（2026.V2）NCCN临床实践指南：慢性淋巴细胞白血病／小淋巴细胞淋巴瘤

指南血液内科· 淋巴瘤与骨髓瘤 · 2026

NCCN Guidelines Version 2.2026

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

NCCN Guidelines Index Table of Contents Discussion

*William G. Wierda, MD, PhD/Chair ‡ ‡

The University of Texas MD Anderson Cancer Center

* Jennifer Brown, MD, PhD/Vice-Chair ‡ Dana-Farber/Brigham and Women's Cancer Center

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

Farrukh Awan, MD ‡† B UT Southwestern Simmons Comprehensive Cancer Center

Greg Bociek, MD, MSc † § Fred & Pamela Buffett Cancer Center

Daniel Boyer, MD, PhD # University of Michigan Rogel Cancer Center

Matthew Cortese, MD, MPH ‡†b Roswell Park Comprehensive Cancer Center

Larry Cripe, MD ‡ Indiana University Melvin and Bren Simon Comprehensive Cancer Center

Christopher D'Angelo, MD ‡ Fred & Pamela Buffett Cancer Center

Elijah Darnell, MD ‡ The UChicago Medicine Comprehensive Cancer Center

Randall S. Davis, MD ‡ O'Neal Comprehensive Cancer Center at UAB

Herbert Eradat, MD, MS †‡ UCLA Jonsson Comprehensive Cancer Center

Naseem Esteghamat, MD, MS ‡ UC Davis Comprehensive Cancer Center

Lindsey Fitzgerald, MD †‡ b

Huntsman Cancer Institute at the University of Utah

Christopher D. Fletcher, MD ‡ University of Wisconsin Carbone Cancer Center

Sameh Gaballa, MD ‡ Moffitt Cancer Center

Scott Huntington, MD, MPH, MSc †‡

Yale Cancer Center/ Smilow Cancer Hospital

Brad Kahl, MD ‡ Seman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

Manali Kamdar, MD ‡ University of Colorado Cancer Center

Thomas J. Kipps, MD, PhD UC San Diego Moores Cancer Center

Shuo Ma, MD, PhD † Robert H. Lurie Comprehensive Cancer Center of Northwestern University

Claudio A. Mosse, MD, PhD Vanderbilt-Ingram Cancer Center

Shazia Nakhoda, MD ‡ Fox Chase Cancer Center

Sameer A. Parikh, MBBS ‡ Mayo Clinic Comprehensive Cancer Center

Peter Riedell, MD ‡ The UChicago Medicine Comprehensive Cancer Center

Andrew Schorr, MS ¥ Patient advocate

Stephen Schuster, MD ‡ Abramson Cancer Center at the University of Pennsylvania

Madhav Seshadri, MD ‡ UCSF Helen Diller Family Comprehensive Cancer Center

Tait Shanafelt, MD ‡ Stanford Cancer Institute

Tanya Siddiqi, MD ‡ City of Hope National Medical Center

Andrea Sitlinger, MD ‡ Duke Cancer Institute

Meghan Thompson, MD ‡ Memorial Sloan Kettering Cancer Center

Chaitra Ujjani, MD ‡ Fred Hutchinson Cancer Center

Nina Wagner-Johnston, MD † Johns Hopkins Kimmel Cancer Center

Jennifer A. Woyach, MD ‡ The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute

NCCN Mary Dwyer, MS Hema Sundar, PhD

ξ Bone marrow transplantation

‡ Hematology/Hematology oncology

$\bullet$ Internal medicine

† Medical oncology

* Pathology/Hematopathology

¥ Patient advocacy

* Discussion Writing Committee Member

NCCN Guidelines Version 2.2026

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Version 2.2026, 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 Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Panel Members

Summary of the Guidelines Updates

CLL/SLL Diagnosis (CSLL-1)

CLL/SLL Workup (CSLL-2)

SLL/Localized (Lugano Stage I) (CSLL-3)

CLL (Rai Stages 0–IV) or SLL (Lugano Stage II–IV) (CSLL-3)

First-Line Therapy (CSLL-4)

Relapsed or Refractory Disease (CSLL-5A)

Prognostic Variables in Patients with CLL/SLL (CSLL-A)

CLL/SLL Staging Systems (CSLL-B)

Supportive Care for Patients with CLL/SLL (CSLL-C)

Suggested Treatment Regimens (CSLL-D)

Measurable Residual Disease (MRD) Assessment (CSLL-E)

Histologic Transformation (Richter) (HT-1)

Use of Immunophenotyping/Genetic Testing in Differential Diagnosis of Mature B-Cell

and NK/T-Cell Neoplasms (See NCCN Guidelines for B-Cell Lymphomas)

Abbreviations (ABBR-1)

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 2.2026

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

NCCN Guidelines Index Table of Contents Discussion

UPDATES

Continued

Updates in Version 1.2026 of the NCCN Guidelines for CLL/SLL from Version 3.2025 include:

Global

• References updated throughout the guidelines.

• Regimens for CLL/SLL clarified as time-limited vs continuous and fixed duration vs MRD-guided as appropriate.

• "Response Definitions After Treatment for CLL/SLL" table removed from the Guidelines.

• "Venetoclax: Recommended TLS Prophylaxis and Monitoring Based on Tumor Burden" table removed from the Guidelines.

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

CSLL-1

• Diagnosis, Essential

Bullet removed: Biopsy is generally not required. If diagnosis is not established by flow cytometry, then proceed with lymph node biopsy. Bone marrow aspirate

with biopsy can be pursued if peripheral blood and lymph node biopsy material are nondiagnostic. Fine-needle aspiration (FNA) or core needle biopsy alone is not

generally suitable for the initial diagnosis of CLL/SLL. In certain circumstances, when a lymph node is not easily accessible for excisional or incisional biopsy, a

combination of core needle biopsy and FNA biopsy in conjunction with appropriate ancillary techniques for the differential diagnosis (ie, immunohistochemistry [IHC],

flow cytometry) may be sufficient for diagnosis.

2nd bullet, 3rd sub-bullet revised by adding two sub-bullets:

◊ Excisional or incisional biopsy, if lymph node is accessible. FNA biopsy alone is inadequate for the 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 may be required) in conjunction with appropriate

ancillary techniques, such as FNA, may be sufficient for diagnosis.

◊ Bone marrow aspirate with biopsy can be pursued if peripheral blood and lymph node biopsy material are nondiagnostic.

CSLL-2

• Workup

Essential, 7th bullet added: Assess for distress. Corresponding footnote f added: Refer to the NCCN Distress Thermometer and Problem List, which includes social

determinants of health. See NCCN Guidelines for Distress Management (DIS-A). (Also for HT-2)

Useful,

◊ 2nd bullet added: Serum protein electrophoresis (SPEP) with serum immunofixation electrophoresis (SIFE) to evaluate for monoclonal protein.

◊ 11th bullet revised: Whole body FDG-PET/CT scan...

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

cryopreservation. (Also for HT-2)

CSLL-3

• Branch point CLL revised from "CLL Rai Low (0) and Intermediate (I–II) risk" and "CLL Rai High (III–IV) risk" to "CLL (Rai Stage 0–IV)"

• After indication present,

2nd bullet revised: IGHV mutation status (if not previously done when considering chemoimmunotherapy [CIT])

• Footnote p added: Consider next generation sequencing (NGS)-based clonality testing for measurable residual disease (MRD) assessment if MRD-guided treatment is planned and MRD flow is not being used for MRD assessment. See CSLL-E.

Updates in Version 2.2026 of the NCCN Guidelines for CLL/SLL from Version 1.2026 include:

• References updated on CSLL-D 5 of 5 and HT-A 3 of 3.

CSLL-D 3 of 5

• Footnote i revised: TKIs are available in different formulations, dosage forms, and strengths that are subject to different administration instructions. The choice of cBTKi should be made by the treating clinician based on patient-specific factors (eg, age, functional status, comorbid conditions) and the agent’s toxicity profile.

These products are not interchangeable.

MS-1

• The discussion section has been updated to reflect the changes in the algorithm.

NCCN Guidelines Version 2.2026

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

NCCN Guidelines Index Table of Contents Discussion

UPDATES

Continued

Updates in Version 1.2026 of the NCCN Guidelines for CLL/SLL from Version 3.2025 include:

CSLL-4

• First-line therapy

Recommendations for CLL with and without del(17p)/TP53 were combined.

Chemoimmunotherapy or immunotherapy pathway removed.

Time-limited treatment, BCL2 inhibitor (BCL2i)-containing regimens clarified as "BCL2 inhibitor (BCL2i) + anti-CD20 mAb" and "BCL2 inhibitor (BCL2i) + cBTKi ± antiCD20 mAb"

Continuous treatment, "Covalent BTK inhibitor (cBTKi)-based regimens" clarified as "Covalent BTK inhibitor (cBTKi-based regimens) ± anti-CD20 mAb" (Also for

CSLL-5)

• Note added to page: Sequencing therapy following CIT as first-line therapy (See CSLL-D 1 of 6 for suggested treatment regimens): Observation until relapse with

indications for treatment is recommended for response after completion of CIT. Time-limited treatment with BCL2i-containing regimens or cBTKi-based regimens are

options for relapse after a period of remission or progression on treatment. See CSLL-D 2 of 6 for suggested treatment regimens for second-line and subsequent

therapy. (Also for CSLL-5)

CSLL-5A

• Footnotes

Footnote r added: Clinical trial is preferred when available.

Footnote t added: Time-limited treatment with BCL2i + cBTKi ± CD20 mAb may be fixed-duration or MRD-guided (based on undetectable MRD (uMRD)-stopping

criteria as described in clinical trials). See MRD Assessment (CSLL-E).

Footnote u revised from, "Response Definition After Treatment for CLL/SLL (CSLL-E)" to "See Discussion for iwCLL response criteria."

Footnote v added: Adverse reactions can be managed by following the recommended dose modifications in the FDA-approved package insert (https://www.

accessdata.fda.gov/scripts/cder/daf/index.cfm).

Footnote x revised: Consider the possibility of histologic transformation in patients with progressive disease. Biopsy is recommended to confirm histologic

transformation. If histologic transformation or histologic progression of CLL/SLL, see HT-1.

Footnote y revised by adding: ncBTKi can be considered for resistance or intolerance to prior cBTKi-based regimens.

Footnote aa revised: Patients with CLL/SLL without del(17p)/TP53 mutation who discontinue a cBTKi for intolerance can remain off treatment (if not progressive if

there is no disease progression) for an extended period of time and alternate BTKi can be reinitiated when symptomatic.

Footnote bb revised: Venetoclax ± anti-CD20 mAb (obinutuzumab preferred) or venetoclax + cBTKi is a treatment option for relapse after a period of remission.

Single agent venetoclax (continuous) can also be considered as a treatment option for relapse after a period of remission.

Removed: CIT or immunotherapy is not an option for patients who have received these regimens for first-line therapy.

Removed: CpG-stimulated karyotype is useful to identify patients with high-risk disease, particularly for patients receiving BTKi therapy.

CSLL-A 3 of 5

• Prognostic Variables In Patients With CLL/SLL

Table 3, first row revised by adding BTK A428D.

CSLL-B 1 of 2

• CLL Staging Systems

Footnote removed: Immune-mediated cytopenias are not the basis for these stage definitions.

CSLL-C 1 of 6

• Anti-infective Prophylaxis

3rd bullet revised: Monitor blood counts and consider growth factor support or fluoroquinolone and/or fungal prophylaxis for the management of venetoclax-induced

neutropenia.

CSLL-C 2 of 6

• New page added: Precautions when initiating treatment or transitioning to next therapy for disease progression while on treatment

NCCN Guidelines Version 2.2026

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

NCCN Guidelines Index Table of Contents Discussion

UPDATES

Continued

CSLL-C 3 of 6

• Tumor Lysis Syndrome (TLS)

Laboratory hallmarks of TLS. Added: High serum creatinine

TLS features: 3rd sub-bullet revised: Bulky (>5 cm) lymph nodes

Treatment of TLS

◊ 1st sub-bullet added: For BCL2i-associated TLS, see venetoclax prescribing information

◊ 4th sub-bullet added: Allopurinol, febuxostat, and rasburicase according to prescribing information and institutional standards

◊ 4th sub-bullet: Removed low-risk, intermediate-risk, and high-risk disease

CSLL-D 1 of 5

• CLL/SLL without del(17p)/TP53 mutation, First-line therapy

Ibrutinib (continuous)(category 1) moved from Other recommended to Useful in certain circumstances

• Venetoclax + Ibrutinib (fixed duration) changed from category 2A to category 1 recommendation.

• Venetoclax + Ibrutinib (MRD-guided) added as a new treatment option with a category 1 recommendation.

Useful in certain circumstances

◊ 3rd bullet revised: Consider only when cBTKi and BCL2i are not available or not feasible contraindicated or rapid disease debulking needed." (Also for CLL/SLL with del(17p)/TP53 mutation)

◊ Added: Venetoclax/Zanubrutinib (MRD-guided) (category 2A)

◊ FC (Fludarabine/Cyclophosphamide) + Rituximab moved from "Consider for IGHV-mutated CLL in patients aged <65 y without significant comorbidities" to

"Consider only when cBTKi and BCL2i are not available or not feasible."

◊ High-dose methylprednisolone (HDMP) + anti- CD20 mAb (category 2B; category 3 for patients <65 y without significant comorbidities) moved from "Consider only when cBTKi and BCL2i are not available or not feasible" and listed under Useful in certain circumstances (also for CLL with del (17p)/TP53 mutation)

• CLL/SLL with del(17p)/TP53 mutation, First-line therapy

Preferred

◊ Added: Venetoclax/Zanubrutinib (MRD-guided) (category 2A)

◊ Added: Venetoclax/acalabrutinib + Obinutuzumab (MRD-Guided) (category 2A)

◊ Removed: Venetoclax/Acalabrutinib (fixed duration) .

Ibrutinib (continuous)(category 1) moved from Other recommended to Useful in certain circumstances

CSLL-D 2 of 5

• CLL/SLL with or without del(17p)/TP53 mutation

For both "Second-line and Subsequent therapy" and "Therapy For Relapsed or Refractory Disease After Prior cBTKi-Based and BCL2i-Containing Regimens" the

suggested treatment recommendations for CLL/SLL with and without del(17p)/TP53 mutation were combined.

Second-line or subsequent therapy

◊ Preferred, Pirtobrutinib changed from a category 2A to category 1

Therapy for Relapsed or Refractory Disease After Prior cBTKi-and Venetoclax-Based Regimen

◊ Chimeric antigen receptor (CAR) T-cell therapy - Lisocabtagene maraleucel (CD19-directed) revised by adding "± Ibrutinib" (category 2A recommendation)

◊ Pirtobrutinib (if not previously given) changed from a category 2A to category 1

• Statement revised: Venetoclax ± anti-CD20 mAb (obinutuzumab preferred) or venetoclax + cBTKi is a treatment option for relapse after a period of remission. Single

agent venetoclax (continuous) can also be considered a treatment option for relapse after a period of remission.

Updates in Version 1.2026 of the NCCN Guidelines for CLL/SLL from Version 3.2025 include:

NCCN Guidelines Version 2.2026

Authors

NCCN Guidelines Index Table of Contents Discussion

Updates in Version 1.2026 of the NCCN Guidelines for CLL/SLL from Version 3.2025 include:

CSLL-D 3 of 5 • Footnote g added: Time-limited treatment with BCL2i + cBTKi ± CD20 mAb may be fixed-duration or MRD-guided (based on uMRD-stopping criteria as described in clinical trials). See MRD Assessment (CSLL-E). For MRD-guided treatment, serial MRD evaluations using either flow cytometry (MRD flow) or NGS with a limit of detection (sensitivity) of at least 10 -4 CLL cells in blood or bone marrow may be performed every 3 to 6 months during active treatment as directed in the published trial results that support MRD-guided treatment regimens. See the publications for details on MRD assessments and management, including criteria for treatment discontinuation (CSLL-E 2 of 2). Either flow cytometry (MRD flow) or NGS are acceptable assays as long as the limit of detection (sensitivity) is achieved. When assessing MRD in blood, be aware that anti-CD20 monoclonal antibody administration within the prior 3 months can lead to false undetectable MRD (uMRD) status, particularly in blood.

CSLL-E 2 of 2 • Added Table 1: MRD-guided treatment regimens

Histologic Transformation (Richter) HT-1 • Diagnosis Essential, ◊ 1st bullet revised from "Excisional biopsy, if lymph node is accessible. Biopsy the lesion with highest standardized uptake value (SUV) on PET scan" to "An excisional or incisional biopsy of the suspected lymph node/lesion with an increased standardized uptake value (SUV) on FDG-PET/CT scan (particularly if discordant with the remaining disease)" ◊ 2nd bullet revised: Bone marrow aspirate with biopsy can be pursued if lymph node excisional or incisional biopsy material is nondiagnostic. Useful under certain circumstances, added: should be done with CLL/SLL specimen -blood or bone marrow aspirate) • Footnotes Footnote a added: Biopsy of lesions with SUV ≥5 is recommended if there is high clinical suspicion or the lesion has a differentially higher uptake than the remaining disease. (Added to HT-2) Footnote f revised by adding: Comparative clonality testing for immunoglobulin heavy chain (IGH) gene rearrangement should be done on defined CLL tissue and biopsy specimen of transformed tissue to establish clonal relatedness between CLL/SLL and DLBCL cells (either using commercial NGS-based assay or lab-based assay for IGH clonality). (Added to HT-2 and HT-3)

References

NCCN Guidelines Version 2.2026

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

NCCN Guidelines Index Table of Contents Discussion

UPDATES

Updates in Version 1.2026 of the NCCN Guidelines for CLL/SLL from Version 3.2025 include:

Histologic Transformation (Richter)

HT-2

• Workup

Essential,

◊ 1st bullet revised: Whole body FDG-PET/CT scan (preferred) or C/A/P CT with contrast of diagnostic quality (if PET/CT scan not feasible)

◊ 2nd bullet added: An excisional or incisional biopsy of the suspected lymph node/lesion with an increased SUV on FDG-PET/CT scan (particularly if discordant

with the remaining disease)

◊ 3rd bullet added: FNA biopsy alone is not suitable inadequate for the initial diagnosis of histologic transformation. In certain circumstances, when a lymph node/lesion is not easily accessible for excisional or incisional biopsy, a combination of core needle biopsy and FNA biopsy (multiple biopsies may be required) in

conjunction with appropriate ancillary techniques for the differential diagnosis (ie, IHC, flow cytometry) may be sufficient for diagnosis

HT-3

• Algorithm extensively revised with recommendations separated by "Untreated CLL or Clonally unrelated" and " Previously treated CLL and clonally related or Clonal

relation unknown"

HT-A 1 of 3

• Suggested Treatment Regimens

Chemoimmunotherapy,

◊ 5th bullet added: Patients who are frail or patients with poor left ventricular ejection fraction (LVEF): See NCCN Guidelines for B-Cell Lymphomas (First-line

therapy for DLBCL (BCEL-C): Patients with Poor LVEF or Very Frail Patients and Patients >80 Years of Age with Comorbidities)

Non-CIT based regimens

◊ ICI-based regimens, added: Venetoclax + Atezolizumab + Obinutuzumab (category 2A)

◊ Bispecific antibody therapy, added:

– Epcoritamab-bysp (category 2A)

– Glofitamab-gxbm (category 2A)

◊ CAR T-cell therapy, added:

– Axicabtagene ciloleucel (category 2A)

– Tisagenlecleucel (category 2A)

HT-A 2 of 3

• Footnote a, second sentence revised from, "An FDA-approved biosimilar is an appropriate substitute for rituximab" to "An FDA-approved biosimilar is an appropriate substitute for any recommended systemic biologic therapy in the NCCN Guidelines"

• Footnote e added: It is reasonably safe to combine cBTKi (given continuously for disease control) with CIT regimens without the addition of other targeted agents.

• Footnote g added: ICI-based combination regimens with cBTki used for prior therapy are not appropriate for patients who are intolerant to or have disease progression on the same cBTKi.

• Footnote h added: Atezolizumab and hyaluronidase-tqjs subcutaneous injection may be substituted for IV atezolizumab. Atezolizumab and hyaluronidase-tqjs has

different dosing and administration instructions compared to atezolizumab for intravenous infusion.

• Footnote i added: Nivolumab and hyaluronidase-nvhy subcutaneous injection may be substituted for IV nivolumab. Nivolumab and hyaluronidase-nvhy has different

dosing and administration instructions compared to IV nivolumab.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 2.2026 Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

NCCN Guidelines Index Table of Contents Discussion

DIAGNOSIS

ESSENTIAL:

* Hematopathology review of peripheral blood smear and all slides with at least one paraffin block representative of the tumor, if the diagnosis was made on a lymph node or bone marrow biopsy.

$\bullet$ Flow cytometry of blood is adequate for the diagnosis of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).

$\bullet$ CLL diagnosis requires the presence of monoclonal B lymphocytes ≥5 x 10$^{9}$/L in peripheral blood based on flow cytometry$^{a}$

◇ Adequate immunophenotyping to establish diagnosis by flow cytometry$^{b}$: kappa/lambda, CD19, CD20, CD5, CD23, CD10, CD200

◇ If flow cytometry is used to establish diagnosis, also include cytospin for cyclin D1 or fluorescence in situ hybridization (FISH) for t(11;4); t(11q; v) to exclude mantle cell lymphoma (MCL).

$\bullet$ Clonality of B cells should be confirmed by flow cytometry

$\bullet$ SLL diagnosis requires presence of lymphadenopathy and/or splenomegaly with monoclonal B lymphocytes ≤5 x 10$^{9}$/L in peripheral blood. SLL diagnosis should be confirmed by histopathology evaluation of lymph node biopsy

$\bullet$ Excisional or incisional biopsy, if lymph node is accessible. Fine-needle aspiration (FNA) biopsy alone is inadequate for the 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 may be required) in conjunction with appropriate ancillary techniques, such as FNA, may be sufficient for diagnosis.

$\bullet$ Bone marrow aspirate with biopsy can be pursued if peripheral blood and lymph node biopsy material are nondiagnostic.

◇ Adequate immunophenotyping to establish diagnosis by immunohistochemistry (IHC)$^{b}$: CD3, CD5, CD10, CD20, CD23, cyclin D1, LEF1, SOX1$^{c}$

$\bullet$ Absolute monoclonal B lymphocyte count$^{a}$

INFORMATIVE FOR PROGNOSTIC AND/OR THERAPY DETERMINATION$^{d}$:

* FISH to detect: +12; del(11q); del(13q); del(17p)

$\bullet$ TP53 sequencing

* CpG-stimulated metaphase karyotype for complex karyotype (CK)

$\bullet$ Molecular analysis to detect: Immunoglobulin heavy chain variable region gene (IGHV) mutation status

$\bullet$ Beta-2-microglobulin

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

Footnotes on CSLL-1A

NCCN Guidelines Version 2.2026

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

NCCN Guidelines Index Table of Contents Discussion

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

CSLL-1A

a Absolute monoclonal B lymphocyte count <5000/mm3 that persists more than 3 months in the absence of palpable adenopathy or other clinical features of

lymphoproliferative disorder is MBL. Cells of the same phenotype may be seen in reactive lymph nodes; therefore, diagnosis of SLL should only be made when

effacement of lymph node architecture is seen. Bone marrow examination is not helpful for the diagnosis of MBL.

b Typical immunophenotype: CD5+, CD23+, CD43+/-, CD10-, CD19+, CD20 dim, sIg dim+, and cyclin D1-. Note: Some cases may be sIg bright+ or CD23- or dim; some MCL may be CD23+; cyclin D1 immunohistochemistry or FISH for t(11;14) should be considered in all cases, especially for those with an atypical immunophenotype

(ie, CD23 dim or negative, CD20 bright, sIg bright). CD200 positivity may distinguish CLL from MCL, which is usually CD200-.

c LEF1 and SOX11 may be helpful in suspected cases of MCL that are cyclin D1-negative.d Prognostic Variables for CLL/SLL (CSLL-A).e Outside of clinical trials, CT scans are not required for diagnosis, serial monitoring, surveillance, routine monitoring of treatment response, or progression.

