postpheresis therapy as needed;BCEL-C 2 of 7) (if eligible)Lisocabtagene maraleucelGEMOX + Epcoritamab-bysp°GEMOX + Glofitamab-gxbm0GEMOX + Polatuzumab vedotin-piiq + RituximabLenalidomide + Tafasitamab-cxixPPolatuzumab vedotin-piiq ± BendamustineM ± RituximabMosunetuzumab-axgb^{n,0} + Polatuzumab vedotin-piiqOther recommended (in alphabetical order)CEOP ± RituximabGDP ± RituximabGEMOX ± Rituximab (if unable to receive epcoritamab-bysp, glofitamab-gxbm, or polatuzumab vedotin-piiq)RituximabUseful in certain circumstancesBrentuximab vedotin lbrutinib^{n} (non-GCB DLBCL)Lenalidomide ± Rituximab (non-GCB DLBCL)

表 21
SYSTEMIC THERAPY REGIMENS
Intention to proceed to transplant	PreferredCHOP + Rituximab (if not previously given)If previously treated with anthracycline-based regimen (in alphabetical order)DHA + platinum (Carboplatin, Cisplatin, or Oxaliplatin) ± RituximabGDPICE ± Rituximab
No intention to proceed to transplant	PreferredCHOP + Rituximab (if not previously given)If previously treated with anthracycline-based regimen (in alphabetical order)Polatuzumab vedotin-piiq ± Bendamustinec ± RituximabLenalidomide + Tafasitamab-cixd

表 22
Classification	HGBL with MYC and BCL2 rearrangements with or without BCL6 rearrangements (ICC) DLBCL/HGBL with MYC and BCL2 rearrangements (WHO5)$^{b}$	HGBL with MYC and BCL6 rearrangements (ICC)$^{b}$	HGBL-NOS (ICC and WHO5)$^{c}$
Treatment $options^{d,e}$	Clinical trial is recommended. • Consolidative ISRT is preferred for localized disease.$^{f}$ While the optimal treatment approach is not established, the following induction regimens have been used: • DA-EPOCH + Rituximab • CHOP + Rituximab may be associated with a suboptimal outcome. Could be considered for patients with low risk disease (IPI <2). • Mini-CHOP + Rituximab may be considered for patients who are frail or older • Potentially toxic regimens; performance status and comorbidities should be considered: ◇ HyperCVAD + Rituximab ◇ CDOX-M alternating with IVAC + Rituximab • Relapsed/refractory disease, see <12 months (BCEL-7) or >12 months (BCEL-8).	• Manage as DLBCL (BCEL-1). • HGBL with BCL6 and MYC rearrangements appear to have outcomes equivalent to DLBCL NOS; however many of these patients were managed with DA-EPOCH + Rituximab. Therefore, the optimal chemotherapy regimen remains uncertain.	• Clinical trial is recommended. • Consider consolidative ISRT for early-stage disease.$^{f}$ • While the optimal treatment approach is not established, the following induction regimens have been used: • DA-EPOCH + Rituximab • Pola-R-CHP (category 2B) • CHOP + Rituximab • Mini-CHOP + Rituximab may be considered for patients who are frail or older • Potentially toxic regimens; performance status and comorbidities should be considered ◇ HyperCVAD + Rituximab ◇ CODOX-M alternating with IVAC + Rituximab • Relapsed/refractory disease, see <12 months (BCEL-7) or >12 months (BCEL-8).

表 23
AGE	RISK	INDUCTION THERAPY (Regimens are listed in alphabetical order)
<60 y	Low Risk	CODOX-M (original or modified) (Cyclophosphamide/Vincristine/Doxorubicin with intrathecal [IT] Methotrexate and Cytarabine followed by high-dose systemic Methotrexate) + Rituximab (3 cycles)DA-EPOCH + RR (Etoposide/Prednisone/Vincristine/Cyclophosphamide/Doxorubicin) + Rituximab on day 1 and 5 x 2 cycles followed by PET $scan^{d}$:CR (PET-negative) after 2 cycles: DA-EPOCH-RR (Rituximab day 1 and 5) x 1 cycle (total of 3 cycles)PR (PET-positive) after 2 cycles: DA-EPOCH-R (Rituximab day 1 only) x 4 cycles (total of 6 cycles) + IT MethotrexateHyperCVAD (Cyclophosphamide/Vincristine/Doxorubicin/Dexamethasone) alternating with Cytarabine/high-dose Methotrexate + Rituximab (regimen includes IT therapy)
<60 y	High Risk	Patients presenting with symptomatic CNS disease:Initiate treatment with the portion of the systemic therapy that contains CNS-penetrating drugsCDOOX-M (original or modified) alternating with IVC (Ifosfamide/Etoposide/High-Dose Cytarabine) + IT Methotrexate+Rituximab HyperCVAD alternating with Cytarabine/high-dose Methotrexate + Rituximab + Rituximab for 6 cycles + IT Methotrexatee (for patients not able to tolerate aggressive therapy)
≥60 y	Low Risk	DA-EPOCH + RR (Rituximab day 1 and 5) x 2 cycles followed by PET $scan^{d}$:CR (PET-negative) after 2 cycles: DA-EPOCH-RR (Rituximab day 1 and 5) x 1 cycle (total of 3 cycles)PR (PET-positive) after 2 cycles: DA-EPOCH-RR (Rituximab day 1 only) x 4 cycles (total of 6 cycles) + IT Methotrexate
≥60 y	High Risk	Dose-adjusted EPOCH + Rituximab$^{d}$ for 6 cycles + intensive IT Methotrexatee (for patients presenting with symptomatic CNS disease)

表 24
Event	Action
ANC nadir on any cycle <500/mm³ on 2 nonconsecutive days at least 3 days apart and/or platelet nadir <25,000/mm³ in the previous cycle	Reduce cyclophosphamide dose by 187 mg/m²
ANC nadir <500/mm³ x ≥ 3 days or platelets <25,000/mm³ x ≥ 3 days, AND patient was receiving no cyclophosphamide in the previous cycle	Reduce doxorubicin and etoposide by 25% of the full dose
ANC nadir ≥500/mm³ AND platelet nadir ≥50,000/mm³ in the previous cycle	Increase cyclophosphamide dose by 187 mg/m² each cycle to a maximum dose of 750 mg/m²