FOOTNOTES

NCCN Guidelines Version 2.2026

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

NCCN Guidelines Index Table of Contents Discussion

CSLL-2

f Refer to the NCCN Distress Thermometer and Problem List, which includes social determinants of health. See NCCN Guidelines for Distress Management (DIS-A).g Outside of clinical trials, CT scans are not required for diagnosis, serial monitoring, surveillance, routine monitoring of treatment response, or progression. CT scans

may be warranted for the evaluation of symptoms of bulky disease or for the assessment of risk for TLS prior to initiating venetoclax.

h Hepatitis B testing is indicated because of the risk of reactivation during treatment (eg, immunotherapy, chemoimmunotherapy [CIT], chemotherapy, targeted therapy). See Treatment and Viral Reactivation (CSLL-C 1 of 6). 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. If positive, check viral load and consult with a gastroenterologist.

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

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

WORKUP

ESSENTIAL:

• History and physical exam including measurement of size of liver and spleen and palpable lymph nodes

• Performance status

• B symptoms

• Complete blood count (CBC) with differential

• Comprehensive metabolic panel

• Beta-2-microglobulin

• Assess for distressf

USEFUL UNDER CERTAIN CIRCUMSTANCES:

• Quantitative immunoglobulins

• Serum protein electrophoresis (SPEP) with serum immunofixation electrophoresis (SIFE) to evaluate for monoclonal protein

• Reticulocyte count, haptoglobin, and direct antiglobulin test (Coombs)

• Chest/abdomen/pelvis (C/A/P) CT with contrast of diagnostic quality, if clinically indicatedg

• Uric acid

• Lactate dehydrogenase (LDH)

• Unilateral bone marrow aspirate and biopsy (may be informative for the diagnosis of

immune-mediated or disease-related cytopenias)

• Hepatitis Bh and C testing if treatment is contemplated

• Pregnancy testing in patients of childbearing age if systemic therapy or RT is planned

• Discussion of fertility preservationi

• Whole body FDG-PET/CT scan to direct nodal biopsy, if histologic transformation is

suspected. See HT-1.

SLL/Localized

(Lugano Stage I)

(CSLL-3)

CLL (Rai Stages 0–IV)

SLL (Lugano Stage II–IV)(CSLL-3)

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 2.2026

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

NCCN Guidelines Index Table of Contents Discussion

PRESENTATION$^{j}$

![graph TD\n A1[Locheional involve-site radiation therapy(ISRT)(if indicated)] --> A2[Observe]\n A2 --> A3[Evaluate for indications for treatment:m: Eligible for clinical trial Significant disease-related symptoms: Fatigue(severe) Drenching night sweats Unintentional weight loss(≥10% in previous 6 months) Fever without infection Threatened end-organ function Progressive, symptomatic, or bulky disease(spleen >6 cm below costal margin, lymph nodes >10 cm) Progressive thrombocytopenia,n,o Progressive anemia,n Steroid-refractory autoimmune cytopenias]\n A3 -->|indication present| A4[Prior to initiation of treatment, evaluate: FISH for del(17p) TP53 mutation status CpG-stimulated metaphase karyotypeIGHV mutation statusq Imaging as appropriate Bone marrow aspirate and biopsy as clinically indicated]\n A3 -->|No indication| A2\n A4 --> A5[First-line therapy(CSLL-4)]\n A6[SLL(Localized(Lugano Stage I)k] --> A1\n A7[SLL(Localized Stages II-IV)k] --> A3\n A8[CLL(Rai Stage 0-IV)k] --> A3\n](1/parseimages/figure9b3e5ddb00f34ee496ef1edfcac82d14_0_5.png)

Histologic transformation (Richter) $\rightarrow$ HT-1

e Outside of clinical trials, CT scans are not required for diagnosis, serial monitoring, surveillance, routine monitoring of treatment response, or progression.

j Supportive Care for Patients with CLL/SLL (CSLL-C).

k See Rai and Binet Classification Systems (CSLL-B 1 of 2) and Lugano Modification of Ann Arbor Staging System (CSLL-B 2 of 2).

$^{1}$ See NCCN Guidelines for B-Cell Lymphomas, Principles of Radiation Therapy for additional details.

$^{m}$ Absolute lymphocyte count (ALC) alone is not an indication for treatment in the absence of leukostasis, which is rarely seen in CLL.

$^{n}$ Platelet counts >100,000/µL are typically not associated with clinical risk.

$^{0}$ Select patients with mild, stable cytopenia (ANC <1000/µL, Hgb <11 g/dL, or platelet <100,000/µL) may continue to be observed. Other causes of anemia/thrombocytopenia (eg, autoimmune disorders, vitamin/iron deficiency) should be excluded.

$^{p}$ Consider next generation sequencing (NGS)-based clonality testing for measurable residual disease (MRD) assessment if MRD-guided treatment is planned and MRD flow is not being used for MRD assessment. See CSLL-E.

$^{9}$ IGHV mutation status does not change over time and analysis does not need to be repeated if previously done prior to initiation of treatment.

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

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![graph TD\n A1[Time-limited treatmenta BCL2 inhibitor(BCL2i) + anti-CD20 mAb See Suggested Regimens(CSLL-D 1 of 6)] --> A2[BCL2i intolerancea]\n A1 --> A4[Response after completion of treatment]\n A1 --> A10[Progression on treatmentw,x]\n A2 --> A3[cBTKi]\n A3 --> A6[Relapsed or Refractory disease after prior therapy with cBTKi or ncBTKi.v and BCL2i-containing regimens]\n A4 --> A5[Observe until relapse with indication for treatment]\n A5 --> A6\n A5 --> A7[BCL2i-containing regimensbb or cBTKi]\n A6 --> A7\n A7 --> A8[cBTKi]\n A7 --> A6\n A8 --> A6\n A9[Progression on treatmentw,x] --> A3\n A10 --> A3\n A11[BCL2 inhibitor(BCL2i) + cBTKi ± anti-CD20 mAb See Suggested Regimens(CSLL-D 1 of 6)] --> A12[BCL2i intolerancea]\n A11 --> A14[cBTKi intolerancea]\n A11 --> A16[Response after completion of treatment]\n A11 --> A20[Progression on BCL2i + cBTKiᵇ,w,x,y]\n A12 --> A13[cBTKi]\n A13 --> A6\n A14 --> A15[BCL2i + alternate cBTKi or BCL2i ± anti-CD20 mAb]\n A15 --> A6\n A16 --> A17[Observe until relapse with indication for treatment]\n A17 --> A18[BCL2i-containing regimensbb or cBTKi]\n A18 --> A6\n A18 --> A6\n A19[Noncovalent(reverseable) BTKi(ncBTKi)] --> A6\n A20 --> A19\n A21[Continuous treatment Covariant BTK inhibitor(cBTKi-based regimens)± anti-CD20 mAb] --> A22[CSLL-5]\n A22 --> A6\n](1/parseimages/figurebe2ed21984284cf9880f9076fbe91c24_0_4.png) Note: All recommendations are category 2A unless otherwise indicated.

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FIRST-LINE THERAPYr, s

RESPONSE TO THERAPY$^{U}$

SECOND-LINE THERAPYr,s,v,z,aa,bb

THIRD-LINE THERAPYr,s,v,z,aa,bb

Suggested Regimens (CSLL-D 2 of 6)

![graph TD\n A1[Continuous treatment Covariant BTK inhibitor(cBTKi-based regimens)±anti-CD20 mAb See Suggested Regimens(CSLL-D 1 of 6)] --> A2[Response]\n A1 --> A3[Progression while on treatment<w,x>]\n A1 --> A4[Intoleranceν]\n A2 --> A5[Continue treatment with the same cBTKic until intolerance and/or progression]\n A3 --> A6[BCL2i-containing regimens or ncBTKi]\n A4 --> A7[Alternate cBTKi or ncBTKi]\n A4 --> A8[Alternate or ncBTKi or BCL2i-containing regimens]\n A5 --> A6\n A6 --> A9[Relapsed or refractory disease after prior therapy with cBTKi or ncBTKi-y and BCL2i-containing regimens]\n A7 --> A10[BCL2i-containing regimens]\n A8 --> A9\n A9 --> A11[CSLL-5A]\n](1/parseimages/figure3e75bfbcfeac4a5e819fa1099ae66df0_0_9.png) Sequencing therapy following CIT as first-line therapy (See CSLL-D 1 of 6 for suggested treatment regimens): Observation until relapse with indications for treatment is recommended for response after completion of CIT. Time-limited treatment with BCL2i-containing regimens or cBTKi-based regimens are options for relapse after a period of remission or progression on treatment. See CSLL-D 2 of 6 for suggested treatment regimens for second-line and subsequent therapy.

Footnotes on CSLL-5A

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

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RELAPSED OR REFRACTORY THERAPY$^{r,s}$

![graph TD\n A1[Relapsed or Refractory disease after prior therapy with cBTKi or ncBTKi-y and BCL2i-containing regimens] --> A2[Clinical trial or CAR T-cell Therapy(CSLL-D 2 of 6) or ncBTKi(if not previously given)(CSLL-D 2 of 6) or Other Recommended Regimens(CSLL-D 2 of 6; Therapy for relapsed or refractory disease after BTKi- and BCL2i-containing regimens) or Consider allogeneic hematopoietic cell transplant(HCT) if without significant comorbidities]\n```\n](1/parseimages/figure91eee3f18ba64f47b1b2579ea2bef542_0_5.png)

FOOTNOTES FOR CSLL-4 and CSLL-5

* [Clinical trial](#) is preferred when available.

$^{s}$ Supportive Care for Patients with CLL/SLL (CSLL-C).

$^{t}$ Time-limited treatment with BCL2i + cBTKi ± CD20 mAb may be fixed-duration or MRD-guided (based on undetectable MRD [uMRD]-stopping criteria as described in clinical trials). See MRD Assessment (CSLL-E).

$^{u}$ See [Discussion] in wJCL response criteria.

$\blacktriangledown$ Adverse reactions can be managed by following the recommended dose modifications in the FDA-approved package insert (https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm).

* If progression with indication for subsequent therapy: Re-evaluate with FISH for del(17p)/TP53 mutation status and CpG-stimulated metaphase karyotype, prior to initiation of subsequent therapy.

* Consider the possibility of histologic transformation in patients with progressive disease. Biopsy is recommended to confirm histologic transformation. If histologic transformation see HT-1.

$^{7}$ Testing for BTK and PLCG2 mutations may be useful in patients with disease progression or no response while on BTKi therapy including if poor adherence is considered as a possible cause. BTK and PLCG2 mutation status alone is not an indication to change treatment in absence of disease progression. Alternate cBTKi (acalabrutinib, ibrutinib, or zanubrutinib) could be considered for intolerance in absence of disease progression. ncBTKi can be considered for resistance or intolerance to prior cBTKi-based regimens.

$^{2}$ In patients with disease responding to therapy: Continue the same BTKi until progression and/or intolerance. At time of disease progression, transition to next therapy as soon as possible. Treatment-free interval should be as short as possible. It is safe to overlap with venetoclax while on a BTKi. If treated with BCL2i-containing time-limited treatment, observe until relapse with indications for retreatment.

$^{aa}$ Patients with CLL/SLL without del(17p)/TP53 mutation who discontinue a cBTKi for intolerance can remain off treatment (if there is no disease progression) for an extended period of time and alternate BTKi can be reinitiated when symptomatic.

$^{bb}$ Venetoclax ± anti-CD20 mAb (obinutuzumab preferred) or venetoclax + cBTKi is a treatment option for relapse after a period of remission. Single agent venetoclax (continuous) can also be considered as a treatment option for relapse after a period of remission.

$^{CC}$ In patients with no intolerance, cBTKi can be continued until disease progression while following recommended dose modification guidance as needed.

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

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PROGNOSTIC VARIABLES IN PATIENTS WITH CLL/SLL

Table 1: Cytogenetics and gene mutations

|Method of Detection|Prognostic Variable|Clinical $Association^{a}$| |---|---|---| |Interphase cytogenetics (FISH)|Del(13q) as a sole abnormality|Favorable prognosis: longest median overall survival (OS) in patients treated with chemoimmunotherapy (CIT).$^{1}$| |Interphase cytogenetics (FISH)|Trisomy 12|Intermediate prognosis for time-to-first treatment (TTFT) in patients with newly diagnosed CLL; and intermediate OS in patients treated with chemoimmunotherapy.$^{1}$| |Interphase cytogenetics (FISH)|None|Intermediate prognosis for TTFT in patients with newly diagnosed CLL; and intermediate OS in patients treated with chemoimmunotherapy.$^{1}$| |Interphase cytogenetics (FISH)|Del(11q)|Shortened TTFT, and shorter median OS with chemoimmunotherapy.$^{1}$| |Interphase cytogenetics (FISH)|Del(17p)$^{b}$|Inferior response, shorter treatment-free interval, and inferior survival with chemoimmunotherapy.$^{1-3}$ Good responses but shorter progression-free survival (PFS) and OS with both time-limited venetoclax-based regimens$^{4,5}$ and covalent BTK inhibitor (cBTKi).$^{6-10}$| |DNA sequencing|$IGHV^{c}$ Mutated: >2% mutation or <98% homology with germline gene sequence Unmutated: ≤2% of mutation or ≥98% homology with germline gene sequence)|Unmutated IGHV is associated with shorter TTFT and PFS with chemoimmunotherapy and time-limited venetoclax-based regimens, compared to mutated IGHV.$^{3,5,11-15}$.Overall response rates are not correlated with IGHV mutation status in patients treated with cBTKi or time-limited venetoclax-based regimens.$^{6-10}$.PFS and OS are not correlated with IGHV mutation status in patients treated with cBTKi.$^{6,7,16}$| |DNA sequencing|$TP53 mutation^{d}$ with del(17p)|Shorter PFS and OS with chemoimmunotherapy,$^{e,17-20}$ time-limited venetoclax-based regimens$^{4,5}$ and cBTKi.$^{6-10}$ Increased resistance to chemoimmunotherapy and targeted therapies; significantly shortened TTFT and time-to-next treatment (TTNT) and potentially increased risk for Richter transformation. Low burden variant allele frequencies (VAF, <10%) may behave similar to wild type (WT).$^{21,22}$| |DNA sequencing|$TP53 mutation^{d}$ without del(17p)|TP53 mutation in the absence of del(17p) is associated with shortened PFS and OS. However, PFS and OS outcomes on treatment with TP53 mutation but in absence of del(17p) may be more favorable than with concurrent TP53 mutation and del(17p).$^{18,23}$| |DNA sequencing|Other Significant Mutations|See Table 2 and Table 3 (CSLL-A 3 of 5)|

Footnotes

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

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PROGNOSTIC VARIABLES IN PATIENTS WITH CLL/SLL

Table 1: Cytogenetics and gene mutations (continued)

|Method of Detection|Prognostic Variable|Clinical $Association^{a}$| |---|---|---| |CpG-stimulated metaphase $karyotype^{f}$|Complex karyotype (CK) (≥3 unrelated clonal chromosome abnormalities in more than one cell on karyotype)|Inferior survival and shorter time to disease progression with chemoimmunotherapy, time-limited venetoclax based regimens, and cBTKi.$^{24-27}$ High CK (≥5 unrelated chromosomal abnormalities) is an adverse prognostic factor independent of clinical stage, IGHV mutation status, del(17p) and/or TP53 mutation.$^{28,29}$| |Serum test|Beta-2 Microglobulin (B2M) (can be affected by renal dysfunction in a CLL- independent manner)|Correlates with CLL/SLL disease burden and retains independent prognostic significance in multivariate $models^{30,31}$ Elevated $levels^{9}$ are associated with overall response, treatment free intervals, and OS in patients treated with frontline chemoimmunotherapy^{32}$ Reduction in levels associated with prolonged PFS in patients treated with ibrutinib$^{33,34}$|

References on CSLL-A (4 of 5) and (5 of 5)

a This table provides the impact of molecular and cytogenetic variables on time-to-first treatment and survival for patients treated with chemoimmunotherapy and/or small molecule inhibitors. Prognostic markers and scoring systems (including CLL-IPI) can aid in integrating multiple variables, but OS can be underestimated for cohorts treated prior to the availability of current targeted/novel therapies.

b Prognostic significance may be dependent on the percentage of malignant cells with the deletion; prognosis is more favorable when the percentage of cells with del(17p) is low (Tam CS, et al. Blood 2009;114:957-964; Van Dyke DL, et al. Br J Haematol 2016;173:105-113). Patients with del(17p) often also have a concurrent TP53 mutation.

c IGHV gene usage involving VH3-21 is considered higher risk regardless of the IGHV mutation status (Tobin G, et al. Blood 2002;99:2262-2264; Oscier DG, et al. Blood 2002;100:1177-1184; Oscier D, et al. Haematologica 2010;95:1705-1712). IGHV4-39 usage is associated with a higher risk for Richter's transformation (Rossi D, et al. Blood 2007;11: Abstract 3086).

d Patients can have TP53 mutations independent of del(17p). TP53 mutation status also provides additional prognostic information in addition to the cytogenetic abnormalities detected by FISH.

e Hazard ratios (HR) for PFS and OS with TP53 mutation on treatment versus TP53 WT are higher with chemoimmunotherapy compared to targeted therapies.

f Conventional metaphase FISH is difficult in CLL due to the very low in vitro proliferative activity of the leukemic cells. CK is based on results of metaphase karyotyping of CpG-stimulated CLL cells. Interphase FISH is the standard specific chromosomal abnormalities that may have prognostic significance. CpG oligonucleotide stimulation can be utilized to enhance metaphase cytogenetics.

$^{9}$ Cutoff values vary between institutions and studies. CLL-IPI utilizes a cutoff of >3.5 mg/L; other studies use a cutoff of 4 mg/L in patients treated with chemoimmunotherapy.

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

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Table 2: Baseline and acquired gene mutations

|Mutated Gene|Clinical Association| |---|---| |ATM35-38|Shorter TTFT, PFS, TTNT and OS with CIT compared to WT| |BIRC336,39,40|Shorter TTNT, PFS with CIT compared to WTMay be more sensitive to BCL2i-containing regimens| |NOTCH14,36,41,42|Shorter TTFT and PFS irrespective of the IGHV mutation status and shorter TTNT with CIT compared to WTShorter OS in historical cohortsCorrelated with higher risk for Richter transformation| |SF3B136,43|Shorter TTFT and OS with CIT compared to WT| |TP53|See Table 1 (CSLL-A 1 of 5)|

Table 3: Gene mutations associated with resistance to targeted therapies

|Mutated Gene|Clinical Association| |---|---| |BTK (C481, L528, A428D, and T474)$^{27,44-46}$|BTK C481 and BTK A428D mutations have been detected in patients with disease progressing on cBTKiBTK L528 or T474 mutations have been detected in patients with disease progressing on cBTKi and noncovalent (reversible) BTKi (ncBTKi)| |$CARD11^{47}$|Identified in patients with disease progressing on BTK inhibitors| |$PLCG2^{27,44-47}$|Identified in patients with disease progressing on BTK inhibitors| |BCL2 (G101V and $D103Y$)$^{48,49}$|Identified in patients with disease progressing on venetoclax|

References on CSLL-A (4 of 5) and (5 of 5)

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

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Authors

Keywords

References

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Abstract

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References

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CLL STAGING SYSTEMS

Rai Systemª

|Stage|Description|Modified Risk Status| |---|---|---| |0|Lymphocytosis, lymphocytes in blood >5 x 10°/L clonal B cells and/or >40% lymphocytes in the bone marrow|Low| |I|Stage 0 with enlarged node(s)|Intermediate| |II|Stage 0-I with splenomegaly, hepatomegaly, or both|Intermediate| |III|Stage 0-II with hemoglobin <11.0 g/dL or hematocrit <33%|High| |IV|Stage 0-III with platelets <100,000/mm³|High|

Binet Systemb

|Stage|Description| |---|---| |A|Hemoglobin ≥10 g/dL and Platelets ≥100,000/mm³ and <3 enlarged areas| |B|Hemoglobin ≥10 g/dL and Platelets ≥100,000/mm³ and ≥3 enlarged areas| |C|Hemoglobin <10 g/dL and/or Platelets <100,000/mm³ and any number of enlarged areas|

ª This research was originally published in Blood. Rai KR, Sawitsky A, Cronkite EP, et al. Clinical staging of chronic lymphocytic leukemia. Blood 1975;46:219-234. © The American Society of Hematology.

b From: Binet JL, Auquier A, Dighiero G, et al. A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis. Cancer 1981;48:198-206.

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

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SLL STAGING SYSTEM Lugano Modification of Ann Arbor Staging System$^{c}$ (for primary nodal lymphomas)

|$Stage^{d}$|$Involvement^{f}$|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 $bulky^{e}$|Il 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|

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.

c Extent of disease is determined by FDG-PET/CT for avid lymphomas and CT for non-avid histologies.

d Categorization of A versus B has been removed from the Lugano Modification of Ann Arbor Staging System.

e Whether stage II bulky is treated as limited or advanced disease may be determined by histology and a number of prognostic factors.

f Note: Tonsils, Waldeyer's ring, and spleen are considered nodal tissue.

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

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SUPPORTIVE CARE FOR PATIENTS WITH CLL/SLL

Anti-infective Prophylaxis

* Recommended during treatment and thereafter (if tolerated) for patients receiving phosphoinositide 3-kinase (PI3K) inhibitors, purine analog- or bendamustine-based CIT, and/or alemtuzumab > Herpes virus prophylaxis with acyclovir or equivalent

$\bullet$ Pneumocystis jiroveci pneumonia (PJP) prophylaxis with sulfamethoxazole/trimethoprim or equivalent

* Consider PJP and varicella zoster virus (VZV) prophylaxis in patients at increased risk for opportunistic infection and receiving BTKi therapy. Monitor for fungal infection.

* Monitor blood counts and consider growth factor support or fluoroquinolone and/or fungal prophylaxis for the management of venetoclax-induced neutropenia.

$\bullet$ Hepatitis B virus (HBV) and cytomegalovirus (CMV) prophylaxis and monitoring is recommended for patients at high risk. See Viral Reactivation below.

Viral Reactivation

HBV:

$\bullet$ Hepatitis B surface antigen (HBsAg) and Hepatitis B core antibody (HBcAb) testing for all patients receiving therapy $\bullet$ Quantitative hepatitis B viral load by quantitative RT-PCR (qPCR) and surface antibody only if one of the screening tests is positive

$\bullet$ Patients receiving intravenous 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 treatment. If there is active disease (qPCR+), 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.ª Avoid lamivudine due to risks of resistance development.

$\bullet$ Other antivirals including adefovir, telbivudine, and tenofovir are proven active treatments and are acceptable alternatives.

Viral Reactivation (continued)

$\bullet$ Monitor hepatitis B viral load with qPCR monthly through treatment and every 3 months thereafter.

$\bullet$ If viral load is consistently undetectable, treatment is considered prophylactic.

$\bullet$ If viral load does not drop or previously undetectable qPCR becomes positive, consult hepatologist.

$\bullet$ Maintain prophylaxis up to 12 months after oncologic treatment ends.

◇ Consult with hepatologist for duration of therapy in patient with active HBV.

Hepatitis C virus (HCV):

* Evidence from large epidemiology studies, molecular biology research, and clinical observation supports an association of HCV and B-cell non-Hodgkin lymphoma (NHL). Direct-acting antiviral (DAA) agents for chronic carriers of HCV with genotype 1 demonstrated a high rate of sustained viral responses.

$\blacktriangleright$ Low-grade B-cell NHL

$\bullet$ According to the American Association for the Study of Liver Diseases, combined therapy with DAA should be considered in asymptomatic patients with HCV genotype 1 since this therapy can result in regression of lymphoma.

CMV reactivation in patients with previous CMV infection (seropositive):

* Clinicians must be aware of the high risk of CMV reactivation in patients receiving PI3K inhibitors or alestumuzamab. The current recommendations for appropriate screening are controversial. CMV viremia should be measured by PCR at least every 4 weeks. Some clinicians use ganciclovir (oral or IV) pre-emptively if viremia is present; others use ganciclovir only if viral load is rising. Consultation with an infectious disease expert may be necessary.

John Cunningham virus (JCV):

$\bullet$ Progressive multifocal leukoencephalopathy (PML) related to JCV can be seen in patients receiving treatment.

Continued

a Huang YH, et al. J Clin Oncol 2013;31:2765-2772; Huang H, et al. JAMA 2014;312:2521-2530.

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CSLL-C 2 OF 6

SUPPORTIVE CARE FOR PATIENTS WITH CLL/SLL

Precautions when initiating treatment or transitioning to next therapy for disease progression while on treatment

• Workup prior to new/next treatment to assess tumor lysis syndrome (TLS) risk and additional management needs:

CBC with ALC

Staging CT scan to evaluate extent of lymphadenopathy if using a BCL2i-based regimen or if concern for bulky adenopathy not accessible

by physical exam and currently using a BTKi-based regimen

Bone marrow evaluation if clinically indicated

• Agent considerations

BTK-inhibitor (covalent or noncovalent BTKi; cBTKi or ncBTKi)

◊ Potential for significant transient increase in ALC on initiation due to egress of lymphocytes from tissue microenvironment into

peripheral blood

◊ Low risk for TLS

◊ If transitioning from cBTKi to BCL2i or ncBTKi, can see flare with abrupt discontinuation and time off treatment, hence should minimize time off treatment between drugs; and when transitioning from a cBTKi or ncBTKi to BCL2i, consider overlapping of BTKi and BCL2i

during the BCL2i ramp-up until disease control is achieved

BCL2-inhibitor (BCL2i)

◊ TLS risk – see venetoclax prescribing information for risk assessment, mitigation, and management (https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm)

◊ For patients with progression on prior BTKi, continue the BTKi through the venetoclax ramp-up to reduce the risk of tumor flare and consider administering obinutuzumab prior to venetoclax for cytoreduction

◊ TLS prophylaxis for hyperuricemia with allopurinol, febuxostat, and rasburicase according to prescribing information and institutional standards

◊ Consider hospitalization for TLS monitoring, mitigation, and management according to venetoclax prescribing information

◊ Potassium may be falsely elevated due to pseudohyperkalemia, particularly in patients with high ALC; this should be evaluated and

clarified prior to initiation of therapy. Venetoclax should not be initiated unless a reliable measurement of potassium can be obtained.

Methods to avoid pseudohyperkalemia include a fresh stick without a tourniquet, sample maintained on ice and taken directly to the lab,use of a blood gas tube, obtaining potassium result from a blood gas, or whole blood potassium.

Anti-CD20 mAb (obinutuzumab)

◊ TLS risk similar in type to chemoimmunotherapy

◊ First-infusion reaction can be mitigated by administration of corticosteroids for 1 to 3 days prior to the initiation of obinutuzumab

◊ High-dose methylprednisolone (eg, 1000 mg daily for 3 doses) has been effective at reducing obinutuzumab first-infusion-related

reactions and reducing bulk of disease

◊ Infection risk

▪ See obinutuzumab prescribing information for further guidance (https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm),

including guidance on holding antihypertensive medications surrounding the initial dose

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SUPPORTIVE CARE FOR PATIENTS WITH CLL/SLL

Tumor Lysis Syndrome (TLS)

* Laboratory hallmarks of TLS:

$\bullet$ High serum creatinine

$\bullet$ High potassium

$\bullet$ High uric acid

$\bullet$ High phosphorous

$\bullet$ Low calcium

$\bullet$ High LDH

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:

* 6 Patients receiving treatment with venetoclax, CIT, lenalidomide, and obinutuzumab

* * Progressive disease after small-molecule inhibitor therapy

$\bullet$ Bulky (>5 cm) lymph nodes

* Spontaneous TLS

$\bullet$ Elevated white blood cell (WBC) count

$\bullet$ Pre-existing elevated uric acid

* Renal disease or renal involvement by tumor

* Treatment of TLS:

$\bullet$ For BCL2i-associated TLS, see venetoclax prescribing information

$\bullet$ TLS is best managed if anticipated and management is started prior to treatment.

$\bullet$ Centerpiece of treatment includes:

* Rigorous hydration

* Management of hyperuricemia

* Frequent monitoring of electrolytes and aggressive correction (essential)

$\bullet$ First-line and at retreatment for hyperuricemia

$\bullet$ ^{Allopurinol, febuxostat, and rasburicase according to prescribing information and institutional standards

$\bullet$ 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.

$\bullet$ Rasburicase is indicated for patients with any of the following risk factors (Doses of 3-6 mg are usually effective.$^{b}$ One dose of rasburicase is frequently adequate. Re-dosing should be individualized):

* Urgent need to initiate therapy in a patient with bulky disease

$\bullet$ Situations where adequate hydration may be difficult or impossible

$\bullet$ Acute renal failure

$\blacktriangleright$ If TLS is untreated, its progression may cause acute kidney failure, cardiac arrhythmias, seizures, loss of muscle control, and death.

b There are data to support that fixed-dose rasburicase is very effective in adult patients.

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CSLL-C

4 OF 6

SUPPORTIVE CARE FOR PATIENTS WITH CLL/SLL

Autoimmune Cytopenias• Autoimmune hemolytic anemia (AIHA): Diagnosis with reticulocyte count, haptoglobin, and direct antiglobulin test (Coombs).

AIHA that develops in the setting of treatment with fludarabine: Stop, treat, and avoid subsequent fludarabine.• Immune thrombocytopenic purpura (ITP): Evaluate bone marrow for cause of low platelets.• Pure red cell aplasia (PRCA): Consider bone marrow evaluation and testing for parvovirus B19, herpesviruses, and drug effects.• Treatment: Corticosteroids, rituximab, IVIG, cyclosporin A, splenectomy, eltrombopag, or romiplostim (ITP), or BTKi-based therapy for steroid-refractory or recurrent AIHA.

Blood Product Support• Transfuse according to institutional or published standards.• Irradiate all blood products to avoid transfusion-associated graft-versus-host disease (GVHD).

Cancer Screening• Patients with CLL/SLL have a higher risk of developing secondary cancers, including melanoma and non-melanoma skin cancers.c• Risk factors for skin cancers include inability to tan, fair skin that sunburns easily, and a history of intensive sun exposure at a young age.Annual dermatologic skin screening is recommended.• Age appropriate screening guidelines should be closely followed for breast, cervical, colon, and prostate cancers.

Complications of mAb Therapy

• Obinutuzumab infusion-related reactions (initial reaction and reactions in patients with high ALC [>100,000 μL]) can be severe and patients should be monitored closely. Consider premedication with corticosteroid, antihistamine, and acetaminophen. Monitoring and prophylaxis for TLS is recommended for patients with high ALC.

• Rare complications such as mucocutaneous reactions including paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoiddermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis can occur. Consultation with a dermatologist is recommended formanagement of these complications. Re-challenge with the same mAb in such settings is not recommended. It is unclear if re-challengewith alternative anti-CD20 mAb poses the same risk of recurrence. An alternative anti-CD20 mAb could be used for patients with intolerance(including those experiencing severe hypersensitivity reactions requiring discontinuation of chosen anti-CD20 mAb).

Rituximab Rapid Infusion and Subcutaneous Administration

• If no severe infusion reactions were experienced with prior cycle of rituximab, a rapid infusion over 90 minutes can be used.

• Rituximab and hyaluronidase human injection for subcutaneous use may be used in patients who have received at least one full dose of a

rituximab product by intravenous route.

c Mehrany K, et al. Dermatol Surg 2005;31:38-42; Mehrany K, et al. Arch Dermatol 2004;140:985-988; Mehrany, K et al. J Am Acad Dermatol 2005;53:1067-1071.

NCCN Guidelines Version 2.2026

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

NCCN Guidelines Index Table of Contents Discussion

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

CSLL-C 5 OF 6

SUPPORTIVE CARE FOR PATIENTS WITH CLL/SLL

Recurrent Sinopulmonary Infections (requiring IV antibiotics or hospitalization)

• Antimicrobials as appropriate

• Evaluate serum IgG, if <500 mg/dL

Begin monthly IVIG 0.3–0.5 g/kg or may substitute a subcutaneous immunoglobulin (SCIG) product given weekly at appropriately adjusted

equivalent doses

Adjust dose/interval to maintain nadir level of approximately 500 mg/dL

Thromboprophylaxis

• Recommended for prevention of thromboembolic events in patients receiving lenalidomide:

Aspirin 81 mg PO daily if platelets above 50 x 1012/L

Patients already on anticoagulants, such as warfarin, do not need aspirin

• Note that the above may differ from the NCCN Guidelines for Cancer-Associated Venous Thromboembolic Disease in which the

recommendations with lenalidomide pertain only to patients with multiple myeloma

Tumor Flare Reactions

• Management of tumor flare is recommended for patients receiving lenalidomide

• Painful lymph node enlargement or lymph node enlargement with evidence of local inflammation, occurring with treatment initiation; may

also be associated with spleen enlargement, low-grade fever, and/or rash

• Treatment:

Steroids (eg, prednisone 25–50 mg PO daily for 5–10 days)

Antihistamines for rash and pruritus

• Prophylaxis:

Consider in patients with bulky lymph nodes (>5 cm)

Steroids (eg, prednisone 20 mg PO daily for 5–7 days followed by rapid taper over 5–7 days)

Bleeding and Hemorrhage Risk with BTKi

• Increased risk for bleeding and bruising with cBTKI and ncBTKi. Hold 3 days before and after a minor surgical procedure and 7 days before and after a major surgical procedure.

• Consider the benefit-risk in patients requiring antiplatelet or anticoagulant therapies; concomitant use of ≥3 anti-platelet agents not

recommended (eg, BTKi, aspirin or other anti-platelet agents, direct oral anticoagulants).

• Thrombocytopenia (platelets <100,000/μL) and increased risk for bleeding should also be taken into consideration.

NCCN Guidelines Version 2.2026

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

NCCN Guidelines Index Table of Contents Discussion

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

CSLL-C 6 OF 6

SUPPORTIVE CARE FOR PATIENTS WITH CLL/SLL

Immunizations

• Avoid all live vaccines including live attenuated influenza vaccine

• Recommended vaccines

Annual influenza vaccined

Pneumococcal vaccine: see CDC Guidelines for Pneumococcal Vaccination

Zoster vaccine recombinant, adjuvanted for all patients treated with BTKi

Respiratory syncytial virus (RSV) vaccine: single dose vaccination for patients with CLL/SLL, including patients age <60 y

COVID-19 vaccine for all patients with CLL/SLL. See CDC COVID-19 Vaccination Clinical & Professional Resources

◊ See Management of Concurrent COVID-19 and Cancer in Patients in the NCCN Guidelines for Prevention and Treatment of CancerRelated Infections

d In patients who have received rituximab, B-cell recovery occurs by approximately 9 months. Prior to B-cell recovery, patients generally do not respond to influenza vaccine and if given should not be considered vaccinated.

NCCN Guidelines Version 2.2026

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

NCCN Guidelines Index Table of Contents Discussion

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

CSLL-D 1 OF 5

SUGGESTED TREATMENT REGIMENSa,b,c,d

Suggested Regimens for Second-Line and Subsequent Therapy (CSLL-D 2 of 5)Therapy for Relapsed or Refractory Disease After Prior BTKi-Based and BCL2iContaining Regimens (CSLL-D 2 of 5)

FIRST-LINE THERAPYe,f,g

Preferred

Other Recommended

Useful in Certain Circumstances

• BCL2i-containing regimens

Venetoclax/Acalabrutinibj ± Obinutuzumab

(fixed duration)h (category 1)

Venetoclax + Obinutuzumab (fixed

duration) (category 1)

• cBTKi-based regimensi,j

Acalabrutinib (continuous) ±

Obinutuzumab (category 1)

Zanubrutinib (continuous) (category 1)

• BCL2i-containing regimen

Venetoclax/Ibrutinibj (category 1;fixed duration)k Venetoclax/Ibrutinibj (category 1;MRD-guided)l

• BCL2i-containing regimen

Venetoclax/Zanubrutinibj (MRD-guided)m

• cBTKi-based regimensi,j

Ibrutinibn (continuous) (category 1)

Ibrutinib (continuous) + anti-CD20 mAb (category 2B)o

• High-dose methylprednisolone (HDMP) + anti-CD20

mAbo (category 2B; category 3 for patients <65 y

without significant comorbidities)

• Consider only when cBTKi and BCL2i are not available or not feasible

Bendamustinep + anti-CD20 mAbo,q

FC (Fludarabine/Cyclophosphamide)r,s,t + Rituximab Chlorambucilu + Obinutuzumab

Obinutuzumab

Footnotes

FIRST-LINE THERAPYe,f,g

Preferred

Other Recommended

Useful in Certain Circumstances

• BCL2i-containing regimens

Venetoclax + Obinutuzumab (fixed

duration)

Venetoclax/Acalabrutinib +

Obinutuzumab (MRD-guided)v

Venetoclax/Zanubrutinib j (MRD-guided)m

• cBTKi-based regimensi,j

Acalabrutinib (continuous) ±

Obinutuzumab

Zanubrutinib (continuous)

• BCL2i-containing regimen

Venetoclax/Ibrutinibj,w (fixed duration)

• cBTKi-based regimeni,j

Ibrutinibn (continuous)

• HDMP + anti-CD20 mAbo• Consider only when cBTKi and BCL2i are notavailable or not feasible Obinutuzumab

CLL/SLL without del(17p)/TP53 Mutation (alphabetical by category)

CLL/SLL with del(17p)/TP53 Mutation (alphabetical by category)

References

NCCN Guidelines Version 2.2026

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

NCCN Guidelines Index Table of Contents Discussion

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

CSLL-D 2 OF 5

SUGGESTED TREATMENT REGIMENSa,b,c,d CLL/SLL with or without del(17p)/TP53 Mutation(alphabetical by category)

SECOND-LINE OR SUBSEQUENT THERAPYe,f

Preferred

• BCL2i-containing regimen*

Venetoclax + Obinutuzumab

• cBTKi-based regimensi,j,x

Acalabrutinib (continuous) (category 1)

Zanubrutinib (continuous) (category 1)

• ncBTKi-based regimen:

Pirtobrutinib (continuous) (category 1) (resistance

or intolerance to prior cBTKi-based regimens)

Other Recommended

• BCL2i-containing regimens*

Venetoclax + Rituximab (category 1)Venetoclax*

Venetoclax/Ibrutinibj,y,z (category 2B)

• cBTKi-based regimeni,j

Ibrutinibn (continuous) (category 1)

THERAPY FOR RELAPSED OR REFRACTORY DISEASE

AFTER PRIOR cBTKi-BASED AND BCL2i-CONTAINING REGIMENSe,f

Preferred

• Chimeric antigen receptor (CAR) T-cell therapy Lisocabtagene maraleucel (CD19-directed)aa ±

Ibrutinibj

• ncBTKi-based regimen:

Pirtobrutinib (continuous) (category 1) (if not

previously given)

Other Recommended

• PI3Ki-based regimens

Duvelisib

Idelalisibbb ± Rituximab

• FC + Rituximabs,t,**

• Lenalidomidecc ± Rituximab

• Obinutuzumab

• Alemtuzumabdd ± Rituximab (with del(17p)/TP53 mutation)

• Bendamustinep + Rituximabq,** (category 2B for patients ≥65 y or patients <65 y with significant comorbidities)

• HDMP + anti-CD20 mAbo (category 2A with del[17p]; category 2B without del[17p] )

* Venetoclax ± anti-CD20 mAb (obinutuzumab preferred) or venetoclax + cBTKi is a treatment option for relapse after a period of

remission. Single agent venetoclax (continuous) can also be considered a treatment option for relapse after a period of remission.

** Not recommended for CLL/SLL with del(17p)/TP53 mutation.

Footnotes References

NCCN

NCCN Guidelines Version 2.2026

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

NCCN Guidelines Index Table of Contents Discussion

SUGGESTED TREATMENT REGIMENS FOOTNOTES

ª See references for regimens on CSLL-D 4 of 5 and CSLL-D 5 of 5.

b Supportive Care for Patients with CLL/SLL (CSLL-C).

c Rituximab and hyaluronidase human injection for subcutaneous use may be used in patients who have received at least one full dose of a rituximab product by intravenous route.

d Re-challenge with the same mAb is not recommended in patients experiencing rare complications (eg, mucocutaneous reactions including paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermalitis, vesiculobullous dermatitis, and toxic epidermal necrolysis). It is unclear whether re-challenge with alternative anti-CD20 mAbs poses the same risk of recurrence.

e An FDA-approved biosimilar is an appropriate substitute for rituximab.

f Please 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.

9 Time-limited treatment with BCL2i + cBTKi ± CD20 mAb may be fixed-duration or MRD-guided (based on uMRD-stopping criteria as described in clinical trials). See MRD Assessment (CSLL-E).

h AMPLIFY: Brown JR, et al. N Engl J Med 2025;392:748-762.

i TKIs are available in different formulations, dosage forms, and strengths that are subject to different administration instructions. The choice of cBTKi should be made by the treating clinician based on patient-specific factors (eg, age, functional status, comorbid conditions) and the agent's toxicity profile. These products are not interchangeable.

$^{1}$ A baseline cardiovascular risk assessment should be considered prior to initiation of cBTKi. Awan F, et al. Blood Adv 2022;18:5516.

$^{1}$ See publication for duration of treatment (GLOW: Munir T, et al. J Clin Oncol 2023;41:3689-3699; Niemann CU, et al. Blood 2024;144:Abstract 1871).

$^{1}$ See the publication for details on MRD assessments and management, including criteria for treatment discontinuation (FLAIR: Munir T, et al. N Engl J Med 2025;393:1177-1190). See CSLL-E.

m See the publication for details on MRD assessments and management, including criteria for treatment discontinuation (SEQUOIA [Arm D]: Shadman M, et al. J Clin Oncol 2025;43:2409-2417). See CSLL-E.

$^{n}$ The Panel consensus to not list ibrutinib as a preferred regimen is based on the toxicity profile.

º Anti-CD20 mAbs include: obinutuzumab or rituximab.

P For patients aged ≥65 y or patients aged <65 y with significant comorbidities (CrCl <70 mL/min) dose is 70 mg/m$^{2}$ in cycle 1 with escalation to 90 mg/m$^{2}$ if tolerated.

$^{9}$ Not recommended for patients who are frail.

* Data from the CLL10 study confirmed the superiority of FCR over bendamustine + rituximab (BR) in younger patients. For patients >65 y, the outcome was similar for both regimens with less myelosuppression and infection for BR. FCR was associated with improved PFS (with a plateau in PFS beyond 10-year follow-up) in patients with mutated IGHV without del (17p)TPV3 mutation (Thompson P, et al. Blood 2016;127:303-309).

s AIHA should not preclude the use of combination therapy containing fludarabine; however, patients should be observed carefully and fludarabine should be avoided in those where a history of fludarabine-associated AIHA is suspected.

†t Recommended only for patients aged <65 y without significant comorbidities.

u Recommended only for patients aged ≥65 y or patients aged <65 y with significant comorbidities (creatinine clearance [CrCl] <70 mL/min).

* See the publication for details on MRD assessments and management, including criteria for treatment discontinuation (Davids MS, et al. J Clin Oncol 2025;43:788-799). See CSLL-E.

w CAPTIVATE: Allan JN, et al. Clin Cancer Res 2023;29:2593 -2601; Ghia P, et al. J Clin Oncol 2025;43:Abstract 7036.

× Acalabrutinib or zanubrutinib has not been shown to be effective for ibrutinib-refractory CLL with BTK C481S mutations. Patients with ibrutinib intolerance have been successfully treated with acalabrutinib or zanubrutinib without recurrence of symptoms.

Y CLARITY: Hillmen P, et al. J Clin Oncol 2019;37:2722-2729.

2. Venetoclast containing combinations with irubutinib are not appropriate for patients who are intolerant to or have disease progression on irutinib.

aa See CAR T-Cell-Related Toxicities in the NCCN Guidelines for Management of CAR T-Cell and Lymphocyte Engager-Related Toxicities for the management of cytokine release syndrome (CRS) and neurologic toxicity management.

bb Indicated for patients for whom rituximab monotherapy would be considered appropriate due to the presence of other comorbidities (reduced renal function as measured by CrCl <60 mL/min, or NCI CTCAE grade ≥3 neutropenia or grade ≥3 thrombocytopenia resulting from myelotoxic effects of prior therapy with cytotoxic agents).

cc Lenalidomide can be given as continuous or intermittent dosing for patients with CLL. Growth factors and/or dose adjustment may be needed to address cytopenias, without necessitating holding treatment. See Andritsos L, et al. J Clin Oncol 2008;26:2519-2525; Wendtner C, et al. Leuk Lymphoma 2016;57:1291-1299. dd While alemtuzumab is no longer commercially available for CLL, it may be obtained for clinical use. Alemtuzumab is less effective for bulky (>5 cm) lymphadenopathy; monitor for CMV reactivation. See Viral Reactivation (CSLL-C 1 of 4).

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

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NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 2.2026

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

NCCN Guidelines Index Table of Contents Discussion

SUGGESTED TREATMENT REGENS REFERENCES

AcaLaburitinib ± obinutumazum

Sharman JP, Egyed M, Jurzak W, et al. Acalabrutinib-obutinuzumab improves survival vs chemoimmunotherapy in treatment-naïe cell in the 6-year follow-up of ELEVATE-TN. Blood 2025;146:1276-1285.

Byrd JC, Hillmen P, Ghia P, et al. Acaalbrutinib versus 1brutinib in previously treated chronic lymphocytic leukemia: Results of the first randomized phase III trial. J Clin Oncol 2021; 39:3441-3452.

Ghia P, Pluta A, Wach M, et al. ASCEND: Phase III, randomized trial of acalabrutinib versus idealisib plus rituximab or bendamustine plus rituximab in relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol 2020;38:2849-2861.