表 25
Response	Site	PET-CT (Metabolic response)	CT (Radiologic response)$^{d}$
Complete response	Lymph nodes and extralymphatic sites	Score 1, 2, 3ª with or without a residual mass on 5-point scale (5-PS)$^{b,c}$	All of the following: Target nodes/nodal masses must regress to ≤1.5 cm in longest transverse diameter of a lesion (LDi) No extralymphatic sites of disease
Complete response	Non-measured lesion	Not applicable	Absent
Complete response	Organ enlargement	Not applicable	Regress to normal
Complete response	New lesions	None	None
Complete response	Bone marrow	No evidence of FDG-avid disease in marrow	Normal by morphology; if indeterminate and flow cytometry IHC negative
Partial response	Lymph nodes and extralymphatic sites	Score 4 or $5^{b}$ with reduced uptake compared with baseline. No new progressive lesions. At interim these findings suggest responding disease. At end of treatment these findings may indicate residual disease.	All of the following: ≥50% decrease in SPD of up to 6 target measurable nodes and extranodal sites When a lesion is too small to measure on CT, assign 5 mm x 5 mm as the default value. When no longer visible, 0x0 mm For a node >5 mm x 5 mm, but smaller than normal, use actual measurement for calculation
Partial response	Non-measured lesion	Not applicable	Absent/normal, regressed, but no increase
Partial response	Organ enlargement	Not applicable	Spleen must have regressed by >50% in length beyond normal
Partial response	New lesions	None	None
Partial response	Bone marrow	Residual uptake higher than update in normal marrow but reduced compared with baseline (diffuse uptake compatible with reactive changes from chemotherapy allowed). If there are persistent focal changes in the marrow in the content of a nodal response, consider further evaluation with biopsy, or an interval scan.	Not applicable
No response or stable disease	Target nodes/ nodal masses, extranodal lesions	Score 4 or $5^{b}$ with no significant change in FDG uptake from baseline at interim or end of treatment. No new or progressive lesions.	<50% decrease from baseline in SPD of up to 6 dominant, measurable nodes and extranodal sites; no criteria for progressive disease are met
No response or stable disease	Non-measured lesion	Not applicable	No increase consistent with progression
No response or stable disease	Organ enlargement	Not applicable	No increase consistent with progression
No response or stable disease	New lesions	None	None
No response or stable disease	Bone marrow	No change from baseline	Not applicable
Progressive disease	Individual target nodes/ nodal masses, extranodal lesions	Score 4 or $5^{b}$ with an increase in intensity of uptake from baseline and/or New FDG-avid foci consistent with lymphoma at interim or end-of-treatment $assessment^{e}$	Requires at least one of the following PPD progression: An individual node/lesion must be abnormal with: LDi >1.5 cm and Increase by ≥50% from PPD nadir and An increase in LDi or SDi from nadir 0.5 cm for lesions ≤2 cm 1.0 cm for lesions >2 cm In the setting of splenomegaly, the splenic length must increase by >50% of the extent of its prior increase beyond baseline. If no prior splenomegaly, must increase by at least 2 cm from baseline New or recurrent splenomegaly
Progressive disease	Non-measured lesion	None	New or clear progression of preexisting nonmeasured lesions
Progressive disease	New lesions	New FDG-avid foci consistent with lymphoma rather than another etiology (eg, infection, inflammation). If uncertain regarding etiology of new lesions, biopsy or interval scan may be $considered^{e}$	Regrowth of previously resolved lesions A new node >1.5 cm in any axis A new extranodal site >1.0 cm in any axis; if <1 cm in any axis, its presence must be unequivocal and must be attributable to lymphoma Assessable disease of any size unequivocally attributable to lymphoma
Progressive disease	Bone marrow	New or recurrent FDG-avid foci	New or recurrent involvement

表 27
The International Consensus Classification (ICC) of Mature Lymphoid Neoplasms (2022)	WHO Classification of Hematolymphoid Tumors: Lymphoid Neoplasms (2024; 5th edition)
Mature B-cell lymphomas	Mature B-cell lymphomas
Pre-neoplastic and neoplastic small lymphocytic proliferations
Monoclonal B-cell lymphocytosis • Chronic lymphocytic leukemia type • Non-chronic lymphocytic leukemia type	Monoclonal B-cell lymphocytosis
Chronic lymphocytic leukemia/small lymphocytic lymphoma	Chronic lymphocytic leukemia/small lymphocytic lymphoma
B-cell prolymphocytic leukemia	Not included
Splenic B-cell lymphomas and leukemias
Hairy cell leukemia	Hairy cell leukemia
Splenic marginal zone lymphoma	Splenic marginal zone lymphoma
Splenic B-cell lymphoma/leukemia, unclassifiable • Splenic diffuse red pulp small B-cell lymphoma • Hairy cell leukemia-variant	Splenic diffuse red pulp small B-cell lymphoma
Lymphoplasmacytic lymphoma
Lymphoplasmacytic lymphoma • Waldenström macroglobulinemia	Lymphoplasmacytic lymphoma
Marginal zone lymphoma
Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma)	Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue
Primary cutaneous marginal zone lymphoproliferative disorder	Primary cutaneous marginal zone lymphoma
Nodal marginal zone lymphoma • Pediatric nodal marginal zone lymphoma	Nodal marginal zone lymphoma
Nodal marginal zone lymphoma • Pediatric nodal marginal zone lymphoma	Pediatric nodal marginal zone lymphoma
Mature B-cell lymphomas	Mature B-cell lymphomas
Follicular lymphoma	Follicular lymphoma
Follicular Lymphoma (FL) grades 1, 2, 3AFL grade 3BNot IncludedIn situ follicular neoplasiaDuodenal-type follicular lymphoma
Pediatric-type follicular lymphoma	Pediatric-type follicular lymphoma
BCL2-R negative, CD23-positive follicale center lymphoma	FL with predominantly diffuse growth pattern (dFL)
Testicular follicular lymphoma	Not included
Mantle cell lymphoma	Mantle cell lymphoma
Mantle cell lymphoma	Mantle cell lymphoma
In situ mantle cell neoplasiaLeukemic non-nodal mantle cell lymphoma	In situ mantle cell neoplasm
In situ mantle cell neoplasiaLeukemic non-nodal mantle cell lymphoma	Leukaemic non-nodal mantle cell lymphoma
Transformations of indolent B-cell lymphomas
Not included	Transformations of indolent B-cell lymphomas
Mature B-cell lymphomas	Mature B-cell lymphomas
Large B-cell lymphomas
Diffuse large B-cell lymphoma, NOS • Germinal center B-cell • Activated B-cell	Diffuse large B-cell lymphoma, NOS
High-grade B-cell lymphoma with MYC and BCL6 rearrangements	Not included
High-grade B-cell lymphoma with MYC and BCL2 rearrangements	Diffuse large B-cell lymphoma/high-grade B-cell lymphoma with MYC and BCL2 rearrangements
High-grade B-cell lymphoma, NOS	High-grade B-cell lymphoma, NOS
T-cell/histocyte-rich large B-cell lymphoma	T-cell/histocyte-rich large B-cell lymphoma
ALK-positive large B-cell lymphoma	ALK-positive large B-cell lymphoma
Large B-cell lymphoma with IRF4 rearrangement	Large B-cell lymphoma with IRF4 rearrangement
Large B-cell lymphoma with 11q aberration	High-grade B-cell lymphoma with 11q aberrations
Epstein-Barr virus-positive mucocutaneous ulcer	See Lymphoid proliferations and lymphomas associated with immune deficiency and dysregulation
EBV-positive diffuse large B-cell lymphoma, NOS	EBV-positive diffuse large B-cell lymphoma
Diffuse large B-cell lymphoma associated with chronic inflammation • Fibrin-associated diffuse large B-cell lymphoma	Diffuse large B-cell lymphoma associated with chronic inflammation
Diffuse large B-cell lymphoma associated with chronic inflammation • Fibrin-associated diffuse large B-cell lymphoma	Fibrin-associated large B-cell lymphoma
HHV8 and EBV-negative primary effusion-based lymphoma	Fluid overload-associated large B-cell lymphoma
Lymphomatoid granulomatosis	Lymphomatoid granulomatosis
Plasmablastic lymphoma	Plasmablastic lymphoma
Primary DLBCL of the central nervous system	Primary large B-cell lymphoma of immune-privileged sites • Primary LBCL of the CNS • Primary LBCL of the vitreoretina • Primary LBCL of the testis
Primary DLBCL of the testis	Primary cutaneous diffuse large B-cell lymphoma, leg type
Primary cutaneous diffuse large B-cell lymphoma, leg type	Prinvascular large B-cell lymphoma
Intravascular large B-cell lymphoma	Intravascular large B-cell lymphoma
Primary mediastinal large B-cell lymphoma	Primary mediastinal large B-cell lymphoma
Mediastinal grey zone lymphoma	Mediastinal grey zone lymphoma
Mature B-cell lymphomas	Mature B-cell lymphomas
Burkitt lymphoma	Burkitt lymphoma
Burkitt lymphoma	Burkitt lymphoma
HHV-8-associated lymphoproliferative disorders	KSHV/HHV8-associated B-cell lymphoid proliferations and lymphomas
Multicentric Castleman disease	See Tumour-like lesions with B-cell predominance
Primary effusion lymphoma	Primary effusion lymphoma
HHV8-positive diffuse large B-cell lymphoma, NOS	KSHV/HHV8-positive diffuse large B-cell lymphoma
HHV8-positive germinotropic lymphoproliferative disorder	KSHV/HHV8-positive germinotropic lymphoproliferative disorder
Immunodeficiency-associated lymphoproliferative disorders	Lymphoid proliferations and lymphomas associated with immune deficiency and dysregulation
Posttransplant lymphoproliferative disorders	Hyperplasias arising in immune deficiency/dysregulation
Nondestructive posttransplant lymphoproliferative disorders	Hyperplasias arising in immune deficiency/dysregulation
Plasmacytic hyperplasia posttransplant lymphoproliferative disorder	Polymorphic lymphoproliferative disorders arising in immune deficiency/dysregulation
Infectious mononucleosis posttransplant lymphoproliferative disorder	EBV-positive mucocutaneous ulcer
Florid follicular hyperplasia posttransplant lymphoproliferative disorder	Lymphomas arising in immune deficiency / dysregulation
Polymorphic posttransplant lymphoproliferative disorder	Lymphomas arising in immune deficiency / dysregulation
Monomorphic posttransplant lymphoproliferative disorder (B-cell and T-cell/ NK-cell types)	Inborn error of immunity-associated lymphoid proliferations and lymphomas
Other iatrogenic immunodeficiency-associated lymphoproliferative disorders	Tumour-like lesions with B-cell predominance
	Reactive B-cell-rich lymphoid proliferations that can mimic lymphoma
Not included	IgG4-related disease
Not included	Unicentric Castleman disease
See HHV8-associated lymphoproliferative disorders	Idiopathic multicentric Castleman disease
See HHV8-associated lymphoproliferative disorders	KSHV/HHV8-associated multicentric Castleman disease