Awan FT, Schuh A, Brown JR, et al. Acalabrutinib monotherapy in patients with chronic lymphocytic leukemia who are intolerant to ibrutinib. Blood Adv 2019;3:1553-1562.

Rogers KA, Thompson PA, Allan JN, et al. Phase II study of acalabrutinib in ibrutinib-intolerant patients with relapsed/refractory chronic lymphocytic leukemia. Haematologica 2021;106:2344-2373.

Altemuzumab ut ritikumax

Lozanski G, Heerema NA, Flinn IW, et al. Alemtuzumab is an effective therapy for chronic lymphocytic leukemia with p53 mutations and deletions. Blood 2004;103:3278-3281.

Fader S, Ferrajoli A, Wierda W, et al. Alemtuzumab by continuous intravenous infusion followed by subcutaneous injection plus rituximab in the treatment of patients with chronic lymphocytic leukemia recurrence. Cancer 2010;116:2360-2365.

Bendamustine + rituximab or obinutuzumab

Eichorst H, Bink AM, Bahlo J, et al. First-line chemmoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): an international, open-label, randomised, phase 3, non-inferiority trial. Lancet Oncol 2016;17:928-942.

Fischer K, Cramer P, Busch R, et al. Bendamustine combined with rituximab in patients with relapsed and/or refractory chronic lymphocytic leukemia: A multicenter phase II trial of the German Chronic lymphocytic Leemia Study Group. J Clin Oncol 2011:29:3559-3566.

Stilgenbauer S, Bosch F, Ilhan O, et al. Safety and efficacy of obinutuzamab alone or with chemotherapy in previously untreated or relapsed/refractory chronic lymphocytic lekaemia patients. The final analysis of the Phase Ilib GREEN study. Br J Haematol 2021;193:325-338.

CAR T-cell therapy

Siddiqi T, Maloney D, Kenderian S, et al. Lisocabtagene maraleucel in relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma: 24-month median follow-up of TRANSCEND CLL 0042023 [abstract]. Blood 2023;142:Abstract 330.

Siddiqi T, Maloney D, Kenderian S, et al. Lisocabtagene maraleucel in chronic lymphocytic leukaemia and small lymphocytic lymphoma (TRANSCEND CLL 004): a multicentre, open-label, single-arm, phase 1-2 study. Lancet 2023;402:641-654.

Duvelisib

Danilov AV, Flinn IW, Davids MS, et al. The phase III DUO trial of PI3K inhibitor duvelisib versus ofatumumab in relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma: final analysis including overall survival. Haematologica 2024;109:3379-3382.

FC (fludarabine/cyclophosphamide) + rituximab

Fischer K, Bahlo J, Fink AM, et al. Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial. Blood 2016;127:208-215.

SUGGESTED TREATMENT REGENS REFERENCES

Eichhorst B, Fink AM, Bahlo J, et al. First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): an international, open-label, randomised, phase 3, non-inferiority trial. Lancet Oncol 2016;17:928-942.

Thompson PA, Tam CS, O'Brien SM, et al. Fludarabine, cyclophosphamide, and rituximab treatment achieves long-term disease-free survival in IGHV-mutated chronic lymphocytic leukemia. Blood 2016;127:303-309. Badoux XC, Keating MJ, Wang X, et al. Fludarabine, cyclophosphamide, and rituximab chemoinmotherapy is highly effective treatment for relapsed patients with CLL. Blood 2011;117:3016-3024.

HDMP (high-dose methylprednisolone) + rituximab or obinutuzumab

Bowen DA, Call TG, Jenkins GD, et al. Methylprednisolone-rituximab is an effective salvage therapy for patients with relapsed chronic lymphocytic leukemia including those with unfavorable cytogenetic features. Leuk lymphoma 2007:48:2412:2417.

Castro JE, James DF, Sandoval-Sus JD, et al. Rituximab in combination with high-dose methylprednisolone for the treatment of chronic lymphocytic leukemia. Leukemia 2009;23:1779-1789.

Thornton PD, Matutes E, Bosanquet AG, et al. High dose methylprednisolone can induce remissions in CLL patients with p53 abnormalities. Ann Hematol 2023;82:756-79.

Castro JE, Amaya-Chanaga CI, Velez Lujan J, et al. Obinutuzumab (Gazyva) and High-Dose Methylprednisolene (HMDP) Combination for Patients with Chronic Lymphocytic Leukemia (CLL) - a Phase lb/Il Study [abstract]. Blood 2017;130:Abstract 1730.

brutinib

Barr PM, Owen C, Robak T, et al. Up to 8-year follow-up from RESONATE:2: first-line irbutin treatment for patients with chronic lymphocytic leukemia. Blood Adv 2022;6:3440-3450.

O'Brien S, Jones JA, Coutre SE, & et al. Ibrutinib for patients with relapsed or refractory chronic lymphocytic leukaemia with 17p deletion (RESONATE: 17: a phase 2, open-label, multicentre study. Lancet Oncol 2016;17:1409;1418.

Farooqui MZ, Valdez J, Martyr S, et al. Ibrutinib for previously untreated and relapsed or refractory chronic lymphocytic lekaemia with TP53 aberrations: A phase 2, single-arm trial. Lancet Oncol 2015;16:169-176.

Munin T, Brown JR, O'Brien S, et al. Final analysis from RESONATE: Up to six years of follow-up on ibrutinib in patients with previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma. Am J Hematol 2019;94:1353-1363.

Brown JR, Davids MS, JE, et al. Outcomes of irbutinib (lbr) therapy in Ibr-naïve patients (pts) with chronic lymphocytic leukemia (CLL) progressing after venetoclax (ven) [abstract]. Blood 2019,134.Abstract 432.

Lin VS, Lew TE, Handunnetti SM, et al. BTK inhibitor therapy is effective in patients with CLL resistant to venetoclax. Blood 2020;135:2266-2270.

Mato AR, Roeker LE, Jacobs R, et al. Assessment of the efficacy of therapies following venetoclaste continuation in CLL reveals BTK inhibition as an effective strategy. Clin Cancer Res 2020;26:3589-3596.

Ibrutinib + rituximab

Shanafelt TD, Wang XV, Hanson CA, et al. Long-term outcomes for ibrutinib-rituximab and chemomunotherapy in CLL: updated results of the E1912 trial. Blood 2022;140:112-120.

Munin T, Girvan S, Cairns DA, et al. Measurable residual disease-guided therapy for chronic lymphocytic leukemia. N Engl J Med 2025;393:1177-1190

Woyach JA, Perez Burbano G, Ruppert AS, et al. Follow-up from the A041202 study shows continued efficacy of orbitinib regimens for older adults with CLL. Blood 2024;143:1616-1627.

Ibrutinib + obinutuzumab

Moreno C, Greil R, Demirkan F, et al. First-line treatment of chronic lymphocytic leukemia with irbutinib plus obinutuzumab versus chlorambucil plus obinutuzumab: final analysis of the randomized, phase III iLLUMINATE trial. Haematologica 2022;107:2108-2120.

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

Continued

CSLL-D 4 OF 5

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NCCN

National Cancer Network®

NCCN Guidelines Version 2.2026

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

NCCN Guidelines Index Table of Contents Discussion

SUGGESTED TREATMENT REGIMENS REFERENCES

Idelalisib ± rituximab

Sharman JP, Coutre SE, furman RR, et al. Final results of a randomized, phase III study of rituximab with or without idealisib followed by open-label idelalisib in patients with relapsed chronic lymphocytic leukemia. J Clin Oncol 2019;37:1391-1402. Gopal AK, Kahl BS, De Vos S, et al. PI3K36 inhibition by idelalisib in patients with relapsed indentolympha. N Engl J Med 2014;37:1008-1018.

Chanan-Khan A, Miller KC, Musial L, et al. Clinical efficacy of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia: results of a phase II study. J Clin Oncol 2006;24:5343-5349.

Ferrajoli A, Lee BN, Schlette EJ, et al. Lenalidomide induces complete and partial remissions in patients with relapsed and refractory chronic lymphocytic leukemia. Blood 2008;111:5291-5297. Badoux XC, Keating MJ, Wen S, et al. Phase II study of lenalidomide and ritukimab as salvage therapy for patients with relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol 2013;31:584-591.

Lisocabtagene ± ibrutinib

Siddigi T, Maloney DG, Kenderian SS, et al. Lisocabtagene maraleucel (liso-cel) in R/RCL/SLL: 24-month median follow-up of TRANSCEND CLL 004 [abstract]. Blood 2023;142:Abstract 330. Wierda WG, Dorrite K, Gauthier J, et al. Lisocabtagene maraleucel (liso-cel) combined with irbutinib (ibr) for patients (pts) with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL); Primary results from the open-label, phase 1/2 Transcend CLL 004 study [abstract]. Blood 2024;144:Abstract 887.

Obinutuzumab ± chlorambucul

Byrd JC, Flynn JM, Kipbs TJ, et al. Randomized phase 2 study of obinutuzumab monotherapy in symptomatic, previously untreated chronic lymphocytic leukemia. Blood 2016;127:79-78.

Carton G, de Guibert S, Dilhuyd MS, et al. Obinutuzumab (GA101) in relapsed/refractory chronic lymphocytic leukemia: final data from the phase 1/2 GAUGUIN study. Blood 2014;124:2196-2202.

Goede V, Fischer K, Engelke A, et al. Obinutuzumab as frontline treatment of chronic lymphocytic leukemia: updated results of the CLL11 study. Leukemia 2015;29:1602-1604.

Moreno C, Greil R, Demirkan F, et al. First-line treatment of chronic lymphocytic leukemia with irbutinib plus obinutuzumab versus chlorambucul plus obinutuzumab: final analysis of the randomized, phase III IULUMINATE trial. Haematologica 2022; 107:218-2102.

Pirtobrutinib

Sharman JP, Munir T, Grosicki S, et al. Phase III Trial of Pirtobrutinib Versus Idelalisib/Rituximab or Bendamustine/Rituximab in Covalent Bruton Tyrosine Kinase Inhibitor-Pretreated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (BRUIN CLL-321). J Clin Oncol 2025;43:2538-2549.

Venetoclax

Kater AP, Harrup R, Kipps TJ, et al. The MURANO study: final analysis and treatment/ crossover substudy results of VenR for patients with relapsed/refractory CLL. Blood 2025;145:2733-2745.

Stilgenbauer S, Tausch E, Roberts AW, et al. Six-year follow-up and subgroup analyses of a phase 2 trial of venetoclax for del(17p) chronic lymphocytic leukemia. Blood Adv 2024;8:1992-2004.

Thompson MC, Harrup RA, Coombs CC, et al. Venetoclax retreatment of patients with chronic lymphocytic leukemia after a previous venetoclax-based regimen. Blood Adv 2022;6:4553-4557.

Coutre S, Choi M, Furman RR, et al. Venetoclax for patients with chronic lymphocytic leukemia who progressed during or after idelisib therapy. Blood 2018;131:1704-1711.

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

REFERENCES

Jones J A, Mato AR, Wierda WG, et al. Venetoclax for chronic lymphocytic leukaemia progressing after ibrutinib: an interim analysis of a multicentre, open-label, phase 2 trial. Lancet Oncol 2018;19:65-75.

Venetocaxl/Acaalabrutinib ± obinutuzumab

Brown JR, Seymour JR, Eurzak W, et al. Fixed-duration acalabrutinib combinations in untreated chronic lymphocytic leukemia, N Engl J Med 2025;392:748-762.

Davids M, Ryan CE, Lampson BL, et al. Phase II study of acalabrutinib, venetoclax, and obinutuzumab in a treatment-naive chronic lymphocytic leukemia population enriched for high-risk disease. J Clin Oncol 2025;43:788-799.

Venetocaxl + ibrutinib

Allan JN, Flinn IW, Siddiq T, et al. Outcomes in patients with high-risk features after fixed-duration ibrutinib plus venetoclax: Phase II CAPTIVATE study in first-line chronic lymphocytic leukemia. Clin Cancer Res 2023;29:2593 -2601:1921.

Ghia P, Barr 平, Allan JN, et al. Final analysis of fixed-duration ibrutinib + venetoclax for chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) in the phase 2 CAPTIVATE study [abstract]. J Clin Oncol 2025;43:Abstract 7036.

Niemann CU, Munir T, Owen C, et al. First-line arributinib plus venetoclas vs chlorambucil plus obintuzumab in elderly or comorbid patients (pts) with chronic lymphocytic leukemia (CLL): GLOW study 64-month follow-up (FU) and adverse event (AE)-free progression-free survival (PFS) analysis [abstract]. Blood 2024;144:Abstract 1871.

Hillmen P, Rawstron AC, Brock K, et al. Ibrunitib plus venetoclas or relapsed/refractory chronic lymphocytic

Munir T, Girvan S, Cairn's DA, et al. Measurable residual disease-guided therapy for chronic lymphocytic leukemia. N Engl J Med 2025;393(12):1177-1190.

Venetocax + obinutuzumab

Al-Sawaf O, Robrecht S, Zhang C, et al. Venetoclas-obinutuzumab for previously untreated chronic lymphocytic leukemia: 6-year results of the randomized phase 3 CLL14 study. Blood 2024;144:1924-1935.

Furstenau M, Kater AP, Robrecht S, et al. Enotavclax obinituutzumans versus chemoimmunotherapy in fit patients with chronic lymphocytic leukemia (GAIA/CLL31): 4-year follow-up from a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol 2024;25:744-759.

Venetoclax + rituximab

Kater AP, Wu JQ, Kipps T, et al. Venetoclas plus rituximab in relapsed chronic lymphocytic leukemia: 4-Year results and evaluation of impact of genomic complexity and gene mutations from the MURANO phase III study. J Clin Oncol 2020;38:4042-4054.

Seymour JF, Kipps TJ, Eichhorst BF, et al. Enduring undetectable MRD and updated outcomes in relapsed/refractory CLL after fixed-duration venetoclax-rituximab. Blood 2022;140:839-850.

Zanubrutinib

Brown JR, Eichhorst B, Lamanna N, et al. Sustained benefit of zanubrutinib vs irutinib in patients with R/R CLL/LL: final comparative analysis of ALPINE. Blood 2024;144:2706-2717.

Tam C, Mital A, Weinkove R, et al. Long-term results of patients receiving zanubrutinib in the phase 3 ALPINE study confirm sustained benefit of zanubrutinib in patients with relapsed/refractory chronic lymphocytic leukemia of small lymphocytic lymphoma (R/R CLL/SLL): Up to 6 years of follow-up with the long-term extension (LTE1) [abstract]. Blood 2025;146:Abstract 2123.

Shadman M, Munir T, Robak T, et al. Zanubrutinib versus bendamustine and rituximab in patients with treatment-naive chronic lymphocytic leukemia/small lymphocytic lymphoma: Median 5-year follow-up of SEQUIOIA. J Clin Oncol 2025;43:780-787.

Tam C, Munir T, Robak T, et al. Sustained efficacy of zanubrutinib (zana) vs bendamustine + rituximab (BR) in treatment (tx)-naive chronic lymphocytic leukemia/small lymphocytic lymphoma (TN SLL/CLL) and continued favorable survival in non-randomized patients (pts) with del(17p): 6-year follow-up in the phase 3 SEQUOA study [abstract]. Blood 2025;146:Abstract 2129.

Venetoclax + Zanubrutinib

Shadman M, Munir T, Ma S, et al. Zanubrutinib and venetoclax for patients with treatment-naive chronic lymphocytic lymphocytic lymphoma with and without del(17p)/tp53 mutation: SEQUOIA Arm D Resulta. J Clin Oncol 2025;43:2409-2417.

CSLL-D 5 OF 5

NCCN Guidelines Version 2.2026

Authors

NCCN Guidelines Index

Abstract

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

Abstract

Table of Contents Discussion 1 OF 2 MEASURABLE RESIDUAL DISEASE (MRD) ASSESSMENT a Al-Sawaf O, Robrecht S, Zhang C, et al. Venetoclax-obinutuzumab for previously untreated chronic lymphocytic leukemia: 6-year results of the randomized phase 3 CLL14 study. Blood 2024;144:1924-1935. b Wierda WG, Allan JN, Siddiqi T, et al. Ibrutinib plus venetoclax for first-line treatment of chronic lymphocytic leukemia: Primary analysis results from the minimal residual disease cohort of the randomized phase II CAPTIVATE Study.

• Evidence from clinical trials suggests that undetectable MRD in the peripheral blood after the end of time-limited treatment is an important predictor of efficacy. a-e • Allele-specific oligonucleotide polymerase chain reaction (ASO-PCR) and six-color flow cytometry (MRD flow) are the two validated methods used for the detection of MRD at the level of 10 -4 to 10 -5 . f,g Next-generation sequencing (NGS)-based assays have been shown to be more sensitive, thus allowing for the detection of MRD at the level of 10 -6 . h-j • MRD evaluation should be performed using an assay with a sensitivity of 10 -4 according to the standardized European Research Initiative on CLL (ERIC) method or standardized NGS method. • For MRD-guided treatment, serial MRD evaluations using either flow cytometry (MRD flow) or NGS with a limit of detection (sensitivity) of at least 10 -4 CLL cells in blood or bone marrow may be performed every 3 to 6 months during active treatment as directed in the published trial results that support MRD-guided treatment regimens. See the publications for details on MRD assessments and management, including criteria for treatment discontinuation (CSLL-E 2 of 2). • Either flow cytometry (MRD flow) or NGS are acceptable assays as long as the limit of detection (sensitivity) is achieved.

• When assessing MRD in blood, be aware that anti-CD20 monoclonal antibody administration within the prior 3 months can lead to false undetectable MRD (uMRD) status, particularly in blood.

References

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 2.2026 Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

NCCN Guidelines Index Table of Contents Discussion

MEASURABLE RESIDUAL DISEASE (MRD) ASSESSMENT

|Trial|First-line Therapy|Regimen| |---|---|---| |$FLAIR^{k}$|CLL/SLL without del(17p) or TP53 mutation|Venetoclax/lbrutinib^{n} (category 1; other recommended)| |$SEQUOIA$ (Arm $D^{l}$)|CLL/SLL without del(17p) or TP53 mutation|Venetoclax/Zanubrutinib^{o} (category 2A; useful in certain circumstances)| |$SEQUOIA$ (Arm $D^{l}$)|CLL/SLL with del(17p) or TP53 mutation|Venetoclax/Zanubrutinib^{o} (category 2A; preferred)| |Phase II $study^{m}$|CLL/SLL with del(17p) or TP53 mutation|Venetoclax/Acalabrutinib + Obinutuzumab^{p} (category 2A; preferred)|

k Munir T, Girvan S, Cairns DA, et al. Measurable residual disease-guided therapy for chronic lymphocytic leukemia. N Engl J Med 2025:Online ahead of print.

$^{1}$ Shadman M, Munir T, Ma S, et al. Zanubrutinib and venetoclax for patients with treatment-naive chronic lymphocytic leukemia/small lymphocytic lymphoma with and without del(17p)/tp53 mutation: SEQUOIA Arm D Results. J Clin Oncol 2025;43:2409-2417.

m Davids MS, Ryan CE, Lampson BL, et al. Phase II study of acalabrutinib, venetoclax, and obinutuzumab in a treatment-naive chronic lymphocytic leukemia population enriched for high-risk disease. J Clin Oncol 2025;43:788-799.

n The duration of combined ibrutinib + venetoclax was determined based on serial MRD monitoring and treatment discontinuation in patients meeting with the uMRD-guided stopping criteria.

$^{0}$ Discontinuation of treatment (venetoclax after a minimum of 12 cycles or zanubrutinib after a minimum of 27 cycles) was allowed in patients meeting with the uMRD-guided stopping criteria.

P Patients could discontinue treatment if CR with uMRD in the bone marrow was achieved at the start of cycle 16.

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

Table of Contents Discussion

DIAGNOSIS

a Biopsy of lesions with SUV ≥5 is recommended if there is high clinical suspicion or the lesion has a differentially higher uptake than the remaining disease. b While occasionally an increase in proliferative rate can be shown with Ki-67, this is not considered diagnostic of a transformation. c Proliferation centers in CLL may express c-MYC and/or cyclin D1. This does not change the diagnosis. d Accelerated CLL or CLL with expanded proliferation centers may be diagnosed in cases where proliferation centers in CLL are expanded or fused together ( > 20x field or 0.95 mm 2 ) AND show Ki-67 proliferative rate > 40% or > 2.4 mitoses/proliferation center. Progression to CLL with increased prolymphocytes may occur when there are increased prolymphocytes in the blood ( > 15%). Neither of these findings should be considered as Richter transformation, but rather as progression of CLL associated with more aggressive disease and poorer outcome (Gine E, et al. Haematologica 2010; 95:1526 -1533; Ciccone M, et al. Leukemia 2012; 26:499-508; Campo E, et al. Blood 2022; 140:1229 -1253; Alaggio R, et al. Leukemia 2022; 36:1720 -1748) . Optimal management for these cases has not been established. e If morphologic RS cells are identified but the background cells are still the B cells of CLL, an EBV stain such as Epstein-Barr virus-encoded RNA (EBER) should be performed. EBV infection of CLL can produce RS-like proliferations, but the background cells are still CLL and not the reactive mix typically seen in Hodgkin lymphoma. These cases should NOT be considered a Richter transformation event. f Immunoglobulin gene rearrangement studies of CLL and histologically transformed tissue may be performed to establish the clonal relationship. Comparative clonality testing for immunoglobulin heavy chain (IGH) gene rearrangement should be done on defined CLL tissue and biopsy specimen of transformed tissue to establish clonal relatedness between CLL/SLL and DLBCL cells (either using commercial NGS-based assay or lab-based assay for IGH clonality).

Workup (HT-2)

References

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 2.2026 Histologic Transformation (Richter)

NCCN Guidelines Index Table of Contents Discussion

WORKUP

ESSENTIAL:

* Whole body FDG-PET/CT scan (preferred) or C/A/P CT with contrast of diagnostic quality (if PET/CT scan not feasible)

* An excisional or incisional biopsy of the suspected lymph node/lesion with an increased SUV on FDG-PET/CT scan (particularly if discordant with the remaining disease).$^{a}$

* FNA biopsy alone is inadequate for the diagnosis of histologic transformation. In certain circumstances, when a lymph node/lesion is not easily accessible for excisional or incisional biopsy, core needle biopsy (multiple biopsies may be required) in conjunction with appropriate ancillary techniques (ie, IHC, flow cytometry) may be sufficient for diagnosis.

* History and physical exam with attention to node-bearing areas, including Waldeyer's ring, and the size of liver and spleen

* Performance status

* B symptoms

* CBC with differential

* Comprehensive metabolic panel

$\bullet$ LDH, uric acid

$\bullet$ Molecular analysis to establish clonal relatedness between CLL and DLBCL cells$^{f}$

* Assess for distress$^{9}$

USEFUL IN SELECTED CASES:

* Unilateral bone marrow aspirate and biopsy

* Multigated acquisition (MUGA) scan/echocardiogram if anthracycline-based regimen is indicated

* Hepatitis B^h and C testing

* Epstein-Barr virus (EBV) evaluation by EBV-latent membrane protein 1 (LMP1) or Epstein-Barr virus-encoded RNA in situ hybridization (EBER-ISH)

* Pregnancy testing in patients of childbearing age

* Discussion of fertility preservation$^{1}$

* Human leukocyte antigen (HLA) typing

ª Biopsy of lesions with SUV ≥5 is recommended if there is high clinical suspicion or the lesion has a differentially higher uptake than the remaining disease.

f Immunoglobulin gene rearrangement studies of CLL and histologically transformed tissue may be performed to establish the clonal relationship.

Comparative clonality testing for IGH gene rearrangement should be done on defined CLL tissue and biopsy specimen of transformed tissue to establish clonal relatedness between CLL/SLL and DLBCL cells (either using commercial NGS-based assay or lab-based assay for IGH clonality).

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 2.2026

Histologic Transformation (Richter)

NCCN Guidelines Index Table of Contents Discussion

![graph TD\n A1[Richter transformation] --> A2[Clonality testing compared to CLL¹ (initiation of therapy should not be delayed for clonality testing)]\n A2 --> A3[Untreated CLL or Clonally unrelated]\n A2 --> A4[Previously treated CLL and clonally related or Clonal relation unknown¹]\n A3 --> A5[Clinical trial or CIT regimens (HT-A)]\n A4 --> A6[HT-4]\n A5 --> A7[Complete response]\n A5 --> A8[Partial response or Refractory disease or Progression while on treatment]\n A7 --> A9[Observation]\n A8 --> A10[Clinical trial or CAR T-cell therapy (HT-A) （if eligible, after at least 1 prior systemic therapy regimen) or Non-CIT regimens （other than CAR T-cell therapy) (HT-A)]\n A10 --> A11[If CR, consider allogeneic HCT⁸]\n](1/parseimages/figuref6df1954f1fb4f0e979b57d740094313_0_4.png) f Immunoglobulin gene rearrangement studies of CLL and histologically transformed tissue may be performed to establish the clonal relationship. Comparative clonality testing for IGH gene rearrangement should be done on defined CLL tissue and biopsy specimen of transformed tissue to establish clonal relatedness between CLL/SLL and DLBCL cells (either using commercial NGS-based assay or lab-based assay for IGH clonality).

j Supportive Care for Patients with CLL/SLL (CSLL-C).

k Richter transformation to DLBCL (clonally related or clonal relation unknown) is generally managed with treatment regimens recommended for DLBCL. However, these regimens typically result in poor responses and optimal first-line therapy is not established. The regimens listed on HT-A are used at NCCN Member Institutions based on published data.

It is recommended that clonal relatedness be determined; however, if is not feasible and CLL has not been previously treated, consider treating as clonally unrelated.

m PET/CT scan is required for response assessment and should be interpreted via the PET 5-Point Scale (5-PS). See Lugano Response Criteria for Non-Hodgkin Lymphoma (NHODG-C) in the NCCN Guidelines for B-Cell Lymphomas.

n Herrera AF, et al. Blood Adv 2021;5:3528-3539; Kharfan-Dabaja MA, et al. Biol Blood Marrow Transplant 2016;22:2117-2125.

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

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 2.2026

Histologic Transformation (Richter)

NCCN Guidelines Index Table of Contents Discussion

![graph TD\n A1[Previously treated CLL and clonally related or Clonal relation unknownk,I] --> A2[Clinical trial （preferred） Treatment with non-CIT regimens （other than CAR T-cell therapy）（preferred） or CIT regimens （HT-A）]\n A2 --> A3[Complete response]\n A2 --> A4[Partial response]\n A2 --> A5[Refractory disease or Progression while on treatment]\n A3 --> A6[Observation or Consider allocneic HCT and/or evaluate eligibility for CAR T-cell therapy or Continue treatment with non-CIT regimen until progression]\n A4 --> A7[CAR T-cell therapy （HT-A）（if eligible, after at least 1 prior systemic therapy regimen） or Non-CIT regimens （other than CAR T-cell therapy）（not previously used）（HT-A） or If not a candidate for HCT or CAR T-Cell therapy: • Continue the same non-CIT regimen until progression or switch to an alternate non-CIT regimen （HT-A）]\n A5 --> A8[Clinical trial or CAR T-cell therapy （HT-A）（if eligible, after at least 1 prior systemic therapy regimen） or Non-CIT regimens （other than CAR T-cell therapy）（not previously used）（HT-A）]\n](1/parseimages/figure67a5afe8b81e4246a9e883726c7c4e5a_0_4.png) * i Supportive Care for Patients with CLL/SLL (CSLL-C).

$^{1}$ It is recommended that clonal relatedness be determined; however, if is not feasible and CLL has not been previously treated, consider treating as clonally unrelated.

n Herrera AF, et al. Blood Adv 2021;5:3528-3539; Kharfan-Dabaja MA, et al. Biol Blood Marrow Transplant 2016;22:2117-2125.

° In patients with previously treated CLL, options depend on treatment received for CLL prior to transformation.

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

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 2.2026

Histologic Transformation (Richter)

NCCN Guidelines Index Table of Contents Discussion

SUGGESTED TREATMENT REGIMENS

RICHTER TRANSFORMATION$^{a,b,c,d}$ (Regimens listed by alphabetical order and category of evidence)

|Chemoimmunotherapy (CIT)$^{e}$| |---| |CHOP (Cyclophosphamide/Doxorubicin/Vincristine/Prednisone) + Rituximab ± Venetoclax* (category 2B with Venetoclax)Dose-Adjusted EPOCH (Etoposide/Prednisone/Vincristine/Cyclophosphamide/Doxorubicin) + RituximabHyperCVAD (Cyclophosphamide/Vincristine/Doxorubicin/Dexamethasone) + Rituximab alternating with Cytarabine/High-Dose MethotrexateOFA (Oxaliplatin/Fludarabine/Cytarabine) + RituximabPatients who are frail or patients with poor left ventricular ejection fraction (LVEF): See NCCN Guidelines for B-Cell Lymphomas (First-line therapy for DLBCL (BCEL-C): Patients with Poor LVEF or Very Frail Patients and Patients >80 Years of Age with Comorbidities)|

|NON-CIT BASED REGIMENS|||| |---|---|---|---| |ICI-based $regimens^{f}$|BTKi (monotherapy)|Bispecific Antibody Therapy|CAR T-cell Therapy (CD19-directed; after at least 1 prior systemic therapy $regimen^{i}$)| |Venetoclax* + Atezolizumab^{g} + Obinutuzumab^{Nivolumab^{h}} ± Ibrutinib^{†}Pembrolizumab ± Ibrutinib^{†}Zanubrutinib^{†} + Tislelizumab.jsgr|Pirtobrutinib**Acalabrutinib† (category 2B)|Eporitamab-byspGlofitamab-gxbm|Axicabtagene ciloleucelLiscabtagene maraleucelTisagenlecleucel|

BCL-2-inhibitor (BCL2i) ** Noncovalent (reversible) BTKi (ncBTKi) † Covalent BTKi (cBTKi)

Footnotes References

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

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 2.2026 Histologic Transformation (Richter)

NCCN Guidelines Index Table of Contents Discussion

SUGGESTED TREATMENT REGIMEN FOOTNOTES

ª Rituximab and hyaluronidase human injection for subcutaneous use may be used in patients who have received at least one full dose of a rituximab product by intravenous route. An FDA-approved biosimilar is an appropriate substitute for any recommended systemic biologic therapy in the NCCN Guidelines.

b For BCL2i-associated TLS, see venetoclax prescribing information.

c 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.

d The panel acknowledged that there is a paucity of data for the use of these regimens in patients with Richter transformation refractory to chemotherapy or in patients with a del(17p)/TP53 mutation; however, these regimens may be considered given the limited options available for this patient population. Additional data will be forthcoming.

e It is reasonably safe to combine cBTKi (given continuously for disease control) with CIT regimens without the addition of other targeted agents.

f ICI-based combination regimens with cBTki used for prior therapy are not appropriate for patients who are intolerant to or have disease progression on the same cBTKi.

$^{9}$ Atezolizumab and hyaluronidase-tqjs subcutaneous injection may be substituted for IV atezolizumab. Atezolizumab and hyaluronidase-tqjs has different dosing and administration instructions compared to atezolizumab for intravenous infusion.

h Nivolumab and hyaluronidase-nvhy subcutaneous injection may be substituted for IV nivolumab. Nivolumab and hyaluronidase-nvhy has different dosing and administration instructions compared to IV nivolumab.

$^{1}$ See also CAR T-Cell-Related Toxicities in the NCCN Guidelines for Management of CAR T-Cell and Lymphocyte Engager-Related Toxicities for the management of cytokine release syndrome (CRS) and neurologic toxicity.

REFERENCES

Richter Transformation

Chemoimmunotherapy

CHOP + Rituximab ± Venetoclax

Taimberidou AM, O'Brien S, Khouri I, et al. Clinical outcomes and prognostic factors in patients with Richter's syndrome treated with chemotherapy or chemoimmunotherapy with or without stem-cell transplantation. J Clin Oncol 2006;24:2343-2351.

Davids MS, Rogers KA, Jain N, et al. Initial results of a multicenter phase 2 study of venetoclax in combination with R-CHOP (VR-CHOP) for patients with Richter Syndrome [abstract]. Hematol Oncol 2023;41:466-468.

Davids MS, Rogers KA, Tyekucheva S, et al. Venetoclax plus dose-adjusted R-EPOCH for Richter syndrome. Blood 2022;139:686-689.

Dose-adjusted-EPOCH-R

Rogers KA, Huang Y, Ruppert A, et al. A single-institution retrospective cohort study of first-line R-EPOCH chemoimmunotherapy for Richter syndrome demonstrating complex chronic lymphocytic leukaemia karyotype as an adverse prognostic factor. Br J Haematol 2018;180:259-266.

HyperCVAD + Rituximab

Tsimberidou AM, Kantarjian HM, Cortes J, et al. Fractionated cyclophosphamide, vincristine, liposomal daunorubicin, and dexamethasone plus rituximab and granulocyte-macrophage-conystimulating factor (GM-CSF) alternating with methotrexate and cytarabine plus rituximab and GM-CSF in patients with Richter syndrome or fludarabine-refractory chronic lymphocytic leukemia. Cancer 2003;97:1711-1720.

Tsimberidou AM, O'Brien S, Khouri I, et al. Clinical outcomes and prognostic factors in patients with Richter's syndrome treated with chemotherapy or chemoimmunotherapy with or without stem-cell transplantation. J Clin Oncol 2006;24:2343-2351.

OFAR

Tsimberidou AM, Wierda WG, Wen S, et al. Phase I-II clinical trial of oxaliplatin, fludarabine, cytarabine, and rituximab therapy in aggressive relapsed/refractory chronic lymphocytic leukemia or Richter syndrome. Clin Lymphoma Myeloma Leuk 2013;13:568-574.

Continued

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

HT-A 2 OF 3

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 2.2026 Histologic Transformation (Richter)

NCCN Guidelines Index Table of Contents Discussion

SUGGESTED TREATMENT REGIMENS REFERENCES

Richter Transformation (continued)

ICI-based regimens

Venetoclax/Atezolizumab + Obinutuzumab

Tedeschi A, Frustaci AM, Condoluci A, et al. Atezolizumab, venetoclax, and obinutuzumab combination in Richter transformation diffuse large B-cell lymphoma (MOLTO): A multicentre, single-arm, phase 2 trial. Lancet Oncol 2024;25:1298-1309.

Nivolumab

Jain N, Senapati J, Thakral B, et al. A phase 2 study of nivolumab combined with ibrutinib in patients with diffuse large B-cell Richter transformation of CLL. Blood Adv 2023;7:1958-1966.

Rogers KA, Huang Y, Dotson E, et al. Use of PD-1 (PDCD1) inhibitors for the treatment of Richter syndrome: experience at a single academic centre. Br J Haematol 2019;185:363-366.

Pembrolizumab

Armand P, Murawski N, Molin D, et al. Pembrolizumab in relapsed or refractory Richter syndrome. Br J Haematol 2020;190:e117-e120.

Wang Y, LaPlant BR, Parikh SA, et al. Efficacy of pembrolizumab monotherapy and in combination with BCR inhibitors for Richter transformation of chronic lymphocytic leukemia (CLL) [abstract]. J Clin Oncol 2024;42:Abstract 7050.

Rogers KA, Huang Y, Dotson E, et al. Use of PD-1 (PDCD1) inhibitors for the treatment of Richter syndrome: experience at a single academic centre. Br J Haematol 2019;185:363-366.

Zanubrutinib + Tislelizumab-jsgr

Al-Sawaf O, Ligtvoet R, Robrecht S, et al. Tisleizumab plus zanubrutinib for Richter transformation: the phase 2 RT1 trial. Nat Med 2024;30:240-248.

Al-Sawaf O, Robrecht S, Giza A, et al. Correlates of response to combined checkpoint and BTK inhibition for treatment of richter transformation: Extended follow-up from the prospective RT1 trial [abstract]. Blood 2025;146:Abstract 90.

BTKi (monotherapy)

Acalabrutinib

Eyre TA, Schuh A, Wierda WG, et al. Acalabrutinib monotherapy for treatment of chronic lymphocytic leukaemia (ACE-CL-001): analysis of the Richter transformation cohort of an open-label, single-arm, phase 1-2 study. Lancet Haematol 2021;8:e912-e921.

Bispecific Antibody Therapy

Epcoritamab-bysp

Kater A, Janssens A, Eradat H, et al. Epcoritamab monotherapy demonstrates promising efficacy in patients with Richter transformation (RT): 2-year follow-up results from arm 2A of the phase 1b/2 EPCORE CLL-1 trial [abstract]. Blood 2025;146:Abstract 1017.

Glofitamab-gxbm

Carlo-Stella C, Hutchings M, Offner F, et al. Glofitamab monotherapy induces durable complete remissions and has a manageable safety profile in patients with Richter's transformation [abstract]. Hematological Oncology 2023;41:Abstract 28.

Hutchings M, Morschhauser F, Iacoboni G, et al. Glofitamab, a novel, bivalent CD20-targeting cell-engaging bispecific antibody, induces durable complete remissions in relapsed or refractory B-cell Lymphoma: a phase I trial. J Clin Oncol 2021;39:1959-1970.

Pirtobrutinib

Wierda WG, Shah NN, Cheah CY, et al. Pirtobrutinib, a highly selective, non-covalent (reversible) BTK inhibitor in patients with B-cell malignancies: analysis of the Richter transformation subgroup from the multicentre, open-label, phase 1/2 BRUIN study. Lancet Haematol 2024;11:e682-e692.

CAR T-Cell Therapy

Axicabtagene ciloleucel

Kittai AS, Bond D, Huang Y, et al. Anti-CD19 chimeric antigen receptor T-cell therapy for Richter transformation: An international, multicenter, retrospective study. J Clin Oncol 2024;42:2071-2079.

Lisocabtagene maraleucel

Winter AM, Bharadwaj S, Herrera AF, et al. Real-world outcomes of lisocabtagene maraleucel (iso-cel) in patients (pt) with Richter transformation (RT) from the Center for International Blood and Marrow Transplant Research (CIBMTR) [abstract]. J Clin Oncol 2024;42:Abstract 7010.

Tisagencleucel

Kittai AS, Bond D, Huang Y, et al. Anti-CD19 chimeric antigen receptor T-cell therapy for Richter transformation: An international, multicenter, retrospective study. J Clin Oncol 2024;42:2071-2079.

Histologic Transformation to Hodgkin Lymphoma

Stephens D, Boucher K, Kander E, et al. Hodgkin lymphoma arising in patients with chronic lymphocytic leukemia: outcomes from a large multi-center collaboration Haematologica 2021;106:2845-2852.

Parikh SA, Habermann TM, Chaffee KG, et al. Hodgkin transformation of chronic lymphocytic leukemia: Incidence, outcomes, and comparison to de novo Hodgkin lymphoma. Am J Hematol 2015;90:334-338.

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

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 2.2026

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

NCCN Guidelines Index Table of Contents Discussion

ABBREVIATIONS

|AIHA|autoimmune hemolytic anemia|HBcAb|hepatitis B core antibody|PFS|progression-free survival| |---|---|---|---|---|---| |ALC|absolute lymphocyte count|HBsAg|hepatitis B surface antigen|PI3Ki|PI3K inhibitor| |ANC|absolute neutrophil count|HBV|hepatitis B virus|PJP|pneumocystis jirovecii pneumonia| |ASO-PCR|allele-specific oligonucleotide polymerase chain reaction|HCT|hematopoietic cell transplant|PML|progressive multifocal leukoencephalopathy| |BCL2i|BCL2-inhibitor|HLA|human leukocyte antigen|PRCA|pure red cell aplasia| |BTKi|BTK inhibitor|HR|hazard ratio|qPCR|quantitative RT-PCR| |C/A/P|chest/abdomen/pelvis|IHC|immunohistochemistry|RS|Reed-Sternberg| |CAR|chimeric antigen receptor|ISRT|involved-site radiation therapy|RSV|respiratory syncytial virus| |CBC|complete blood count|ITP|immune thrombocytopenic purpura|RT-PCR|reverse transcriptase polymerase chain reaction| |cBTKi|covalent BTK inhibitor|IVF|in vitro fertilization||| |CHL|classic Hodgkin lymphoma|IVIG|intravenous immunoglobulin||| |CIT|chemoimmunotherapy|JCV|SCIG|subcutaneous immunoglobulin|| |CK|complex karyotype|JCV|John Cunningham virus|SIFE|serum immunofixation electrophoresis| |CMV|cytomegalovirus|LDH|lactate dehydrogenase||| |CRCl|creatinine clearance|LVEF|left ventricular ejection fraction|SPEP|serum protein electrophoresis| |CRS|cytokine release syndrome|LVEF|left ventricular ejection fraction|SUV|standardized uptake value| |DAA|direct-acting antiviral||||| |DLBCL|diffuse large B-cell lymphoma|mb|monoclonal antibody|TLS|tumor lysis syndrome| |EBER|Epstein-Barr virus-encoded RNA|MBL|monoclonal B-cell lymphocytosis|TTFT|time-to-first treatment| |EBER-ISH|Epstein-Barr virus-encoded RNA in situ hybridization|MCL|mantle cell lymphoma|TTNT|time-to-next treatment| |EBV|Epstein-Barr virus|MRD|minimal residual disease|uMRD|undetectable MRD| |ERIC|European Research Initiative on CLL|MUGA|multigated acquisition||| |FISH|fluorescence in situ hybridization|ncBTKi|noncovalent BTK inhibitor|VAF|variant allele frequency| |FNA|fine-needle aspiration|NGS|next-generation sequencing|VZV|varicella zoster virus| |G6PD|glucose-6-phosphate dehydrogenase|NHL|non-Hodgkin lymphoma|WBC|white blood cell| |GVHD|graft-versus-host disease|OS|overall survival|WT|wild type|

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NCCN Guidelines Index Table of Contents Discussion

|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

Literature Search Criteria...................................................................................................................................................................................... MS-2

Sensitive/Inclusive Language Usage .................................................................................................................................................................... MS-2

Staging................................................................................................................................................................................................................. MS-3

Prognostic Factors ............................................................................................................................................................................................... MS-3

Response Criteria ................................................................................................................................................................................................. MS-8

Measurable Residual Disease ............................................................................................................................................................................ MS-10

Diagnosis ........................................................................................................................................................................................................... MS-14

Workup .............................................................................................................................................................................................................. MS-15

First-Line Therapy .............................................................................................................................................................................................. MS-16

Second-Line and Subsequent Therapy ............................................................................................................................................................... MS-23

Special Considerations for Treatment ................................................................................................................................................................. MS-28

Histologic Transformation ................................................................................................................................................................................... MS-33

Supportive Care ................................................................................................................................................................................................. MS-38

Summary............................................................................................................................................................................................................ MS-41

References ......................................................................................................................................................................................................... MS-50

This discussion corresponds to the NCCN Guidelines for Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma. Last updated: December 22, 2025.

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Overview

Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are characterized by progressive accumulation of leukemic cells in the peripheral blood, bone marrow, and lymphoid tissues.$^{1}$ Morphologically, these leukemic cells appear as small, mature lymphocytes that can be found admixed with occasional larger or atypical cells, or prolymphocytes. CLL remains the most prevalent adult leukemia in Western countries. In 2025, an estimated 23,690 people will be diagnosed with CLL in the United States, and an estimated 4460 people will die from the disease.$^{2}$

CLL and SLL are essentially different manifestations of the same disease that are similarly managed.$^{1}$ The major difference is that in CLL, a significant number of the abnormal lymphocytes are found circulating in blood in addition to being resident in bone marrow and lymphoid tissue, while in SLL, the bulk of disease is in lymph nodes, bone marrow, and other lymphoid tissues and there are few (if any) abnormal lymphocytes circulating in blood.

Guidelines Update Methodology

The complete details of the Development and Update of the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) are available at www.NCCN.org.

Literature Search Criteria

Prior to the update of this version of the NCCN Clinical Practice Guidelines (NCCN Guidelines®) for CLL/ SLL, an electronic search of the PubMed database was performed to obtain key literature in CLL and SLL published since the previous Guidelines update using the following search terms: chronic lymphocytic leukemia/small lymphocytic lymphoma, Richter syndrome, and histologic transformation. The PubMed database was

chosen as it remains the most widely used resource for medical literature and indexes peer-reviewed biomedical literature.$^{3}$

The search results were narrowed by selecting studies in humans published in English. Results were confined to the following article types: Randomized Controlled Trial; Clinical Trial, Phase II; Clinical Trial, Phase III; Clinical Trial; Guideline; Meta-Analysis; Systematic Reviews; and Validation Studies.

The data from key PubMed articles as well as articles from additional sources deemed relevant to these guidelines as discussed by the Panel during the Guidelines update were 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.

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, anti-misogynist, 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

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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.

Staging

The Rai and Binet systems are the two staging systems currently used for the evaluation of patients with CLL, both in routine practice and clinical trial settings.$^{4,5}$ Both staging systems rely on physical assessments (ie, presence of lymph node involvement, enlarged spleen and/or liver) and blood parameters (presence of anemia or thrombocytopenia) to evaluate the degree of tumor burden.

The modified Rai classification stratifies patients into three risk groups: low-risk disease (Rai stage 0), intermediate-risk disease (Rai stage I–II), and high-risk disease (Rai stage III–IV) with historic median survival times of 150 months, 71 to 101 months, and 19 months, respectively, in the era of chemotherapy- and chemoimmunotherapy-based treatment.$^{4}$ Survival times in the current era of targeted therapy will most assuredly be improved and will become available with longer follow-up for patients who received targeted therapies.

The Binet staging system stratifies patients into three prognostic groups based on the number of involved areas and the level of hemoglobin and platelets and, like the Rai staging system, provides meaningful correlation with clinical outcome.$^{5}$

The Lugano Modification of the Ann Arbor Staging System is used for patients with SLL.$^{6}$

Prognostic Factors

The prognostic significance of molecular and cytogenetic variables may vary depending on the patient population, treatment regimens, and clinical

outcomes being evaluated. The impact of these variables on the clinical outcome is discussed below.