图示：StageInitial TherapyI,Il(FOLL-3Initial TherapyStageIII,IV(FOLL-4

图示：Nodal AreasLeft CervicaRight CervicaPreauricularPreauricularUpper CervicaUpper CervicaMedian or LowerMedian or LowerPostcervicalPostcervicaSupraclavicularSupraclavicularMediastinaParatracheaMediastinalHilarLeft AxillaryRight AxillaryLeft EpitrochleaRight EpitrochlearPara-AorticMesentericPara-AorticMesentericCommon lliacSplenic HilarExternal IliacPortaCeliacRight InguinaLeft InguinaInguinaInguinaFemoraFemoralRight PoplitealLeft PopliteaLegend for labelsBlue = BilateralBlack = Midline

图示：NCCN #NCCN Guidelines Version 1.2026 ##Extranodal Marginal Zone B-Cell Lymphoma ##Extranodal MZL of the Stomach ##Response after completion of antibiotic treatment, ISRT, or $rituximab^{t,u}$ $H.$ pylori negative $H.$ pylori positive, Lymphoma negative $H.$ pylori positive, Lymphoma negative $H.$ pylori positive, Lymphoma positive $H.$ pylori positive, Lymphoma positive $H.$ pylori positive, Lymphoma positive $H.$ pylori positive, Lymphoma positive $H.$ pylori positive, Lymphoma positive $H.$ pylori positive, Lymphoma positive ### Recurrence post ISRT or rituximab #### EmZLG-3 Systemic recurrence recurrence Local recurrence recurrence ISRT$^{n}$ Indication for*sum ######ISRT Indication for*sum #######ISRT Indication for*sum #######ISRT Indication for*sum #######ISRT Indication for*sum #######ISRT Indication for*sum Indication for*sum Indication for*sum Indication for*sum Indication for*sum Indication for*sum Indication for*sum Indication for*sum Indication for*sum Indication for*sum Indication for*sum Indication for*sum Indication for*sum Indication for*sum Indication for*sum Indica

图示：InitialTherapy(EMZLNG-2)

图示：Local recurrence ISRT if not previously given or Manage per advanced-stage NMZL (NMZL-3) Clinical follow-up every 3-6 mo for 5 y and then annually or as clinically indicated^{n,0} Systemic recurrence Evaluate for indications for treatment: Candidate for clinical trial Symptoms Gl bleeding Threatened end-organ function Clinically significant bulky disease Steady or rapid progression Indication present To: All recommendations are category 2A unless otherwise indicated. EMZL-A 2 of 4) (1) In: 2026, 12/22/25 © 2025 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

图示：STAGE INITIAL THERAPY RESPONSE TO THERAPY $^{1,m}$ FOLLOW-UP $^{n}$ Stage I or Contiguous stage II $^{9}$ → ISRT $^{h}$ + anti-CD20 $mAb^{i}$ ± chemotherapy (MZL-A) $^{j}$ or Anti-CD20 $mAb^{i}$ ± chemotherapy (MZL-A) in certain circumstances $^{k}$R Aive surveillance $^{9}$R Active surveillance $^{9}$R C I, II Aive surveillance $^{9}$R I, II Aive surveillance $^{9}$R I, II Aive surveillance $^{9}$R I, II Aive surveillance $^{9}$R I, II Aive surveillance $^{9}$R I, II Aive surveillance $^{9}$R I, II Aive surveillance $^{9}$R I, II Aive surveillance $^{9}$R I, II Aive surveillance $^{9}$R I, II Aive surveillance $^{9}$R I, II Aive surveillance $^{9}$R I, II Aive surveillance $^{9}$R I, II Aive surveillance $^{9}$R I, II Aive surveillance $^{9}$R I, II Aive surveillance $^{9}$R I, II Aive su

图示：Stage III, IV Evaluate for indications for treatment$^{p}$: Candidate for clinical trial Symptoms Threatened end-organ function Clinically significant or progressive cytopenia secondary to lymphoma Clinically significant bulky disease$^{p}$ Steady or rapid progression$^{m}$ Indication No indication Active surveillance category 1 Clinical H&P and labs every 3-6 mo for 5 y and then annually or as clinically indicated Surveillance imaging$^{o}$ Up to 2 y: C/A/P CT scan with contrast no more than every 6 mo >2 y: CT scan no more than annually Progressive disease, see HTBCEL-1 See Suggested Regimens (MZL-A) or Clinical trial and/or Very low-dose ISRT$^{h}$ | Response | = | | | | | | | | | | | | | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |

图示：RESPONSE ASSESSMENT$^{1}$ AND ADDITIONAL THERAPY Extended therapy (optional) for patients treated with single-agent Rituximab (MZL-A) or Active surveillance Clinical H&P and labs every 3-6 mo for 5 y and then annually or as clinically indicated Surveillance imaging$^{0}$ Up to 2 y post completion of treatment: C/A/P CT scan with single-agent Rituximab (MZL-A) or Active surveillance 4C/A/P CT scan with contrast PR$^{1}$,q → PR$^{1}$,q → 4C Extended therapy (optional) for patients treated with single-agent Rituximab with single-agent Rituximab (MZL-A) or Active surveillance (MZL-A 3 of 4) 4C/A/P CT scan with contrast 4C/A-P CT scan with contrast NR or progressive disease$^{1}$,m → Rebiopsy → No histologic transformation, 2025 美国国家综合癌症网络版权所有。 FOLLOW-UP$^{n}$ Clinical H&P and labs every 3-6 mo for 5 y and then annually or as clinically indicated Surveillance imaging$^{0}$ Relapsed or Progressive disease$^{1}$,m → Prebiopsy → No histologic transformation, 2025 美国国家综合癌症网络版权所有。 4C/A/P CT scan with contrast 4C/A/P CT scan with contrast was the HTBCEL-1 4C/A/P CT scan with contrast was the HTBCEL-1 4C/A/P CT scan with contrast was the HTBCEL-1 4C/A/P CT scan with contrast was the HTBCEL-1 4C/A/P CT scan with contrast was the HTBCEL-1 4C/A/P CT scan with contrast was the HTBCEL-1 4C/A/P CT scan with contrast was the HTBCEL-1 4C/A/P CT scan with contrast was the HTBCEL-1 4C/A/P CT scan with contrast was the HTBCEL-1 4C/A/P CT scan with contrast was the HTBCEL-1 4C/A/P CT scan with contrast was the HTBCEL-1 4C/A/P CT scan with contrast was the HTBCEL-1 4C/A/P CT scan with contrast was the HTBCEL-1 4C/A/P CT scan with contrast was the HTBCEL-1 4C/A/P CT scan with contrast was the HTBCEL-1 4C/A/P CT scan with contrast was the HTBCEL-1 4C/A/P CT scan with contrast was the HTBCEL-1 4C/A/P CT scan with contrast was the HTBCEL-1 4C/A/P CT scan with contrast was the HTBCEL-1 4C/A/P CT scan with contrast was the HTBCEL-1 4C/A/P CT scan with contrast was

图示：Asymptomatic, without progressive cytopenia, no splenomegaly Follow-up (SMZL-3) No contraindications for treatment of hepatitis Appropriate treatment CR/PR PROFLOW-UP Splenomegaly Hepatitis C positive^h Hepatology consult Contraindications for treatment of hepatitis Recontraindications for treatment of hepatitis Splenomegaly Cytopenias or Symptoms Rituximab^i (preferred) or Splenectomy^i (category 2B) Hepatitis C negative No symptoms Active surveillance h If hepatitis C positive, treat with an appropriate regimen for hepatitis C. Tsimberidou AM, et al. Cancer 2006;107:125-135. j Pneumococcal, meningococcal, haemophilus influenza, and hepatitis B vaccination should be given at least 2 weeks before splenectomy. Note: All recommendations are category 2A unless otherwise indicated.

图示：Clinical follow-up every 3-6 mo for 5 y and then annually or as clinically indicated^{k,l}^{NCC}$Recurrence If histologic transformation, see HTBCEL-1 Evaluate for indications for treatment: Candidate for clinical trial Symptoms Threatened end-organ function Cytopenias including autoimmune cytopenia Clinically significant bulky disease Steady or rapid progression No indication Active surveillance Treatment naive, then see First-line Therapy for Marginal Zone Lymphomas (MZL-A 1 of 4)$^{1}$ or Prior treatment with rituximab, then see Second-line and Subsequent Therapy for Marginal Zone Lymphomas (MZL-A 2 of 4 and MZL-A 3 of 4)$^{m}$ or Splenectomy$^{j}$ or Very low-dose ISRT$^{n}$

图示：NCCN 授权医脉通提供NCCN指南全文下载。wmlsyy于2025/12/23,21:20在医脉通平台下载,仅供个人使用,严禁分发。2025 美国国家综合癌症网络版权所有。 NCCN Guidelines Index Table of Contents #NCCN Guidelines Network® MANAGEMENT AND FOLLOW-UP1 Classical TP53 → MANT-4 Classical TP53 mutateds have been associated with poor prognosis in patients treated with conventional therapy including transplant Clinical trial is strongly recommended In absence of clinical trial, consider the induction therapy options listed on MANT-A. Stage Il bulky and/or noncontiguous; Stage III, IV Modelentm Common presentations include: Leukemic non-nodal CLL-like with splenomegaly Gl or blood/bone marrow involvement only Low tumor burden, Ki-67 proliferation fraction <10% Symptomatic or other indication for treatment Evaluate for clinical concern of transformation Rebiopsy and TP53 sequencing Treat as described above based on the TP53 mutation status Asymptomatic, no other indication for treatment Active surveillance

图示：INDUCTION THERAPY Maintenance therapy (Rituximab ± covalent BTKi)$^{p}$ CR$^{k,n}$ CR$^{k,n}$ dMRD6 Consider therapy (Rituximab ± covalent BTKi)$^{p}$ Maintenance therapy (MANT-A) Maintenance therapy (MANT-A) Maintenance therapy (MANT-A) Maintenance therapy (MANT-A) Maintenance therapy (Rituximab ± covalent BTKi)$^{p}$ Controling and controling and controling Suitable for aggressive induction therapy Suitable for aggressive induction therapy Suitable for aggressive induction therapy Suitable for aggressive induction therapy Suitable for aggressive induction therapy Suitable for aggressive induction therapy Suitable for aggressive induction therapy Suitable for aggressive induction therapy Suitable for aggressive induction therapy Suitable for aggressive induction therapy Suitable for aggressive induction therapy Suitable for aggressive induction therapy Suitable for aggressive induction therapy Suitable for aggressive induction therapy Suitable for aggressive induction therapy Suitable for negative failure therapy Suitable for negative failure therapy Suitable for negative failure therapy Suitable for negative failure therapy Suitable for negative failure therapy Suitable for negative failure therapy Suitable for negative failure therapy Suitable for negative failure therapy Suitable for negative failure therapy Sabove for negative failure therapy Sabe for negative failure therapy Sabe for negative failure therapy Sabe for negative failure therapy Sabe for negative failure therapy Sabe for negative failure therapy Sabe for negative failure therapy Sabe for negative failure therapy Sabe for negative failure therapy Sabe for negative failure therapy Sabe for negative failure therapy Sabe for negative failure therapy Sabe for negative failure therapy Sabe for negative failure therapy Sabe for negative failure therapy Sabe for negative failure therapy Sabe for negative failure therapy Sabe for negative failure therapy Sabe for negat

图示：NCCN National Comprehensive Cancer Network® ADDITIONAL THERAPY FOLLOW-UP1 SECOND-LINE THERAPY Classical TP53 wild type Stage II bulky and/or noncontiguous; Stage III, IV Not suitable for aggressive induction therapy Clinical maintenance (category 1 following RCHOP) (MANT-A) CRk→ Consider rituximab maintenance (category 1 following RCHOP) (MANT-A) Chemoimmunotherapy (MANT-A) to achieve CR Prk,q→ Conder rituximab maintenance (category 1 following RCHOP) (MANT-A) Relapsed/ Refractory or Progressive Disease cBTKi naïve or Late relapse (>24 mo) after prior cBTKi-containing regimen (MANT-6A) No response or progressive disease | diseasek|