Immunoglobulin Heavy Chain Variable Region Gene Mutation

A cut-off level of ≤2% deviation from germline immunoglobulin heavy chain variable (IGHV) sequence is routinely used in clinical practice to differentiate IGHV unmutated CLL from IGHV mutated CLL.7-9 Percent deviation from the germline sequence was studied and higher levels were incrementally associated with favorable progression-free survival (PFS) and overall survival (OS) following treatment with the FCR (fludarabine, cyclophosphamide, and rituximab), suggesting that IGHV mutation percentage is a continuous variable.10 In addition, IGHV gene usage involving VH3-21 is associated with poor outcomes regardless of the IGHV mutation status (as defined by percent homology with germline sequence).11

Unmutated IGHV (≤2% of mutation or ≥98% homology with germline gene sequence) and/or the VH3-21 gene usage is associated with lower response rates and shorter time-to-first treatment (TTFT) and significantly shorter PFS and OS compared to mutated IGHV in patients receiving chemoimmunotherapy, independent of the stage of the disease.$^{12-17}$

Continuous treatment with a covalent BTKi (cBTKi; ibrutinib, acalabrutinib, or zanubrutinib) with or without anti-CD20 monoclonal antibody (mAb) results in high response rates and survival independent of the IGHV mutation status.$^{18-23}$

IGHV unmutated status remains a prognostic factor for shorter survival after time-limited treatment with BCL2 inhibitor (BCL2i)-containing regimens (venetoclax + anti-CD20 mAb or venetoclax + cBTKi with or without anti-CD20 mAb).$^{24-34}$ IGHV-unmutated status and/or the VH3-21 gene usage was also an independent predictor of shorter treatment-free interval and/or survival after time-limited treatment with BCL2i-containing

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regimens even when high-risk genetic abnormalities were included in the multivariable regression models.$^{14,15}$

BTKi-Based Regimens

The ELEVATE-TN trial showed that acalabrutinib ± obinutuzumab resulted in greater PFS benefit compared to chlorambucil + obinutuzumab both in IGHV-unmutated and IGHV-mutated CLL; however, in patients with IGHV-mutated CLL, the PFS benefit was significant only for combined acalabrutinib + obinutuzumab.$^{19}$

The results of the SEQUOIA study confirmed that PFS was significantly better for zanubrutinib (compared to BR) in patients with IGHV-unmutated CLL.22

In the ECOG-ACRIN Cancer Research Group (E1912) study, ibrutinib + rituximab resulted in superior PFS compared to FCR in patients with IGHV-unmutated CLL (hazard ratio [HR], 0.27; P < .001) and IGHV-unmutated CLL (HR, 0.27; P < .001).$^{23}$

BCL2i-Containing Regimens

Venetoclax + anti-CD20 mAb

The extended follow-up data from the CLL14 study showed that venetoclax + obinutuzumab (VenO) resulted in longer PFS for patients with IGHV-mutated CLL compared to those with IGHV unmutated CLL (after a median follow-up of 76 months, the median PFS was not reached for patients in the IGHV-mutated group compared to 65 months for those in the IGHV-unmutated group).$^{24}$

In the phase III randomized GAIA/CLL13 trial, although VenO with or without ibrutinib resulted in significant PFS benefit compared to chemoimmunotherapy among patients with IGHV unmutated CLL as well as in those with IGHV mutated CLL, in the exploratory subgroup analysis

unmutated IGHV was a predictor of shorter PFS across all treatment groups.$^{25,26}$

In the CLL17 trial (N = 909; venetoclax-obinutuzumab, n = 303; venetoclax-ibrutinib, n = 305; ibrutinib, n = 301) that established the non-inferiority of VenO and venetoclax/ibrutinib compared to continuous treatment with ibrutinib, PFS rates were higher for VenO for patients with IGHV-mutated CLL, the PFS benefit was significant only for combined acalabrutinib + obinutuzumab.$^{19}$

Venetoclax/ibrutinib

Venetoclax/ibrutinib prolonged PFS independent of IGHV mutation status in the GLOW trial. However, the estimated 60-month PFS rate was higher for IGHV mutated CLL compared to IGHV unmutated CLL (83% and 52%, respectively).$^{27}$,$^{28}$

In the FLAIR study, the PFS was significantly better for venetoclax/ibrutinib (compared to FCR) in patients with IGHV unmutated CLL; however, PFS was not significantly different between the treatment arms among patients with IGHV mutated CLL.$^{29}$ The 5-year PFS rates for venetoclax/ibrutinib were 91% and 88% for IGHV unmutated and IGHV mutated CLL, respectively compared to 57% and 76%, respectively for FCR. Venetoclax/ibrutinib was also associated with longer PFS than ibrutinib among patients with IGHV unmutated CLL, but the PFS was similar between these two treatment groups among patients with IGHV mutated CLL.

In the CAPTIVATE study, fixed duration treatment with venetoclax/ibrutinib resulted in higher PFS rates in patients with IGHV mutated CLL than in those with IGHV unmutated CLL. The 5.5-year PFS rates were 79% and 55%, respectively.$^{30,31}$ PFS rates were also higher for patients with IGHV mutated CLL than IGHV unmutated CLL in the phase II study that evaluated venetoclax/ibrutinib as MRD-guided treatment.$^{32}$

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In CLL17 trial discussed above, venetoclax/ibrutinib resulted in similar PFS rates regardless of IGHV mutations status.$^{35}$ The 3-year PFS rate was 79% for patients with IGHV-unmutated CLL compared to 80% for those with IGHV-unmutated CLL.

Venetoclax/Acalabrutinib ± Obinutuzumab

In the AMPLIFY trial, the 36-month PFS rates were 84% and 86% for venetoclax/acalabrutinib + obinutuzumab (AVO) and venetoclax/acalabrutinib, respectively in the subgroup of patients with IGHV mutated CLL and the addition of obinutuzumab to venetoclax/acalabrutinib was associated with higher survival benefit in the subgroup of patients with IGHV-unmutated CLL (36-month PFS rate was 83% for AVO compared to 69% for acalabrutinib + venetoclax).$^{33}$

In the phase II study that evaluated AVO as MRD-guided treatment in patients with previously untreated CLL including CLL with TP53 aberrations, AVO resulted in higher PFS rates in the subgroup of patients with IGHV-mutated CLL than in those with IGHV unmutated CLL.34 The 4-year PFS rates were 93% and 81% in patients with IGHV mutated CLL and IGHV unmutated CLL, respectively.

Cytogenetic Abnormalities

Cytogenetic abnormalities detected by fluorescence in situ hybridization (FISH) are present in >80% of patients with CLL.$^{36}$

Del(13q) (55%), del(11q) (18%), trisomy 12 (16%), del(17p) (7%), and del(6q) (7%) are the most common abnormalities at the time of diagnosis. Del(13q) as a sole abnormality was associated with favorable prognosis and the longest median survival (133 months) after chemoimmunotherapy. Del(11q) is often associated with extensive lymphadenopathy, disease progression, shortened TTFT, and shorter median survival (79 months) after chemoimmunotherapy. Trisomy 12 is

associated with intermediate prognosis for TTFT and OS in patients with newly diagnosed CLL treated with chemoimmunotherapy.$^{36}$

Del(17p) reflects the loss of the TP53 gene and is frequently associated with mutation in the remaining TP53 allele. Del(17p) is more frequently observed in patients with previously treated CLL, suggesting that acquisition and/or expansion of CLL clones with del(17p) may occur through treatment. The prognostic significance of del(17p) may be dependent on the proportion of malignant cells with this abnormality, and the prognosis is more favorable when the percentage of cells with del(17p) is low.$^{37,38}$

TP53 Aberrations

TP53 aberrations [del(17p) or TP53 mutation] are predictors of poor outcomes with chemoimmunotherapy. Del(17p) is associated with inferior response, shorter treatment-free interval, and inferior survival with chemoimmunotherapy.$^{17,36,39}$ TP53 mutations (independent of 17p chromosome status) are predictors of shorter PFS and OS with fludarabine- or bendamustine-containing chemoimmunotherapy regimens.$^{40-43}$

TP53 aberrations also remain an independent predictor of inferior PFS and OS for time-limited treatment with venetoclax-containing regimens.44,45 Del(17p) and TP53 mutation are independent predictors of PFS and OS, whereas del(17p) and/or TP53 mutation with IGHV-unmutated status is associated with the shortest PFS.44,45 Continuous treatment with a cBTKi also results in shorter PFS and OS in patients with del(17p) or TP53-mutated CLL.18,19,23,46,47 However, the survival outcomes for CLL with TP53 aberrations treated with either a BTKi-based regimen or a venetoclax-containing regimen are much better than the survival outcomes following chemoimmunotherapy.

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TP53 mutations with del(17p) are associated with poor prognosis (increased resistance to chemoimmunotherapy and targeted therapies; significantly shortened TTFT and time to next treatment as well as potentially increased risk for Richter transformation). Survival outcomes (PFS and OS) for patients with TP53-mutated CLL in the absence of del(17p) may be more favorable than those with TP53-mutated CLL and del(17p).$^{41}$,$^{48}$

TP53 mutations of low variant allele frequencies (VAF; <10%) may have prognosis similar to TP53 wild type in terms of OS.$^{49-52}$ In a retrospective analysis of 964 patients, TP53 mutations of low VAF (<10%) and high VAF (≥10%) were found in 28% and 53% of patients, respectively.$^{51}$ TP53 mutations of high VAF were associated with shorter TTFT (0.3 years, P < .001) compared to TP53 mutations of low VAF (1.2 years) and TP53 wild type (4 years). The 5-year OS rates were also inferior for patients with TP53 mutations of high VAF (80%) compared to 93% and 91% for those with TP53 mutations of low VAF and TP53 wild type, respectively. Other studies have shown that TP53 mutations of low VAF (1%–10%) were associated with clonal expansion as well as short time to next treatment (TTNT) and OS following treatment with chemoimmunotherapy, but it did not have any prognostic impact on OS in patients with CLL/SLL treated with targeted therapy.$^{49,50,52}$

Complex Karyotype

Complex karyotype (CK; ≥3 unrelated chromosomal abnormalities in more than one cell on CpG-stimulated karyotype of CLL cells) is associated with inferior clinical outcomes. A retrospective analysis of >5000 patients with available cytogenetic data indicated that CK was associated with variable clinical behavior.$^{53}$ High CK (≥5 unrelated chromosomal abnormalities) emerged as an adverse prognostic factor independent of clinical stage, IGHV mutation status, and TP53 aberrations [del(17p) and/or TP53 mutation], whereas low CK (three unrelated chromosomal abnormalities)

and intermediate CK (four unrelated chromosomal abnormalities) were clinically relevant only if coexisting with TP53 aberrations.

CK may be a stronger predictor of poor clinical outcomes than del(17p) or TP53 mutation in patients with CLL treated with ibrutinib-based regimens.$^{54-57}$ It should be noted that in these studies, del(17p) often correlated with the presence of CK. Among patients with relapsed or refractory CLL treated with ibrutinib-based regimens, in a multivariable analysis, only CK was significantly associated with shorter event-free survival (EFS; P = .006), whereas CK (P = .008) and fludarabine-refractory CLL (P = .005) were independently associated with shorter OS.$^{54}$ In an analysis of 308 patients with CLL treated with ibrutinib on four sequential clinical trials, in a multivariable analysis, CK at baseline, presence of del(17p), and age <65 years were all independently associated with shorter time to CLL progression.$^{57}$ In patients ≥65 years without CK or del(17p), the estimated cumulative incidence of CLL progression at 4 years was 2% compared to 44% in patients <65 years with CK and del(17p). CK was not associated with worse PFS in patients with treatment-naïve CLL treated with zanubrutinib in the SEQUOIA study.$^{58}$ The result of another retrospective analysis (n = 1339) also showed that CK is a significant prognostic factor of inferior OS compared to isolated TP53 mutation.$^{59}$ TP53 aberration in univariate (P < .001) and multivariate analysis (P = .002) was a significant predictor of inferior OS; however, TP53 aberration lost its significance (P = .94) in multivariate analysis in the presence of CK (P < .001).

High CK was an adverse prognostic factor in patients with CLL treated with venetoclax-containing regimens.$^{60}$ In a prospective analysis of the GAIA/CLL13 trial, CK (≥3 unrelated chromosomal abnormalities) was associated with shorter PFS (HR, 2.6; P < .001) and OS (HR, 3.25; P = .044) after treatment with chemoimmunotherapy, whereas only high CK (≥5 unrelated chromosomal abnormalities) was an independent adverse

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prognosticator for PFS in the pooled venetoclax arms.$^{60}$ Chemoimmunotherapy resulted in the acquisition of additional chromosomal abnormalities whereas CK remained stable after treatment with venetoclax-containing regimens.

Beta-2 Microglobulin

Beta-2 microglobulin is readily measured by standard laboratory evaluation of blood samples, and an elevated level of serum beta-2 microglobulin was shown to be a strong independent prognostic indicator for treatment-free interval, response to treatment, and OS following treatment with first-line chemoimmunotherapy.$^{61,62}$ Beta-2 microglobulin was incorporated in prognostic models for the risk stratification of patients with CLL.$^{63-66}$ However, it is influenced in a CLL disease-independent manner by renal dysfunction.

Other Gene Mutations

In addition to TP53 mutation, recurrent mutations with prognostic implications were identified in ATM, NOTCH1, SF3B1, and BIRC3 genes. The incidence of these mutations is approximately 4% to 15% in patients with newly diagnosed CLL, and the incidences are much higher (15%—25%) in patients with fludarabine-refractory CLL.57-71 ATM, SF3B1, and NOTCH1 mutations were predictors of shorter TTFT independent of IGHV mutation status, whereas TP53 and NOTCH1 mutations along with IGHV-unmutated status were predictors of shorter OS.70 In the CLL14 study, BIRC3 and SF3B1 mutations were independent predictors of inferior PFS after chemoimmunotherapy with chlorambucil + obinutuzumab, but these mutations had no impact on the clinical outcome after VenO; however, the follow-up was short.44 In the MURANO study, pre-existing TP53, NOTCH1, and BRAF mutations were associated with lower rates of initial attainment of uMRD4 following treatment with VenR.72 BCOR, CCND2, NRAS, and XPO1 mutations at baseline were associated with poor MRD response as well as inferior PFS and OS following MRD-

guided treatment with venetoclax/ibrutinib in relapsed/refractory CLL/SLL.$^{73}$

An integrated prognostic model including NOTCH1, SF3B1, and BIRC3 mutations along with the cytogenetic abnormalities detected by FISH was proposed to classify patients with newly diagnosed or previously untreated CLL who received rituximab-based chemoimmunotherapy or fludarabine or alkylating agent-based chemotherapy into four distinct prognostic subgroups: high risk (TP53 and/or BIRC3 abnormalities); intermediate risk (NOTCH1 and/or SF3B1 mutations and/or del[11q]); low risk (trisomy 12 and wild type for all genetic lesions); and very low risk (del[13q] only).$^{74}$ The 10-year survival rates for the four subgroups were 29%, 37%, 57%, and 69%, respectively. This prognostic model may have limited utility since it excludes the IGHV mutation status.

Prognostic Models

Several scoring systems and prognostic models incorporating traditional and newer prognostic markers were developed to predict the clinical course of disease and outcomes more accurately.

A prognostic nomogram and a more simplified prognostic index (based on age, beta-2 microglobulin, absolute lymphocyte count (ALC), sex, Rai stage, and number of involved lymph nodes) is useful in estimating TTFT in patients with untreated CLL, including those with early-stage disease and the utility of this prognostic index was confirmed in several studies.$^{64,75,76}$ The simplified prognostic index is also useful in estimating the survival probability and stratifies patients with untreated CLL into three different risk groups (low, intermediate, and high) with different survival outcomes.$^{64}$ The 5-year survival rates were 97% for low-risk, 80% for intermediate-risk, and 55% for high-risk groups; the 10-year survival rates were 80%, 52%, and 26%, respectively.

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In another prognostic model, increased size of cervical lymph nodes, three involved nodal sites, del(17p) or del(11q), IGHV-unmutated status, and elevated serum lactate dehydrogenase (LDH) levels were identified as independent predictors of shorter TTFT.$^{77}$ This model may help to identify patients with newly diagnosed CLL at high risk for disease progression who may be candidates for clinical trials of interventions to delay TTFT with chemoimmunotherapy.

The Integrated CLL Scoring System (ICSS) is based on the cytogenetic abnormalities detected by FISH, IGHV mutation status, and CD38 expression.$^{78}$ ICSS stratified patients into three risk groups (low, intermediate, and high) with different TTFT and OS. ICSS is also helpful to identify patients with a high likelihood of early progression who would be candidates for clinical trials evaluating early interventions.

The International Prognostic Index for CLL (CLL-IPI) is based on TP53 and IGHV mutation status, serum beta-2 microglobulin concentration, clinical stage, and age.$^{63}$ The CLL-IPI was validated in an independent cohort of patients with newly diagnosed CLL and is useful for predicting TTFT and risk of progression in patients receiving first-line chemoimmunotherapy.$^{79}$ CLL-IPI stratifies patients into four risk groups (low, intermediate, high, and very high) with significantly different OS. The 5-year OS rates were 93%, 79%, 63%, and 23%, for the four risk groups, respectively.

The International Prognostic Score for Early-Stage CLL (IPS-E) predicts the likelihood of disease progression to need treatment in patients with early-stage CLL and stratifies patients with early-stage CLL into three risk groups with significantly different TTFT.$^{80}$ The cumulative risk for the need of treatment after 1 and 5 years of observation was 14% and 61%, respectively, for patients with high-risk IPS-E compared to 2% and 28% for patients with intermediate-risk IPS-E and <0.1% and 8% for patients with

low-risk IPS-E. These findings need to be validated in a prospective clinical trial.

Targeted therapies with small-molecule inhibitors have significantly improved survival outcomes and prognostic models were developed to predict the outcome following treatment with targeted therapies.$^{65,66}$ The first prognostic model is predictive of survival following treatment with ibrutinib and stratified patients into three risk groups (high [3–4 points]; intermediate [2 points]; and low [0 points]) based on TP53 aberrations, prior treatment, elevated serum beta-2 microglobulin, and LDH.$^{65}$ The 3-year PFS rates were 47%, 74%, and 87% for the high-, intermediate-, and low-risk groups, respectively (P < .0001). The corresponding 3-year OS rates were 63%, 83%, and 93%, respectively (P < .0001). This model remained significant in the stratification of patients with treatment-naïve and relapsed or refractory CLL. The second prognostic model identified patients with high-risk previously treated CLL who do not achieve a good outcome with available targeted therapies (ibrutinib, idelalisib, and venetoclax).$^{66}$ This prognostic model stratified patients into three risk groups based on elevated serum beta-2 microglobulin and LDH, hemoglobin, and time from initiation of last therapy (<24 months): low (score 0–1); intermediate (score 2–3); and high risk (score 4).

Response Criteria

The response criteria developed by the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) provide recommendations for the evaluations and response assessments appropriate for the general clinical practice setting versus for clinical trials.$^{81}$ These response criteria are based on the size of lymph nodes, liver and/or spleen, presence or absence of constitutional symptoms, circulating lymphocyte count and blood parameters.$^{81}$

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In clinical trials, the size of the lymph nodes is evaluated by CT scans and physical examination. There is no firmly established international consensus on the size of a normal liver. Therefore, in clinical trials, the liver size is evaluated by imaging and palpation and recorded according to the definition used in a study protocol. In the clinical practice setting, response assessment involves both physical examination and evaluation of blood parameters.

Complete Response

All of the following criteria must be met at least 2 months after treatment completion: normal circulating lymphocyte count; absence of lymphadenopathy (palpable nodes must be ≤1.5 cm in diameter), splenomegaly or hepatomegaly; absence of constitutional symptoms (weight loss, significant fatigue, fevers, night sweats); and normalization of blood counts without growth factor support.

Patients who fulfill the criteria for a complete response (CR) but present with persistent cytopenias should be considered as having achieved a CR with incomplete bone marrow recovery.

Partial Response

At least two of the following criteria must be met for at least 2 months duration: ≥50% reductions from baseline in peripheral blood lymphocyte counts, lymphadenopathy, hepatomegaly; and/or splenomegaly (if present at baseline). In addition, at least one of the blood counts should be normalized or increase by ≥50% from baseline, for at least 2 months duration.

Partial Response with Lymphocytosis

Treatment with both cBTKi (ibrutinib, acalabrutinib, zanubrutinib) and noncovalent (reversible) BTKi (ncBTKi; pirtobrutinib) and phosphatidylinositol 3-kinase inhibitors (PI3Ki; idelalisib and duvelisib)

cause mobilization of lymphocytes into blood early during treatment initiation, resulting in a significant transient lymphocytosis (increase in absolute lymphocyte count [ALC]) in most patients, which does not signify disease progression. This situation may also occur with investigational kinase inhibitors that target similar pathways. Prolonged lymphocytosis following ibrutinib treatment was reported to represent the persistence of a quiescent clone, and slow or incomplete resolution of lymphocytosis does not appear to impact outcome as measured by PFS.$^{82}$

Considering these findings, the iwCLL response criteria were revised to more precisely predict the outcome of patients with CLL treated with BTKi and PI3Ki.$^{83}$ The revised iwCLL response criteria allow for the response category, partial response (PR) with lymphocytosis (PR-L). In patients receiving BTKi (ibrutinib, acalabrutinib, zanubrutinib, or pirtobrutinib) or PI3Ki (idelalisib or duvelisib), this response category includes clinical response (reduction in lymph nodes and splenomegaly with persistent lymphocytosis, in the absence of other indicators of progressive disease). Isolated progressive lymphocytosis in the setting of reduced lymph node size or organomegaly or improvement in hemoglobin/platelets will not be considered progressive disease.

Progressive Disease

Progressive disease comprises any of the following: at least 50% increase from baseline in lymphocyte counts, lymphadenopathy, hepatomegaly, or splenomegaly; appearance of any new lesions; or occurrence of cytopenias attributable to disease (≥50% decrease from baseline in platelet count or >2 g/dL decrease from baseline in hemoglobin levels).

Stable Disease

Patients who do not meet the criteria for a CR or PR in the absence of disease progression are considered to have stable disease.

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Relapse or Refractory Disease

Relapse is defined as evidence of disease progression after a period of ≥6 months following an initial CR or PR. Refractory disease is defined as lack of response to treatment or disease progression within 6 months of the last treatment.

Measurable Residual Disease

Measurable residual disease (MRD) is a highly sensitive indicator of disease burden in patients with CLL, and assessment of MRD as part of response evaluation is incorporated into some clinical trials.