图示：RELAPSED/REFRACTORY OR PROGRESSIVE DISEASE ### $$\text{SCN}\text{Gulendelines Version 1.2026}$$ ### RELAPSED/REFRACTORY OR PROGRESSIVE DISEASE ### $$\text{SCN}\text{Gulendelines Version 1.2026}$$ ###RELAPSED/REFRACTORY OR PROGRESSIVE DISEASE #### $$\text{SCN}\text{Gulendelines Version 1.2026}$$ #####RELAPSED/REFRACTORY OR PROGRESSIVE DISEASE ########################################################################################################################################################

图示：First-LIne Therapy(BCEL-3

图示：Stage I, II (excluding stage II with extensive mesenteric disease$^{h}$) i, j, k, l Nonbulky (<7.5 cm)$^{l}$ SmlPI 0-1 $\rightarrow$ RCHOP x 3 cycles Interim restaging with PET/CT BCEL-4 Stage I, II (excluding stage II with extensive mesenteric disease or Stage III, IV Bulky (≥7.5 cm)$^{l}$ SmlPI 0-1 $\rightarrow$ RCHOP x 3-4 cycles Interim restaging with PET/CT$^{o}$ BCEL-5 Step 11 with extensive disease$^{h}$ (或) I, i, k, m, n, o First-line therapy See Suggested Regimens (BCEL-C) Interim restaging with PET/ CT$^{q}$ or CT after 2-4 cycles BCEL-6 Stage III, IV i, k, m, n, o

图示：Stage II with extensive mesenteric disease$^{h}$ or Stage III, IV $^{i,k,m,n,o}$ First-line therapy See Suggested Regimens (BCEL-C) CT$^{q}$ or CT after 2-4 cycles BCEL-6 Stage III, IV $^{i,k,m,n,o}$

图示：NCCN 授权医脉通提供NCCN指南全文下载。wmlsyy于2025/12/23,21:20在医脉通平台下载,仅供个人使用,严禁分发。2025 美国国家综合癌症网络版权所有。 NCCN Guidelines Index Table of Contents #NCCN Configuration RELAPSE/REFRACTORY DISEASE ADDITIONAL THERAPY RESPONSE ASSESSMENT Relapsed disease<12 mo or Primary refractory diseasecc Clinical trial or Second-line therapy; see Suggested Regimens (BCEL-C 2 of 7) or Palliative ISRTt or Best supportive care (See NCCN Guidelines for Palliative Care) {12 mo or Primary refractory diseasecc}

图示：RELAPSE/REFRACTORY DISEASE ADDITIONAL THERAPY RESPONSE ASSESSMENT Consolidation/ADDITIONAL THERAPY DILEPSTRAY Complete response CAR T-cell therapy (BCEL-C 2 of 7) or HDT/ASCR ± ISRT$^{t}$,hh or Allogeneic HCT in selected cases$^{ii}$ ± ISRT$^{t}$,hh {Controlention to proceed to transplant} → Second-line therapy; see Suggested Regimens (BCEL-C 3 of 7) or BDT/ASCR ± ISRT$^{t}$,hh or CAR T-cell therapy (BCEL-C 2 of 7) or HDT/ASCR ± ISRT$^{t}$,hh or CAR T-cell therapy (BCEL-C 2 of 7) or BDT/ASCR ± ISRT$^{t}$,hh or CAR T-cell therapy (BCEL-C 3 of 7) or BDT/ASCR ± ISRT$^{t}$,hh or CBR T-cell therapy (BCEL-C 2 of 7) or BDT/ASCR ± ISRT$^{t}$,hh or CBR T-cell therapy (BCEL-C 3 of 7) or BDT/ASCR ± ISRT$^{t}$,hh or CBR T-cell therapy (BCEL-C 3 of 7) or BDT/ASCR ± ISRT$^{t}$,hh or CBR T-cell therapy (BCEL-C 3 of 7) or BDT/ASCR ± ISRT$^{t}$,hh or CBR T-cell therapy (BCEL-C 3 of 7) or BDT/ASCR ± ISRT$^{t}$,hh or CBR T-cell therapy (BCEL-C 3 of 7) or BDT/ASCR ± ISRT$^{t}$,hh or CBR T-cell therapy (BCEL-C 3 of 7) or BDT/ASCR ± ISRT$^{t}$,hh or CBR T-cell therapy (BCEL-C 3 of 7) or BDT/ASCR ± ISRT$^{t}$,hh or CBR T-cell therapy (BCEL-C 3 of 7) or BDT/ASCR ± ISRT$^{t}$,hh or CBR T-cell therapy (BCEL-C 3 of 7) or BDT/ASCR ± ISRT$^{t}$,hh or CBR T-cell therapy (BCEL-C 3 of 7) or BDT/ASCR ± ISRT$^{t}$,hh or CBR T-cell therapy (BCEL-C 3 of 7) or BDT/ASCR ± ISRT$^{t}$,hh or CBR T-cell therapy (BCEL-C 3 of 7) or BDT/ASCR ± ISRT$^{t}$,hh or CBR T-cell therapy (BCEL-C 3 of 7) or BDT/ASCR ± ISRT$^{t}$,hh or CBR T-cell therapy (BCEL-C 3 of 7) or BDT/ASCR ± ISRT$^{t}$,hh or CBR T-cell therapy (BCEL-C 3 of 7) or BDT/ASCR ± ISRT$^{t}$,hh or CBR T-cell therapy (BCEL-C 3 of 7) or BDT/ASCR ± ISRT$^

图示：FOLLOW-UP FOLLOW-UP Follow-up after treatment for relapsed/refractory disease Clinical H&P and labs, every 3-6 mo for 5 y and then annually or as clinically indicated ImagingW C/A/P CT scan with contrast no more often than every 6 mo for 2 y after completion of treatment, then only as clinically indicated Partial response,klk or Relapse |F座 |F座 |F座 |F座 |F座 |F座 |F座 |F座 |F座 |F座 |F座 |F座 |F座 |F座 |F座 |F座 |F座 |F座 |F座 |F座 |F座 |F座 |F座 |F座 |F座 |F座 |F座 |F座 |F座 |F座 |F座 |F座 |F座 |F座 |F座 |F座 |F座 |F座 |F

图示：STAGEPP INITIAL THERAPYqq,rr,ss Clinical H&P and labs, every 3-6 mo for 5 y and then annually or as clinically indicated Imaging C/A/P CT scan with contrast no more often than every 6 mo for 2 y after completion of treatment, then only as clinically indicated Relompire regional, T1-2 → Local ISRTt,uu or Clinical trial PR or NR or Progressive disease Pola-R-CHPtt + local ISRTt or or Local ISRTt,uu or or Clinical trial Pola-R-CHPtt (if not previously received) or or Mar or 6 mo for 2 y after completion of treatment, then only as clinically indicated PR or NR or Progressive disease Pola-R-CHPtt (if not previously received) or Mar or 7 y after completion of treatment, then only as clinically indicated APR or NR or Progressive disease SPRCTTt (60) Pola-R-CHPtt (60) Pola-R-CHPtt (60) Pola-R-CHPtt (60) Pola-R-CHPtt (60) Pola-R-CHPtt (60) Pola-R-CHPtt (60) Pola-R-CHPtt (60) Pola-R-CHPtt (60) Pola-R-CHPtt (60) Pola-R-CHPtt (60) Pola-R-CHPtt (60) Pola-R-CHPtt (60) Pola-R-CHPtt (60) Pola-R-CHPtt (60) Pola-R-CHPtt (60) Pola-R-CHPtt (60) Pola-R-CHPtt (60) Pola-R-CHPtt (60) Pola-R-CHPtt

图示：FIRST-LINE THERAPY a,b Optimal first-line therapy for PMBL c is more controversial than other subtypes. Most commonly used treatment options are listed below. Dose-adjusted EPOCH + rituximab (DA-EPOCH-R) x 6 cycles RCHOP-14 x 4-6 cycles RCHOP-21 x 6 cycles Restage with PET/CT partial response d (PET positive bPSy) e, d Partio response d (PET positive bPSy) e, d Partio response d (PET positive bPSy) e, d No response or Progressive disease d (PET positive bPSy) e, d Partio response d (PET positive bPSy) e, d Partio response d (PET positive bPSy) e, d Partio response d (PET positive bPSy) e, d Partio response d (PET positive bPSy) e, d Partio response d (PET positive bPSy) e, d Partio response d (PET positive bPSy) e, d Partio response d (PET positive bPSy) e, d Partio response d (PET positive bPSy) e, d Partio response d (PET positive bPSy) e, d Partio response d (PET positive bPSy) e, d Partio response d (PET positive bPSy) e, d Partio response d (PET positive bPSy) e, d Partio response d (PET positive bPSy) e, d Partio response d (PET positive bPSy) e, d Partio response d (PET positive bPSy) e, d Partio response d (PET positive bPSy) e, d Partio response d (PET positive bPSy) e, d Partio response d (PET positive bPSy) e, d Partio response d (PET positive bPSy) e, d Partio response d (PET positive bPSy) e, d Partio response d (PET positive bPSy) e,

图示：Histologic transformation after minimal or no prior therapy^{a,b,c}^{a,b,c} DLBCL or HGBL with MYC and BCL6 rearrangements^{f}^{f}^{a,b,c} Chemoimmunotherapy (anthracycline-based regimens preferred unless contraindicated) (See BCEL-C, first-line therapy) ± ISRT$^{g,h}^{a}$ $I_{ISRT}^{g,h}^{g}$ $PET/CT$ → Response to Therapy to Therapy (HTBCEL-2)

图示：Histologic transformation of Indolent Lymphomas to DLBCL ### Histologic transformation after multiple lines of prior $therapies^{d}$ #### Clinical trial or See HTBCEL-A for suggested systemic therapy regimens (Selection of regimen must be highly individualized taking into account prior treatment history) ± $ISRT^{9}$ or $ISRT^{9}$ or $ISRT^{9}$ or $ISRT^{9}$ or $ISRT^{9}$ or $ISRT^{9}$ for localized residual and/or residual FDG-avid disease not previously irradiated (See NCCN Guidelines for Palliative Care) ############################################################################################################################################################################################################################################################################################

图示：RISK ASSESSMENT INDUCTION THERAPY INITIAL RESPONSE RELAPSE Low risk Normal LDH and Stage I (Single extra-abdominal mass <10 cm) or Completely resected abdominal lesion Clinical trial or $N_{\text{Regimens}}^{i}$ Complete $n_{\text{J}}^{i}$ $C_{\text{A}}^{i}$ $C_{\text{A}}^{i}$ $C_{\text{A}}^{i}$ $C_{\text{A}}^{i}$ $C_{\text{A}}^{i}$ $C_{\text{A}}^{i}$ $C_{\text{A}}^{i}$ $C_{\text{A}}^{i}$ $C_{\text{A}}^{i}$ $C_{\text{A}}^{i}$ $C_{\text{A}}^{i}$ $C_{\text{A}}^{i}$ $C_{\text{A}}^{i}$ $C_{\text{A}}^{i}$ $C_{\text{A}}^{i}$ $C_{\text{A}}^{i}$ $C_{\text{A}}^{i}$ $C_{\text{A}}^{i}$ $C_{\text{A}}^{i}$ $C_{\text{A}}^{i}$ $C_{\text{A}}^{i}$ $C_{\text{A}}^{i}$ $C_{\text{A}}^{i}$ $C_{\text{A}}^{i}$ $C_{\text{A}}^{i}$ $C_{\text{A}}^{i}$ $C_{\text{A}}^{i}$ $C_{\text{A}}

图示：SECOND-LINE THERAPY RESPONSE ASSESSMENT CONSOLIDATION/ADDITION THERAPY Consolidation/ADDITIONAL THERAPY Complete response Consider HDT/ASCR ± ISRT$^{m}$ or Consider allogeneic HCT in selected cases$^{n}$ ± ISRT$^{m}$ $^{n}$ Consider allogeneic HCT in selected cases$^{n}$ ± ISRT$^{m}$ Disease relapse >6 to 18 mo after appropriate first-line therapy $^{n}$ Conse Second-line therapy$^{i}$ or $^{(BURK-A)}$ or $^{(BURK-A)}$ or $^{(NCCN Guidelines for Palliative Care)}$ ### Clinical trial or $^{(C)O}$ or $^{(A)O}$ or $^{(BURK-A)}$ or $^{(BURK-A)}$ or $^{(C)O}$ or $^{(A)O}$ or $^{(BURK-A)}$ or $^{(C)O}$ or $^{(A)O}$ or $^{(A)O}$ or $^{(A)O}$ or $^{(A)O}$ or $^{(A)O}$ or $^{(A)O}$ or $^{(A)O}$ or $^{(A)O}$ or $^{(A)O}$ or $^{(A)O}$ or $^{(A)O}$ or $^{(A)O}$ or $^{(A)O}$ or $^{(A)O}$ or $^{(A)O}$ or $^{(A)O}$ or $^{(A)O}$ or $^{(A)O}$ or $^{(A)O}$ or $^{(A)O}$ or $^{(A)O}$ or $^{(A)O}$ or $^{(A)O}$ or $^{(A)O}$ or $^{(A)O}$ or $^{(A)O}$ or $^{(A)O}$ or $^{(A)O}$ or $^{(A)O}$ or $^{(A)O}$ or $^{(A)O}$ or $^{(A)O}$ or $^{(A)O}$ or $^{(A)O}$ or $^{(A)O}$ or $^{(A)O}$ or $^{(A)O}$ or $^{(

图示：BL - First-line therapy - See Suggested Treatment Regimens (HIVLYM-A)$^{e}$ - If CD4 <50, maximize supportive care and monitor closely for cytopenias and infections (BURK-3) - Granulocyte colony-stimulating factor (G-CSF) for all patients

图示：* Initiate ART, if not already receiving * Even with poorly controlled HIV and/or marginal performance status, consider high-dose methotrexatef * For select patients with good performance status on ART, see the NCCN Guidelines for CNS - Primary CNS Lymphoma * Consider RT alone as initial treatment for patients who are not candidates for systemic therapy at presentation, then reassess eligibility for systemic therapy after RT * Best supportive care (See NCCN Guidelines for Palliative Care)