MRD detection can be performed by several methods with different sensitivities using either blood or bone marrow. A commercial next-generation sequencing (NGS)-based assay was reported to be more sensitive, allowing for the detection of undetectable MRD (uMRD) at the level of $10^{-6}$ (uMRD6), and is the only assay currently available in the United States that is cleared by the U.S. Food and Drug Administration (FDA).$^{84-87}$ NGS-based assays require collection of a pretreatment sample. Multicolor (≥4) flow cytometry (MRD flow) and allele-specific oligonucleotide polymerase chain reaction (ASO-PCR) are the two other methods used for the detection of uMRD at the level of $10^{-4}$ (uMRD4) to $10^{-5}$ (uMRD5) with significantly more supporting data from clinical trials. MRD flow is the most widely used method owing to the extensive availability and reliable detection at the level <$10^{-4}$ CLL cells.$^{88}$ ASO-PCR detects at the level <$10^{-5}$ CLL cells; however, it is less widely used since it is expensive and more labor intensive.$^{89}$

Consensus recommendations for the methodology for MRD determination, assay requirements and tissue selection (blood vs. bone marrow), and the use of MRD in clinical trials were published.$^{90,91}$ Few clinical trials have evaluated MRD-guided treatment protocols to determine the duration of treatment.$^{29,34,92}$

BTKi monotherapy does not typically result in uMRD, but the use of cBTKi in combination with anti-CD20 mAb results in higher rates of uMRD compared to monotherapy.$^{19,93,94}$ In the E1912 phase III randomized trial that compared FCR versus ibrutinib + rituximab, among patients randomized to ibrutinib + rituximab there was no significant difference in PFS rates based on uMRD status.$^{95}$ However, PFS was significantly longer in patients with MRD levels <$10^{-1}$ than those with MRD levels >$10^{-1}$ and continuous treatment with ibrutinib was necessary to maintain treatment efficacy. The prognostic value of uMRD has not been confirmed in the context of BTKi monotherapy or in combination with anti-CD20 mAb.

uMRD4 (MRD levels <10⁻$^{4}$) at the end of treatment (EOT) with chemoimmunotherapy is an independent predictor of improved survival among patients with previously untreated CLL.96,97 uMRD4 after EOT with venetoclax + obinutuzumab containing regimens is an independent predictor of longer PFS among patients with previously untreated as well as relapsed or refractory CLL.24,98 Findings from randomized clinical trials suggest that time-limited treatment (fixed duration or MRD-guided) with BCL2i-containing regimens (venetoclax + anti-CD20 mAb or venetoclax + cBTKi with or without anti-CD20 mAb) may result in higher rates of uMRD4 or uMRD6 (MRD levels <10⁻$^{6}$) in blood or bone marrow than single agent BTKi-based regimens or chemoimmunotherapy (Table 1).

Data from clinical trials that have evaluated time-limited treatment with BCL2i-containing regimens are discussed below.

Fixed Duration Regimens

Venetoclax + anti-CD20 mAb

In the CLL14 study, deeper uMRD remissions (uMRD5 and uMRD6) were more frequent with VenO and PFS was longer in patients with uMRD6 compared to those with detectable MRD4 at EOT. The 6-year PFS rates were 62% for patients with uMRD6 and 23% for those with detectable

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MRD4.$^{24}$,$^{45}$ The 6-year OS rate was 87% for patients with uMRD4 and 59% for those with detectable MRD4.

In the GAIA/CLL13 phase III randomized trial, VenO (with or without ibrutinib) resulted in significantly higher uMRD4 rates (P < .001) compared to chemoimmunotherapy, but the uMRD4 rate was not significantly higher with venetoclax + rituximab (VenR; P = .32) compared to chemoimmunotherapy.$^{25}$ VenO also resulted in higher rates of uMRD (blood) at 15 months (uMRD4, 81% vs. 55%; uMRD6, 64% vs. 28%) compared to chemoimmunotherapy with FCR or bendamustine and rituximab (BR) in the phase III CRISTALLO study.$^{99}$

Fixed duration treatment with venetoclax + obinutuzumab also resulted in higher rates of uMRD (blood) at the EOT compared to ibrutinib in the CLL17 trial (73% compared to 0% for ibrutinib).$^{35}$ This trial established venetoclax + obinutuzumab is non-inferior to continuous treatment with ibrutinib in terms of PFS (3-year PFS rates were 81% for both treatment arms).

In the MURANO study, uMRD as best MRD response at any time during the study was higher with VenR than BR (83% vs. 23%) and the 5-year follow-up data showed that uMRD at the EOT with VenR was associated with improved PFS and OS in patients with relapsed/refractory CLL/SLL.$^{98,100}$ The 3-year PFS rates after EOT were 61% for those with uMRD4 compared to 41% for those with low MRD-positive disease ($10^{-4}$ to <10$^{-2}$). The 3-year OS rates after EOT were 95% for those with uMRD4 and 73% for those with low MRD-positive disease ($10^{-4}$ to <10$^{-2}$) or high MRD-positive disease (>10$^{-2}$).$^{98}$ Unmutated IGHV, del(17p), and genomic complexity (≥3 copy number variations) were associated with higher rates of conversion to detectable MRD4 and subsequent progressive disease after attaining uMRD4 at EOT.$^{98}$

Venetoclax/ibrutinib

In the phase III randomized GLOW study, fixed duration treatment with venetoclax/ibrutinib (ibrutinib x 3 cycles followed by 12 cycles of combined venetoclax/ibrutinib) resulted in higher rate of uMRD4 at 3 months after EOT (EOT+3) across all subgroups including del(11q) and IGHV-unmutated CLL.$^{27}$,$^{28}$ The estimated PFS rate for patients with uMRD4 in the bone marrow at 12 months after EOT (EOT+12) was 96% for venetoclax/ibrutinib compared to 83% for chlorambucil + obinutzumab.$^{27}$ The rate of uMRD5 was also higher with venetoclax/ibrutinib (45% in blood; 40% in bone marrow) compared to chlorambucil + obinutzumab (22% and 6%, respectively). After a median follow-up of 64 months, PFS benefit was observed, particularly in patients with IGHV-unmutated CLL, who achieved uMRD4 at EOT+3 (48-month PFS rate was 67% vs. 40% for those with detectable MRD); PFS rates at 48 months after EOT were also higher with venetoclax/ibrutinib among patients with IGHV-unmutated CLL (≥84%) independent of the MRD status at EOT+3.$^{28}$

The results of the phase II randomized CAPTIVATE study showed that fixed duration treatment with venetoclax/ibrutinib (ibrutinib x 3 cycles followed by 12 cycles of combined venetoclax/ibrutinib) resulted in high rates of uMRD4 in all subgroups (del[17p] and/or mutated TP53, del[11q], and IGHV-unmutated CLL).$^{30}$,$^{31}$,$^{101}$,$^{102}$ In the fixed-duration treatment cohort, uMRD4 rates were 83% (blood) and 45% (bone marrow) for patients with del(17p) and/or mutated TP53; uMRD4 rates were higher in patients with IGHV-unmutated CLL (88% in blood; 73% in bone marrow) compared to IGHV-unmutated CLL (72% in blood; 60% in bone marrow).$^{30}$ The 5.5-year PFS rate was higher in patients with uMRD4 (blood) at EOT than those with detectable MRD at EOT (75% vs. 47%).$^{31}$ In the MRD cohort, patients were assigned to subsequent treatment based on the uMRD4 status at EOT.$^{101}$,$^{102}$ Patients without confirmed uMRD4 were randomized to receive venetoclax/ibrutinib (n = 32) or ibrutinib (n = 31);

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post-randomization uMRD4 rates were higher with venetoclax/ibrutinib than with ibrutinib.$^{101}$ The estimated 3-year PFS rates were 97% for patients in both treatment arms. Patients with confirmed uMRD4 (n = 86) were randomized to receive placebo or ibrutinib. The estimated 4-year PFS rates were 95% for those assigned to ibrutinib and 88% for those assigned to placebo. The 4-year OS rates were not significantly different for the two treatment arms (100% and 98%, respectively).$^{102}$

Fixed duration treatment with venetoclax/ibrutinib also resulted in higher rates of uMRD (blood) at the EOT compared to ibrutinib in the CLL17 trial (47% compared to 0% for ibrutinib).$^{35}$ This trial established venetoclax/ibrutinib is non-inferior to continuous treatment with ibrutinib in terms of PFS (3-year PFS rates were 79% and 81% respectively).

In the phase II single-arm CLARITY study, fixed duration treatment with venetoclax/ibrutinib (venetoclax was added after 2 months of ibrutinib and the duration of venetoclax/ibrutinib was determined by the achievement of uMRD) resulted in high rates of uMRD4 in patients with relapsed or refractory CLL/SLL.$^{103,104}$ The duration of treatment was based on the time to achieve uMRD4 in both blood and bone marrow (14 months for patients with uMRD4 at 8 months; 26 months for those with uMRD4 at 14 months and/or at 26-month follow-up; venetoclax was discontinued and ibrutinib was given until disease progression in patients with detectable MRD at 26 months). In an exploratory analysis, the achievement of uMRD4 after 6 months or a 2-log reduction in MRD levels after 2 months of treatment with venetoclax/ibrutinib resulted in sustained uMRD4 status and ability to discontinue treatment.$^{104}$

Venetoclax/Acalabrutinib ± Obinutuzumab

The uMRD4 (blood) rates at the EOT and at EOT+3 was also higher after fixed duration treatment with AVO (95% and 94%, respectively) than with chemoimmunotherapy in the AMPLIFY trial (73% and 78%, respectively).$^{33}$ The corresponding uMRD rates were 45% and 38%,

respectively for venetoclax/acalabrutinib, suggesting that the addition of obinutuzumab increases uMRD rate. However, the lower uMRD rate did not correspond to lower PFS rate with venetoclax/acalabrutinib and longer follow-up is needed to confirm these findings. Acalabrutinib was administered for cycles 1 to 14 and venetoclax was administered from cycles 3 to 14. In the AVO arm, obinutuzumab (1000 mg IV) was administered for cycle 2 to 7 (day 1).

MR-duided Regimens

Venetoclax/ibrutinib

MRD-guided treatment with venetoclax/ibrutinib was evaluated in the FLAIR study (263 patients were assigned to ibrutinib monotherapy; 523 patients were randomized between venetoclax/ibrutinib, n = 260 and FCR, n = 263).$^{29}$ In the venetoclax/ibrutinib arm, ibrutinib was administered for 8 weeks before initiation of venetoclax and the duration of combined venetoclax/ibrutinib was determined by uMRD-guided criteria.

Venetoclax/ibrutinib resulted in higher rates of uMRD compared to FCR and ibrutinib. With a median follow-up of 62 months, uMRD (bone marrow) at 60 months after randomization was observed in 72% of patients in the venetoclax/ibrutinib arm. The uMRD (blood) at 60 months after randomization was also higher with venetoclax/ibrutinib (93%) compared to FCR (69%) and ibrutinib (4%). At 6 years after treatment with venetoclax/ibrutinib, an estimated 79% of patients had stopped treatment due to the achievement of uMRD and this percentage was higher in the IGHV unmutated group than in the IGHV mutated group (81% and 52%, respectively). The subgroup analysis suggest a benefit for MRD-guided treatment for patients with IGHV unmutated CLL.$^{29}$ FLAIR trial also identified IGHV unmutated status as a predictor of early achievement of uMRD following treatment with venetoclax/ibrutinib.$^{105}$ Large ongoing clinical trials will help to clarify the optimal duration of MRD-guided treatment with combined targeted therapy and the importance of the

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difference in uMRD rates between IGHV-mutated and IGHV-unmutated CLL.

The feasibility of MRD-guided treatment with venetoclax/ibrutinib given for 24 cycles was also demonstrated in a phase II study (n = 80; 18 patients had del (17p) and/or TP53 mutation).$^{32}$ Ibrutinib, was administered as monotherapy for 3 cycles and then combined with venetoclax for a total of 24 cycles of combination regimen. After a median follow-up of 39 months, uMRD (bone marrow) was 56% (n = 45) after 12 cycles and 66% (n = 53) after 24 cycles (51 out of the 53 patients who achieved uMRD after 24 cycles discontinued treatment). The estimated 3-year PFS and OS rates were 93% and 96%, respectively. The uMRD rates (bone marrow) for patients with del(17p) and/or TP53 mutation were 69% (n = 9) and 77% (n = 10) after 12 cycles and 24 cycles, respectively.

Venetoclax/Acalabrutinib + Obinutuzumab

A phase II single center study investigated MRD-guided treatment with AVO in patients with previously untreated CLL (N = 72; 45 patients with TP53 aberrations).$^{34}$ AVO was administered as follows: acalabrutinib followed by acalabrutinib + obinutuzumab (cycles 2 and 3) followed by AVO (cycles 4–7) and acalabrutinib + venetoclax (cycles 8–15). Patients could discontinue treatment if CR with uMRD (bone marrow) was achieved at the start of cycle 16. The CR with uMRD (bone marrow) rate was 42% (for the overall study population as well as in patients with TP53 aberrant disease). The uMRD (bone marrow) rate was 71% for the overall study population and 78% in patients with TP53 aberrant disease. Treatment discontinuation after achieving CR with uMRD (bone marrow) was reported in 79% of patients (58% had TP53 aberrant disease). Forty-two percent of patients (n = 30) discontinued treatment after achieving CR with uMRD (bone marrow) before cycle 16 and an additional 38% of patients (n = 27) discontinued treatment after achieving CR with uMRD (bone

marrow) after completing 24 cycles. The median duration of treatment was 25 cycles.

Venetoclax/Zanubrutinib

The SEQUOIA study evaluated MRD-guided treatment with venetoclax/zanubrutinib in the non-randomized cohort (Arm D; n = 114; zanubrutinib was administered as monotherapy for 3 cycles and then combined with venetoclax for cycles 4–28).$^{92}$ The best uMRD (blood) rates (percentage of patients achieving uMRD at least once) were similar in the subgroups of patients with and without TP53 aberrations (59% and 60% respectively). The uMRD (blood) rate at the beginning of cycle 16 and 28 were 43% and 60%, respectively for patients without TP53 aberration. The corresponding uMRD rate at cycle 16 was lower in patients with TP53 aberrations (21%) but increased to 49% by cycle 28 suggesting that patients with TP53 aberrations may require a longer duration of treatment to achieve uMRD rates similar to that in patients without TP53 aberrations. Discontinuation of treatment (venetoclax after a minimum of 12 cycles or zanubrutinib after a minimum of 27 cycles) was allowed in patients meeting the uMRD-guided stopping criteria. Treatment discontinuation rate based on the achievement of uMRD criteria was 10% (the majority of these patients did not have TP53 aberrations).

NCCN Recommendations

The Panel consensus supported the inclusion of the following regimens as MRD-guided treatment options for first-line therapy:

$\bullet$ Venetoclax/ibrutinib for CLL/SLL without del(17p) or TP53 mutation based on the results of FLAIR study (category 1; other recommended).$^{29}$

$\bullet$ Venetoclax/zanubrutinib based on the results of SEQUIOA (Arm D).$^{92}$ This combination is included with a category 2A recommendation (useful in certain circumstances for CLL/SLL

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without del(17p) or TP53 mutation; preferred treatment option for CLL/SLL with del(17p) or TP53 mutation)

$\bullet$ AVO (category 2A; preferred) for CLL with del(17p)/TP53 mutation based on results of phase II single center study.$^{34}$

NCCN Guidelines recommend serial MRD evaluations every 3 to 6 months during active treatment (using either flow cytometry or NGS assay with a sensitivity for the detection of at least $10^{-4}$ CLL cells in blood or bone marrow) as outlined in the published trial protocols that support MRD-guided treatment options. NGS-based clonality testing for MRD assessment should be considered if MRD-guided treatment is planned and MRD-flow is not being used for MRD assessment. It should be noted that administration of anti-CD20 mAb within the prior 3 months can lead to false negative results for uMRD status due to B-cell depletion, especially when assessing MRD in blood.$^{106,107}$

Diagnosis

The diagnosis of CLL requires the presence of at least 5 x 10$^{9}$/L monoclonal B-lymphocytes in the peripheral blood and the clonality of B cells should be confirmed by flow cytometry.$^{81}$ Immunophenotype by flow cytometry (blood) is adequate for the diagnosis of CLL; bone marrow biopsy is generally not required.

The diagnosis of SLL requires the presence of lymphadenopathy and/or splenomegaly with <5 x 10$^{9}$/L monoclonal B lymphocytes in the peripheral blood.$^{81}$ A diagnosis of SLL should ideally be confirmed by excisional or incisional lymph node biopsy, if lymph node is accessible. Fine-needle aspiration (FNA) biopsy alone is inadequate for the diagnosis. In certain circumstances, when a lymph node is not easily accessible, a combination of core needle biopsy (multiple biopsies may be required) in conjunction with appropriate ancillary techniques may be sufficient for diagnosis. Bone marrow aspirate with biopsy can be pursued if lymph node biopsy material

is nondiagnostic. B-cells with a CLL/SLL phenotype may be found in samples from patients with reactive lymph nodes; however, a diagnosis of SLL should only be made when there is effacement of the lymph node architecture by histology.

Evaluation of cyclin D1 (flow cytometry or IHC) or FISH for t(11;14), flow cytometry for CD200, and IHC for LEF1 and SOX11 may be helpful in the differential diagnosis of CLL, especially in suspected cases of mantle cell lymphoma that are cyclin D1-negative.$^{108-111}$

FISH for the detection of del(11q), del(13q), trisomy 12, del(17p), CpG-stimulated metaphase karyotype, TP53 sequencing, and molecular genetic analysis for IGHV mutation status can provide useful prognostic information and may guide selection of therapy.

Interphase FISH is the standard method to detect specific chromosomal abnormalities that may have prognostic significance. Conventional metaphase karyotype is difficult in CLL due to the very low in vitro proliferative activity of the leukemic cells. CpG oligonucleotide stimulation can be utilized to enhance metaphase cytogenetics.$^{112,113}$ CpG-stimulated karyotyping is useful to identify patients with high-risk CLL, particularly for treatment with targeted agents and developing a long-term treatment strategy. NGS (using an assay with a sensitivity to detect TP53 mutations of low VAF of 5%) is preferred over Sanger sequencing for the TP53 sequencing since the latter has a low detection limit that is variable between 10% to 20%.$^{114}$ However, a specific cutoff value for reporting VAF has not been established.

Molecular analysis for IGHV mutation testing is recommended based on reproducibility and ready availability. IGHV mutation status is helpful for the selection of initial treatment when considering time-limited treatment with BCL2i containing combination regimens. IGHV mutation status does not change over time and mutation analysis need not be repeated if

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previously done prior to initiation of treatment. IGHV mutation analysis is performed through amplification of IGHV transcript by polymerase chain reaction (PCR) and gene sequencing through Sanger sequencing.$^{115,116}$ Complementary DNA (cDNA) and genomic DNA (gDNA) are suitable for IGHV mutation analysis. cDNA identifies more functional rearrangements whereas gDNA can be performed on stored samples and it also avoids the need for reverse transcription.

Monoclonal B-Cell Lymphocytosis

Monoclonal B-cell lymphocytosis (MBL) is a condition in which an abnormal monoclonal B-cell population with the immunophenotype of CLL is present but does not meet the diagnostic criteria for CLL.$^{117,118}$ An ALC of <5 x 10$^{9}$/L that is stable over a 3-month period in the absence of palpable lymphadenopathy or other clinical features characteristic of a lymphoproliferative disorder (ie, anemia, thrombocytopenia, constitutional symptoms, organomegaly) is defined as MBL.$^{119}$

MBL is further categorized into low-count MBL (<0.5 x 10$^{9}$/L) that rarely progresses to CLL and high-count MBL (0.5-4.9 x 10$^{9}$/L) that can progress to CLL requiring therapy at a rate of 1% to 2% per year.$^{120,121}$ High-count MBL is distinguished from Rai 0 CLL based on whether the monoclonal B-cell count is above or below 5 x 10$^{9}$/L.$^{122}$ A nodal variant characterized by nodal infiltration of CLL-line cells without apparent proliferation centers and absence of lymphadenopathy was also described in a subset of patients with MBL.$^{123}$

MBL is associated with favorable molecular characteristics, including mutated IGHV and del(13q), lower prevalence of del(11q)/del(17p) and wild-type TP53, slower lymphocyte doubling time, longer treatment-free survival, and very low rate of progression to CLL.$^{118}$ Observation is recommended for all individuals with MBL.

Workup

The workup of patients with CLL/SLL should include history and physical exam (measurement of size of liver and spleen and palpable lymph nodes), evaluation of performance status and B symptoms. Measurement of beta-2 microglobulin may provide useful prognostic information.$^{64}$

CLL/SLL is diagnosed mainly in older adults, with a median age of 72 years at diagnosis. Comorbidities are frequently present in older patients, and the presence of multiple comorbidities (≥2 comorbidities) was an independent predictor of clinical outcome, independent of patients' age or disease stage. Cumulative Illness Rating Scale (CIRS), Charlson Comorbidity Index, and the NCI Comorbidity Index are some of the scoring systems that can be used to assess comorbidities in patients with CLL. CIRS in combination with creatinine clearance (CrCI) was used by the GCLLSG to assess the overall fitness of patients enrolled in clinical trials. In the CLL14 study, CIRS score >6 or an estimated CrCI <70 mL/min was used as the eligibility criteria for patients with significant comorbidities.

Quantitative immunoglobulin (Ig) levels may be informative in patients with recurrent infections. In instances when the quantitative Ig levels are abnormal, serum protein electrophoresis (SPEP) or serum immunofixation electrophoresis (SIFE) would be helpful to initiate additional evaluations (eg, MYD88 mutation analysis or bone marrow biopsy) to rule out the diagnosis of Waldenstrom macroglobulinemia. Additionally, the presence of serum Ig monoclonal proteins or paraproteins has been associated with adverse prognostic factors in patients with CLL/SLL and detection of serum monoclonal proteins by SPEP and SIFE may also provide useful prognostic information.$^{124-126}$ Reticulocyte count, and a direct Coombs test should be performed to evaluate for the possibility of hemolysis and pure red cell aplasia (PRCA) in patients with anemia.

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Bone marrow involvement (diffuse vs. nodular) is no longer a prognostic factor with the availability of more reliable prognostic markers that can be analyzed using peripheral blood (eg, IGHV mutation status and cytogenetic abnormalities detected by FISH). Thus, bone marrow biopsy ± aspirate is no longer considered essential for the diagnostic or prognostic evaluation of patients with suspected CLL, but it may be informative to confirm the presence of immune-mediated or disease-related cytopenias prior to initiation of treatment.

CT scans are not generally recommended for routine monitoring of treatment response or disease progression in asymptomatic patients. CT scans may be useful for the evaluation of symptoms of bulky disease, or for the assessment of risk for tumor lysis syndrome (TLS) prior to the initiation of venetoclax and for treatment response assessment in patients with SLL. Staging CT scan prior to initiating treatment is recommended to evaluate the extent of lymphadenopathy if using a BCL2i-based regimen or if there is concern for bulky adenopathy not accessible by physical exam.

PET scan is generally not useful in CLL but can assist in directing nodal biopsy if histologic transformation is suspected.$^{127,128}$

First-Line Therapy

Localized SLL (Lugano stage I)

Locoregional radiation therapy (RT) is an appropriate induction therapy for patients with symptomatic localized disease. In rare patients, RT may be contraindicated or may be a suboptimal therapy due to the presence of comorbidities or the potential for long-term toxicity. Patients with localized SLL that progressed after initial RT should be treated as described below for patients with SLL (Lugano stage II–IV).

SLL (Lugano stage II-IV) or CLL (Rai stages 0-IV)

Early-stage disease in some patients may have an indolent course and in others may progress rapidly to advanced disease requiring immediate treatment. In a randomized prospective phase III study of patients with early-stage high-risk CLL, although FCR resulted in high overall response rate (ORR) (93%) and significantly prolonged EFS (median, not reached vs. 19 months; P < .001) compared to watch and wait, there was no significant OS benefit (5-year OS rate was 83% with FCR compared to 80% for watch and wait).$^{129}$ The results of the CLL12 trial did not demonstrate survival benefit for early treatment with irutinib in patients with early-stage, high-risk CLL (high risk defined according to the GCLSG index).$^{130}$

These results confirm that a "watch and wait" approach remains the appropriate management strategy for all patients, in the absence of disease symptoms. Treatment will be beneficial if patients become symptomatic or show evidence of progressive disease.$^{81}$ Selected patients with mild, stable cytopenia may continue to be observed and other causes of anemia or thrombocytopenia should be excluded.