图示：$\bullet$ DLBCL $\bullet$ HHV8-positive DLBCL, NOS $\bullet$ PEL $\bullet$ First-line therapy - See Suggested Treatment Regimens (HIVLYM-A)$^{e}$ $\rightarrow$ For relapse, see $\bullet$ G-CSF for all patients $\bullet$ IT therapy as per BCEL-A 3 of 3 $\bullet$ Bortezomib/ICE ± Rituximab (category 2B) $\bullet$ If CD20-, rituximab is not indicated $\bullet$ If CD4 <50, maximize supportive care and monitor closely for cytopenias and infections while administering lymphoma therapy

图示：Plasmablastic lymphoma$^{9}$ - For relapse, Se - Consider HDT/ASCR in first complete remission in select patients with high-risk disease$^{10}$ - Consider consolidation with ISRT in patients with localized disease - See BCEL-C second-line therapy (without rituximab)

图示：PTLD SUBTYPE FIRST-LINE THERAPY INITIAL RESPONSE¹ Manage immunosuppression™ and monitor EBV PCR, and graft organ function Non-destructive lesions (ICC)/ Hyperplasia (WHO5)g Reduction of immunosuppression (RIS)g Partial response, persistent or progressive disease Rituximab and monitor EBV PCRn Partial response, persistent or progressive disease Non-destructive lesions (ICC)/ Hyperplasia (WHO5)g 3 NCCN Guidelines Version 1.2026 Post-Transplant Lymphoproliferative Disorders FOLLOW-UP/SECOND-LINE THERAPY Manage immunosuppression™ and monitor EBV PCR, and graft organ function Complete response Manage immunosuppression™ and monitor EBV PCRn and graft organ function Partial response, persistent or progressive disease Rituximab and monitor EBV PCRn Monomorphic PTLD → RIS, if possible and/or: → Rituximab alone; or → Chemoimmunotherapy; or → Chemoimmunotherapy; or → Partial response, persistent or progressive disease Non-destructive lesions (ICC)/ Hyperplasia (WHO5)g Other than reduction of RIS, there are no established treatments. HDT/ASCR may not be appropriate. → Consider chemotherapy (See NCCN Guidelines for T-Cell Lymphomas) Complete response See appropriate histologic subtype for follow-up If RIS was initial therapy, then Rituximab or chemoimmunotherapy; or If rituximab monotherapy was initial therapy, then chemoimmunotherapy; or consider Rituximab for patients with partial response and IPI 0-2° or or If chemoimmunotherapy was initial therapy, see BCEL-7 or Clinical trial or Immunotherapy with EBV-Specific Cytotoxic T-Cell Lymphomas)

图示：PTLD SUBTYPE FIRST-LINE THERAPY INITIAL RESPONSE$^{1}$ FOLLOW-UP/SECOND-LINE THERAPY Polymorphic PTLD (B-cell type) (ICC/ WHO5) Localized $^{1}$R, if possible$^{1}$ and: $^{2}$Rituximab alone or $^{3}$Chemoimmunotherapy$^{2}$Colummunotherapy$^{3}$ Complete response $^{4}$ $^{1}$Protaient response $^{5}$ $^{1}$Protaient response $^{6}$ $^{1}$Protaient response $^{7}$ $^{1}$Protaient response $^{8}$ $^{1}$Protaient response $^{9}$ $^{1}$Protaient response $^{1}$Protaient response $^{1}$Protaient response $^{1}$Protaient response $^{1}$Protaient response $^{1}$Protaient response $^{1}$Protaient response $^{1}$Protaient response $^{1}$Protaient response $^{1}$Protaient response $^{1}$Protaient response $^{1}$Protaient response $^{1}$Protaient response $^{1}$Protaient response $^{1}$Protaient response $^{1}$Protaient response $^{1}$Protaient response $^{1}$Protaient response $^{1}$Protaient response $^{1}$Protaient response $^{1}$Protaient response $^{1}$Protaient response $^{1}$Protaient response $^{1}$Protaient response $^{1}$Protaient response $^{1}$Protaient response $^{1

图示：NCCN 授权医脉通提供NCCN指南全文下载。wmlsyy于2025/12/23,21:20在医脉通平台下载,仅供个人使用,严禁分发。2025 美国国家综合癌症网络版权所有。 NCCN Guidelines Index Table of Contents NCCN Ancer Network® #USE OF IMMUNOPHENOTYPING/MOLECULAR ANALYSIS IN DIFFERENTIAL DIAGNOSIS OF MATURE B-CELL AND NK/T-CELL NEOPLASMSa (TO BE USED IN CONJUNCTION WITH CLINICAL AND MORPHOLOGIC CORRELATION)INITIAL MORPHOLOGIC, CLINICAL, AND IMMUNOPHENOTYPIC ANALYSIS Small cells NHODG-A 4 of 8 Medium-sized cells NHODG-A 5 of 8 Large cells ± anaplastic morphology Cutaneous localization NHODG-A 8 of 8 Lineage based on immunophenotyped (Pan-B and Pan-T antigens) or Suspected by morphology/ clinical features T-cell neoplasms See NCCN Guidelines for T-Cell Lymphomas

图示：B-CELL NEOPLASMS Small cells Panel: CD5, CD10, CD21, CD23, cyclin D1, BCL2, BCL6, Ki-67, CD11c, (CD25, CD103)$^{e}$ Small cells Small cells: Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL)Mantle cell lymphoma (MCL)Splenic marginal zone lymphoma (SMZL)Hairy cell leukemia (HCL)Lymphoplasmacytic lymphoma (LPL)Lymphoplasmacytic lymphoma (MCL)Extranodal marginal zone lymphoma (EMZL)Nodal marginal zone lymphoma (NMZL)Policular lymphoma (FL)Pediatric-type follicular lymphoma (PTFL) $^{e}$and $^{a}$These are meant to be general guidelines. Interpretation of results should be based on individual circumstances and may vary. Not all tests will be required in every case. $^{e}$Flow cytometry on blood or bone marrow done only if HCL is in differential diagnosis by morphology. $^{f}$Rare cases of cyclin D1- and $^{c}$ or $^{f}$CMLS and $^{c}$ or $^{f}$CMLS and $^{c}$ or $^{f}$CMLS and $^{c}$ or $^{f}$CMLS and $^{c}$ or $^{f}$CMLS and $^{c}$ or $^{f}$CMLS and $^{c}$ or $^{f}$CMLS and $^{c}$ or $^{f}$CMLS and $^{c}$ or $^{f}$CMLS and $^{c}$ or $^{f}$CMLS and $^{c}$ or $^{f}$CMLS and $^{c}$ or $^{f}$CMLS and $^{c}$ or $^{f}$CMLS and $^{c}$ or $^{f}$CMLS and $^{c}$ or $^{f}$CMLS and $^{c}$ or $^{f}$CMLS and $^{c}$ or $^{f}$CMLS and $^{c}$ or $^{f}$CMLS and $^{c}$ or $^{f}$CMLS and $^{c}$ or $^{f}$CMLS and $^{c}$ or $^{f}$CMLS and $^{c}$ or $^{f}$CMLS and $^{c}$ or $^{f}$CM

图示：B-CELL NEOPLASMS Diffuse pattern medium cells ± starry sky pattern$^{1}$ Initial panel: CD5, CD10, cyclin D1, BCL2, BCL6, IRF4/ MUM1, Ki-67m See WHO Classification of Tumours Editorial Board. Haematolymphoid tumours. (WHO classification of tumours series, 5th ed; vol 11). Lyon (France): International Agency for Research on Cancer; 2024. Arber DA, Borowitz MJ, Cook JR, et al. The International Consensus Classification of myeloid and lymphoid neoplasms (ed Edition 1); 2025. King RL, Hsi ED, Chan CC, et al. Diagnostic approaches and future directions in Burkitt lymphoma and high-grade B-cell lymphoma Virchows Arch 2023;482:193-205.

图示：Large cells → PanelP: CD5, CD10, BCL6, IRF4/MUM1, Ki-67m CD5- DLBCL, NOS CD5+q CD10+ IRF4/MUM1+ → LBCL with IRF4 rearrangements (Confirm by FISH) CD10+ IRF4/MUM1- → DLBCL, NOS GCB type (BCL6+) CD5- DLBCL Large cells: ● Diffuse large B-cell lymphoma (DLBCL), NOS 4GB subtype ● Non-GCB subtype ● PCLBCL of the CNS ● Primary cutaneous DLBCL, leg type ● EBV-positive DLBCL (EBV + DLBCL), NOS ● DLBCL associated with chronic inflammation ● Lymphomatoid granulomatosis ● Primary mediastinal large B-cell lymphoma (PMBL) ● Intravascular LBCL ● ALK-positive LBCL ● Plasmablastic lymphoma ● HHV8+ LBCL, NOS 4GB with IRF4 rearrangement ● HHV8+ LBCL, NOS 4GB with IRF4 rearrangement ● Primary effusion lymphoma (PEL) ● Mediastinal gray zone lymphoma (MGZL) ● MCL, pleomorphic variant ● MCL, pleomorphic variant ● NCCN 2010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010- 4010

图示：LARGE CELLS (continued) CD30 - T-cell-rich $\rightarrow$ THRLBCL (May be BCL6+, IRF4/MUM1-) EBER- Mediastinal $\rightarrow$ PMBL (May be BCL6+, IRF4/MUM1-) CD30 + + Morphologically borderline with CHL $\uparrow$ CD15- $\rightarrow$ PMBL (May be BCL6, INGCB, NOS CAD20+ (PAX5+) EDB+ 3D30 - DLBCL, non-GCB Mediastinal $\rightarrow$ PMBL (May be BCL6+, IRF4/MUM1-) DCLBCL, non-GCB Mediastinal $\rightarrow$ PMBL (May be BCL6+, IRF4/MUM1-) Morphologically borderline with CHL $\uparrow$ CD15+ $\rightarrow$ HGBL, NOS EDB+ 3D30 - EDBCL EDB+ 3D30 + + Morphologically borderline with CHL $\uparrow$ CD15+ $\rightarrow$ HGBL, NOS CD20+ (PAX5+) EDB+ 3D30 + EDBCL EDB+ 3D30 + EDBCL EDB+ 3D30 + EDBCL EDB+ 3D30 + EDBCL EDB+ 3D30 + EDBCL EDB+ 3D30 + EDBCL EDB+ 3D30 + EDBCL EDB+ 3D30 + EDBCL EDB+ 3D30 + EDBCL EDB+ 3D30 + EDBCL EDB+ 3D30 + EDBCL EDB+ 3D30 + EDBCL EDB+ 3D30 + EDBCL EDB+ 3D30 + EDBCL EDB+ 3D30 + EDBCL EDB+ 3D30 + EDBCL EDB+ 3D30 + EDBCL EDB+ 3D30 + EDBCL EDB+ 3D30 + EDBCL EDB+ 3D30 + EDBCL EDB+ 3D30 + EDBCL EDB+ 3D30 + EDBCL EDB+ 3D30 + EDBCL EDB+ 3D30 + ED

引用 / 出处

（2026.V1）NCCN临床实践指南：B细胞淋巴瘤. 2026.

（2026.V1）NCCN临床实践指南：B细胞淋巴瘤

NCCN Guidelines Version 1.2026

B-Cell Lymphomas

NCCN Guidelines Version 1.2026

B-Cell Lymphomas

DIAGNOSIS

ADDITIONAL DIAGNOSTIC $TESTING^{b}$

NCCN Guidelines Version 1.2026

Follicular Lymphoma

ADDITIONAL DIAGNOSTIC TESTING$^{a}$

ESSENTIAL:

USEFUL UNDER CERTAIN CIRCUMSTANCES:

NCCN Guidelines Version 1.2026

Classic Follicular Lymphoma

WORKUP

ESSENTIAL:

USEFUL IN SELECTED CASES:

NCCN Guidelines Version 1.2026

Classic Follicular Lymphoma

NCCN Guidelines Version 1.2026

Classic Follicular Lymphoma

NCCN Guidelines Version 1.2026

Classic Follicular Lymphoma

NCCN Guidelines Version 1.2026

Pediatric-Type Follicular Lymphoma

PEDIATRIC-TYPE FOLLICULAR LYMPHOMA IN ADULTS

PATHOLOGIC AND CLINICAL PRESENTATION$^{c,u}$

NCCN Guidelines Version 1.2026

Classic Follicular Lymphoma

NCCN Guidelines Version 1.2026

Classic Follicular Lymphoma

SUGGESTED TREATMENT REGIMENS<sup>a,b,c</sup>

FIRST-LINE THERAPY FOR OLDER OR INFIRM

Preferred

FIRST-LINE EXTENDED THERAPY (optional)

Preferred following chemoimmunotherapy

Other recommended

Consider prophylaxis for tumor lysis syndrome (NHODG-B)

SUGGESTED TREATMENT REGIMENS REFERENCES

Lenalidomide + rituximab

Lenalidomide + obinutuzumab

First-line Extended Dosing

Chemmoimmunotherapy followed by rituximab maintenance

Extended dosing with rituximab

SUGGESTED TREATMENT REGIMENS REFERENCES

Second-line and Subsequent Therapy

Bendamustine + obutinuzumab

Lenalidomide ± rituximab

Lenalidomide + obinutuzumab

Lenalidomide + Rituximab + Epcoritamab-bysp

Rituximab

Lenalidomide + rituximab + tafasitamab-cxix

Tazemetostat

Second-line Extended Dosing

Zunadomide

Obinutuzumab maintenance for rituximab refractory disease

Third-line and Subsequent Therapy

Loncastuximab tesirine-lpyl + rituximab

Zanubrutinib + obutunuzumab

T-Cell-Mediated Therapy

CAR T-Cell Therapy

Tisagenleuclei

Bispecific Antibody Therapy

Mosunetuzumab-axgb

NCCN Guidelines Version 1.2026

Marginal Zone Lymphomas

NCCN Guidelines Version 1.2026

Extranodal Marginal Zone B-Cell Lymphoma

ADDITIONAL DIAGNOSTIC TESTING$^{a,b}$

ESSENTIAL:

USEFUL UNDER CERTAIN CIRCUMSTANCES:

WORKUP

ESSENTIAL:

USEFUL IN SELECTED CASES:

NCCN Guidelines Version 1.2026

NCCN Guidelines Version 1.2026

Extranodal Marginal Zone B-Cell Lymphoma

Extranodal MZL of the Stomach

NCCN Guidelines Version 1.2026

Extranodal Marginal Zone B-Cell Lymphoma