Indications for initiating treatment include severe fatigue, weight loss, night sweats, and fever without infection; threatened end-organ function; progressive bulky disease (enlarged spleen or lymph nodes); progressive anemia or thrombocytopenia; or steroid-refractory autoimmune cytopenia.$^{81}$

ALC alone is not an indication for treatment in the absence of leukostasis, which is rarely seen in patients with CLL.

In patients with indications for initiating treatment, age, functional status, comorbidities, and the presence or absence of del(17p) or TP53 mutation should help to direct treatment options, as discussed below. Reevaluation for TP53 mutation status and del(17p) by FISH, and IGHV mutation status

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(if not previously done) are recommended prior to initiating treatment. NGS-based clonality testing for MRD assessment should be considered if MRD-guided treatment is planned and MRD-flow is not being used for MRD assessment.

In addition to the aforementioned disease- and patient-specific factors, agents' toxicity profile and duration of treatment (continuous vs. fixed duration) should also be considered for the selection of first-line therapy. cBTKis (acalabrutinib, ibrutinib, and zanubrutinib) are given continuously until disease progression, whereas venetoclax-containing regimens are time-limited with a treatment-free remission period. As discussed earlier, time-limited treatment with venetoclax-containing regimens also results in higher rates of uMRD, which is an independent predictor of improved survival.

The NCCN CLL Panel stratified all the regimens into three categories (based on the evidence, efficacy, toxicity, preexisting comorbidities, and in some cases access to certain agents): preferred, other recommended and useful in certain circumstances.

CLL/SLL without del(17p) or TP53 Mutation

BCL2i-containing regimens (venetoclax/acalabrutinib ± obinutuzumab and VenO) and cBTKi-based regimens (acalabrutinib ± obinutuzumab, zanubrutinib) are included as preferred treatment options (with category 1 recommendation), based on the results of the phase III randomized studies (AMPLIFY, CLL14, ELEVATE-TN, and SEQUOIA).$^{19}$,$^{21}$,$^{22}$,$^{33}$,$^{131}$

The efficacy data are discussed below and are summarized in Table 2.

Venetoclax + Obinutuzumab

The CLL14 study established VenO as an effective time-limited, chemotherapy-free, first-line treatment option with significantly improved PFS compared to chlorambucil + obinutuzumab in patients ≥65 years, or

younger patients with comorbidities (CIRS score >6 or an estimated CrCl <70 mL/min).$^{131,132}$ The uMRD4 rate at the EOT was significantly higher with VenO (74% vs. 34%; P < .0001), and this combination was also associated with lower rate of conversion to MRD-positive status 1 year after treatment.$^{133}$

VenO was granted broad FDA approval for the treatment of patients with CLL based on the results of the CLL14 study. The efficacy of VenO in patients <65 years of age without significant comorbidities was established in the phase III randomized GAIA-CLL13 GAIA/CLL13 trial.$^{25}$ The 4-year follow-up data confirmed that VenO with or without ibrutinib was associated with superior PFS compared to chemoimmunotherapy (FCR or BR).$^{26}$ The Panel members agreed that VenO is also an appropriate fixed duration chemotherapy-free treatment option for younger patients without comorbidities, and the Panel consensus was to include fixed duration VenO as a preferred treatment option (category 1) regardless of patient age or the presence of significant comorbidities.

Venetoclax/Acalabrutinib ± Obinutuzumab

In the AMPLIFY study, fixed duration treatment with venetoclax/acalabrutinib ± obinutuzumab resulted in significantly higher ORR ($P < .0001$) and statistically significant improvement in PFS (primary endpoint) compared to investigator's choice of chemoimmunotherapy with either FCR or BR ($P = .0038$ for venetoclax/acalabrutinib vs. FCR/BR; $P < .0001$ for AVO vs. FCR/BR).$^{33}$ There was also a trend towards OS benefit with venetoclax/acalabrutinib compared to chemoimmunotherapy ($P < .0001$).

Fixed duration treatment with venetoclax/acalabrutinib ± obinutuzumab is included as a preferred treatment option with a category 1 recommendation.

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Venetoclax/lbrutinib

The results of the CAPTIVATE study showed that fixed-duration treatment with venetoclax/ibrutinib results in improved PFS with high rates of durable response and uMRD4 across all patient subgroups.$^{30}$,$^{31}$,$^{101}$,$^{102}$ In the fixed-duration treatment cohort (n = 159), with a median follow-up of 69 months, the 5.5 year PFS rate was 66% for the overall study population [70% for patients without del(17p)/TP53 mutation; 55% and 79% for those with IGHV unmutated and IGHV mutated CLL respectively]. The 5.5 year OS rate was 97% for patients in the overall study population.$^{31}$

In the GLOW trial, PFS was also significantly longer for fixed-duration treatment with venetoclax/ibrutinib compared to chlorambucil + obinutuzumab.$^{27}$,$^{134}$ The 64-month follow-up data also showed OS benefit for venetoclax/ibrutinib compared to chlorambucil + obinutuzumab.$^{28}$ However, in this study, venetoclax/ibrutinib was associated with significant toxicity. Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 76% of patients and atrial fibrillation (any grade) was reported in 14% of patients) and treatment-related deaths were reported in 7% of patients.$^{134}$ Cardiac or sudden deaths during treatment occurred in patients with a CIRS score of ≥10 or an Eastern Cooperative Oncology Group performance status (ECOG PS) score of 2 and with a history of hypertension, cardiovascular disease, and/or diabetes. This increase in toxicity may be related to the advanced age of patients enrolled in the study.

The FLAIR study demonstrated that MRD-guided treatment with venetoclax/ibrutinib is superior to FCR in terms of PFS in patients without del(17p)/TP53 mutation.$^{29}$ Long-term follow-up data (median follow-up, 62 months) showed that OS was also longer with venetoclax/ibrutinib compared to ibrutinib monotherapy in patients with IGHV unmutated CLL however the OS was similar in the two treatment groups for patients with IGHV mutated CLL.$^{29}$

Venetoclax/ibrutinib is not approved for the treatment of CLL/SLL in the United States. Based on the safety profile reported in the GLOW trial (increased risk for cardiovascular events and infections particularly in older patients with comorbidities) and the absence of data from randomized studies comparing this regimen with approved targeted therapies for first-line therapy (other than ibrutinib), the Panel consensus was to include venetoclax/ibrutinib (fixed duration treatment) as a category 1 recommendation under other recommended regimens. The Panel consensus also supported the inclusion of venetoclax/ibrutinib (MRD-guided treatment; other recommended regimen) as a category 1 recommendation based on the results of the FLAIR trial.

Venetoclax/Zanubrutinib

The results from the non-randomized cohort of the SEQUOIA study (Arm D) confirmed the efficacy of MRD-guided treatment with venetoclax/zanubrutinib in patients with and without TP53 aberrations.$^{92}$ At a median follow-up of 31 months, venetoclax/zanubrutinib resulted in an ORR of 97% (96% in patients without TP53 aberrations) and 24-month PFS rate was 92% (89% for patients without TP53 aberrations).

Given the favorable toxicity profile of venetoclax/zanubrutinib, the Panel consensus supported its inclusion as a category 2A recommendation (useful in certain circumstances), and MRD-guided treatment with venetoclax/zanubrutinib may be an appropriate option for patients with intolerance to MRD-guided treatment with venetoclax/ibrutinib.

Acalabrutinib ± Obinutuzumab

In the phase III ELEVATE-TN trial, acalabrutinib ± obinutuzumab resulted in superior PFS compared to chlorambucil + obinutuzumab in patients with previously untreated CLL.$^{20}$ Acalabrutinib + obinutuzumab was associated with a PFS benefit in patients with IGHV-unmutated CLL as well as IGHV-mutated CLL compared to chlorambucil + obinutuzumab. At a median follow-up of 75 months, 72-month PFS rate was longer with

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acalabrutinib + obinutuzumab compared to acalabrutinib (78% vs. 62%). There was also a trend towards improved OS for acalabrutinib + obinutuzumab (72-month OS rate was 84% compared to 76% for acalabrutinib monotherapy), although the study was not powered to compare the PFS benefit between the two acalabrutinib arms.$^{135}$

Acalabrutinib was granted broad FDA approval for the treatment of untreated and relapsed or refractory CLL based on the results of the ELEVATE-TN and ELEVATE-RR trials, respectively.$^{20,136}$ Acalabrutinib ± obinutuzumab is included as a preferred treatment option with a category 1 recommendation.

Zanubrutinib

Zanubrutinib is a highly selective/specific cBTKi that is FDA-approved for the treatment of CLL. In the phase III SEQUOIA study, zanubrutinib resulted in higher ORR and statistically significant improvement in PFS compared to BR in patients with untreated CLL without del(17p)/TP53 mutation (HR, 0.29; P = .0001).$^{22}$ The biomarker subgroup analysis from the SEQUOIA study confirmed that PFS benefit with zanubrutinib was observed in all subgroups including patients with del(11q) (P < .001), IGHV-unmutated (P < .0001), and IGHV-mutated (P < .01).$^{58}$

Based on the results of the SEQUOIA study, zanubrutinib is included as a preferred treatment option with a category 1 recommendation. The 6-year follow-up data from the SEQUOIA study also confirmed the superior efficacy and safety profile of zanubrutinib compared to BR.$^{137}$

Ibrutinib

Ibrutinib monotherapy was approved for first-line therapy for all patients based on the results of the RESONATE-2 study that established the efficacy of ibrutinib monotherapy as first-line therapy only in patients ≥65 years without del(17p).$^{18}$,$^{138}$ In the RESONATE-2 study, after a median follow-up of 5 years, ibrutinib resulted in a significantly higher ORR ($P<$

.0001) and significantly longer PFS rate (P < .0001) compared to chlorambucil in patients ≥65 years without del(17p).$^{138}$ With 57% of patients switching to ibrutinib after disease progression on chlorambucil, the estimated 5-year OS rate was also higher with ibrutinib (without censoring for crossover from chlorambucil). Ibrutinib also improved PFS compared to chlorambucil in patients with high-risk CLL and the estimated 5-year PFS rates were 79% and 67% for patients with del(11q) and IGHV-unmutated CLL, respectively. Extended long-term data confirmed the sustained PFS benefit of ibrutinib as first-line therapy for patients with CLL, including those with high-risk genomic features of IGHV-unmutated (HR, 0.109) or del(11q) (HR, 0.033).$^{18}$

With the inclusion of venetoclax/ibrutinib (fixed-duration or MRD-guided) as an option for first-line therapy (category 1; other recommended regimens) and randomized clinical trials demonstrating a more favorable toxicity profile for acalabrutinib and zanubrutinib (compared to ibrutinib),$^{136,139}$ the Panel acknowledged that continuous treatment with ibrutinib monotherapy would no longer be a preferred first-line therapy option for the vast majority of patients. A few Panel members also suggested ibrutinib monotherapy would be more appropriate for patients who can tolerate continuous treatment with ibrutinib and receive clinical benefit as well as for those patients with intolerance to venetoclax. The Panel consensus supported continued listing of ibrutinib monotherapy (continuous treatment) with a category 1 recommendation as an option under useful in certain circumstances.

Ibrutinib + Obinutuzumab or Rituximab

The results from randomized studies have confirmed that ibrutinib + rituximab is more effective than chemoimmunotherapy for previously untreated CLL without del(17p) or TP53 mutation in patients ≥65 years or younger patients with comorbidities.$^{23,43,46,93,94,140}$ The Alliance North American Intergroup Study (A041202) showed primary benefit for

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ibrutinib and ibrutinib + rituximab in patients with IGHV unmutated CLL (61% of patients had IGHV unmutated CLL) rather than IGHV mutated CLL.43 The presence of CK did not have an impact on PFS following treatment with ibrutinib. The estimated 2-year PFS rates were 91% and 87%, respectively, for ibrutinib and ibrutinib + rituximab among patients with CK.93 The E1912 study and the FLAIR study showed that ibrutinib + rituximab was more effective than FCR for patients ≤70 years without del(17p)/TP53 mutation, especially for those with IGHV unmutated CLL, indicating that ibrutinib may also be an appropriate option for younger patients with IGHV unmutated CLL.23,46 However, the addition of rituximab to ibrutinib did not result in improved clinical outcomes compared to ibrutinib monotherapy in two randomized studies. In the Alliance North American Intergroup Study (A041202), the estimated 48-month PFS rates were 76% for both ibrutinib + rituximab and ibrutinib monotherapy.43 In a single-center randomized study of 208 patients with high-risk CLL (27 patients with untreated CLL), at a median follow-up of 36 months, the estimated PFS rates were 86% and 87% for ibrutinib and ibrutinib + rituximab, respectively.140

Ibrutinib + obinutuzumab was approved by the FDA for first-line therapy based on the results of the ILLUMINATE study and there are no randomized clinical trials that compare ibrutinib versus ibrutinib + obinutuzumab.$^{94}$

In all of the above-mentioned randomized clinical trials that evaluated ibrutinib + rituximab or obinutuzumab, ibrutinib was given continuously until disease progression or intolerance and obinutuzumab or rituximab was added to the combination arm only for the first six cycles. Therefore, the consensus was that the longer PFS was more the result of continuous treatment with ibrutinib, rather than due to the contribution of an anti-CD20 mAb (rituximab or obinutuzumab) during the first 6 months of treatment.

Improved outcomes with addition of an anti-CD20 mAb may more likely be seen with time-limited treatment with this regimen.

Ibrutinib + rituximab or obinutuzumab are included as options (useful in certain circumstances) with a category 2B recommendation.

Chemoimmunotherapy

With multiple randomized trials showing the superior efficacy of cBTKi-based regimens and BCL2i-containing regimens over chemoimmunotherapy, the Panel acknowledges that chemoimmunotherapy should no longer be recommended for first-line therapy. However, the majority of Panel members acknowledge that chemoimmunotherapy can be considered only when cBTKi and BCL2i are not available or treatment with these targeted therapies are not feasible.

FCR could be considered as an option for patients <65 years without significant comorbidities.$^{13,17,23,141}$ Bendamustine + anti-CD20 mAb (rituximab or obinutuzumab) may be a reasonable alternative for patients ≥65 years or younger patients with significant comorbidities.$^{141-143}$

for a small fraction of patients for whom more intensive chemoimmunotherapy regimens are not appropriate.$^{146-148}$ Obinutuzumab ± chlorambucil is included with a category 2A recommendation. Obinutuzumab + chlorambucil is recommended for patients ≥65 years or younger patients with significant comorbidities (CrCl <70 mL/min).

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CLL/SLL with del(17p) or TP53 Mutation

Chemoimmunotherapy is contraindicated for del(17p)/TP53-mutated CLL due to low response rates. There are limited data from prospective clinical studies on the efficacy of cBTKis or BCL2i as first-line therapy for patients with del(17p)/TP53-mutated CLL. Enrollment in an appropriate clinical trial is recommended for patients with untreated del(17p)CLL/SLL.

Patients with del(17p) CLL were not eligible for enrollment in the RESONATE-2 study, the E1912 study, the GLOW study, the GAIA/CLL13 study, the FLAIR study, or the AMPLIFY study.$^{18,23,26,27,29,33}$ Data for del(17p) or TP53-mutated CLL available from subgroup analyses of clinical studies that included this patient population are discussed below.

BCL2i-Containing Regimens

In the CLL14 study, the PFS benefit for VenO was seen across all patient subgroups including those with del(17p) or TP53 mutation (del[17p] or mutated TP53 were identified in only 8% and 12% of patients, respectively).$^{131}$

In the CAPTIVATE study (n = 159; 27 patients had del(17p) and/or TP53 mutation), the estimated 5.5 year PFS rate for venetoclax/ibrutinib (fixed duration) was 36% for those with del(17p)/TP53 mutation.$^{31}$ In the phase II study that evaluated venetoclax/ibrutinib as MRD-guided treatment (n = 80; 18 patients had del(17p) and/or TP53 mutations), the estimated 3-year PFS rate was 86% for patients with del(17p) and/or TP53 mutations.$^{32}$

Patients with del(17p) or TP53 mutation were not enrolled in the AMPLIFY study because the control arm included investigator's choice of chemoimmunotherapy.$^{33}$ In an earlier phase II study, the combination of AVO resulted in an ORR of 98% (71% CR) in patients with TP53 aberrations (n = 45).$^{34}$ The CR rate with uMRD in the bone marrow was 58%. After a median follow-up of 55 months, the 4-year PFS and OS

rates were 70% and 88%, respectively for patients with TP53 aberrations. Therefore, the Panel agreed that AVO is an appropriate treatment option for patients with del(17p) or TP53 mutation based on the results of this phase II study and acknowledged that there are no data to recommend venetoclax/acalabrutinib for patients with del(17p) CLL/SLL.

The results from the non-randomized cohort (Arm D) of the SEQUOIA study confirmed the efficacy of venetoclax/zanubrutinib in patients with TP53 aberrant disease.$^{92}$ At a median follow-up of 31 months, venetoclax/zanubrutinib resulted in an ORR of 99% in patients with TP53 aberrant disease and the 24-month PFS rate was 94% for patients with TP53-aberrant disease. Discontinuation of treatment was allowed in patients meeting the strict uMRD achievement criteria. Zanubrutinib was given until disease progression for patients not meeting the uMRD criteria.

The PFS benefit for VenO and venetoclax/ibrutinib for patients with del(17p)/TP53 mutation was also established in the CLL17 trial.$^{35}$

Given currently available data (as discussed above), VenO (fixed duration), AVO (MRD-guided)$^{34}$ and venetoclax/zanubrutinib (MRD-guided)$^{92}$ are included as preferred treatment options with a category 2A recommendation. Venetoclax/ibrutinib (fixed duration) is included as an option under other recommended regimens based on the results of the CAPTIVATE study.$^{31}$

BTKi-Based Regimens

In the RESONATE-2 study, the OS benefit with ibrutinib was observed in patients with TP53 mutation, del(11q), and/or IGHV-unmutated and the estimated 5-year PFS rate was 56% for the group of 12 patients with TP53 mutation.$^{18}$ However, comparison between ibrutinib and chlorambucil could not be made since only three patients in the chlorambucil group had TP53 mutation.

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In a phase II trial that included 34 patients who are treatment-naïve with TP53 aberrations (32 patients with del[17p]; 2 patients with TP53 mutation without del[17p]; median age 62 years), ibrutinib resulted in an ORR of 97% (30% CR; 64% PR; 3% PR-L) and the estimated 6-year PFS and OS were 61% and 79%, respectively.$^{149}$

Results from the pooled analysis of clinical trials (PCYC-1122e, E1912, RESONATE-2, and iLLUMINATE) also confirmed the long-term safety and efficacy of ibrutinib as first-line therapy in patients with TP53 aberrations.$^{150}$ With a median follow-up of 50 months, the estimated 4-year PFS and OS rates were 79% and 88%, respectively. The ORR was 93% (CR in 39% of patients). As mentioned above, the RESONATE-2 and E1912 studies excluded patients with del(17p) CLL and TP53 mutation was identified retrospectively. Additionally, there are also data suggesting that TP53 mutation in the absence of del(17p) also confers increased risk. However, it may not be as notable as that associated with the concurrent presence of TP53 mutation and del(17p).$^{41}$

In the ELEVATE-TN study, the PFS benefit for acalabrutinib ± obinutuzumab was seen across all patient subgroups including those with del(17p) or TP53 mutation but only 14% of patients had del(17p) CLL.$^{19}$ In patients with del(17p) and/or TP53 mutation, the estimated 72-month PFS rate was 56% for both acalabrutinib + obinutuzumab and acalabrutinib monotherapy, indicating no benefit with the addition of obinutuzumab to acalabrutinib. The estimated 72-month OS rates were 68%, 72%, and 53% for acalabrutinib, acalabrutinib + obinutuzumab, and chemoimmunotherapy, respectively.$^{135}$

In the phase III SEQUOIA study, patients with del(17p) were not part of the randomized cohort but were enrolled only to single-agent zanubrutinib or, subsequently, to the combination of zanubrutinib and venetoclax.$^{21}$ In the prospectively enrolled non-randomized cohort (111 patients with del[17p]/TP53-mutated CLL), single-agent zanubrutinib resulted in a

higher ORR and statistically significant improvement in PFS.$^{151}$ The best ORR and 18-month PFS rates were 98% and 89%, respectively, for patients with high del(17p) (≥20%), and 92% and 88%, respectively, for patients with low del(17p) (>7% to <20%). The 6-year follow-up results also confirmed the efficacy of zanubrutinib in patients with del(17p)/TP53 mutation.$^{137}$

Acalabrutinib ± obinutuzumab and zanubrutinib are included as preferred treatment options for first-line therapy.

With the inclusion of BCL2i containing combination regimens as options for first-line therapy and randomized clinical trials demonstrating a more favorable toxicity profile for acalabrutinib and zanubrutinib (compared to ibrutinib), the Panel acknowledged that continuous treatment with ibrutinib monotherapy would no longer be a recommended first-line therapy option for the vast majority of patients. The Panel consensus supported continued listing of ibrutinib monotherapy (continuous treatment) with a category 1 recommendation as an option under useful in certain circumstances.

Other Systemic Therapy Regimens

The Panel emphasizes that the efficacy of BTKi-based regimens in del(17p) CLL exceeds that of the other regimens and BTKi-based regimens should be considered as the best choice in the absence of a contraindication to cBTKi.

HDMP + rituximab or obinutuzumab$^{144}$,$^{145}$ or obinutuzumab$^{146}$ can be considered only when cBTKi and BCL2i are not available or treatment with these targeted therapies are not feasible.

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Second-Line and Subsequent Therapy

The selection of second-line therapy for refractory or progressive disease should be based on the type of first-line therapy, duration of remission, and acquired resistance to treatment.

In patients with disease responding to cBTKi, treatment should be continued until progression and/or intolerance. For patients with disease responding to time-limited treatment with venetoclax-containing regimens, observation is recommended until disease relapse with indications for treatment.

Observation until relapse with indications for treatment is also appropriate for patients with disease responding to CIT. Time-limited treatment with BCL2i-containing regimens or cBTKi-based regimens are options for relapse after a period of remission or progression on treatment.

Recommendations for the selection of second-line therapy based on outcomes after first-line therapy are outlined on CSLL-4 and CSLL-5. The efficacy data from randomized clinical trials that evaluated small-molecule inhibitors for relapsed or refractory CLL/SLL are discussed below and are summarized in Table 3.

BCL2i-Containing Regimens

VenR is approved for the treatment of relapsed or refractory CLL/SLL based on the results of the phase III randomized MURANO trial.$^{98,152}$ VenR was superior to BR with longer PFS across all subgroups of patients, including those with del(17p) or TP53 mutation [HR, 0.21 for del(17p); HR, 0.25 for TP53 mutation], and uMRD at the EOT was also higher for VenR (62% vs. 13% for BR).$^{98}$

Venetoclax monotherapy is effective for relapsed or refractory CLL after prior treatment with ibrutinib or idelalisib,$^{153-157}$ although the results of a pooled analysis from four clinical trials showed that CLL refractory of BTKi

or PI3Ki was significantly associated with lower CR rate and shorter duration of response (DOR).$^{158}$ Results from other retrospective analyses suggest that the use of venetoclax is associated with higher ORR and improved PFS following disease progression on ibrutinib (compared to disease progression on idelalisib) and also in patients who had received only one BTKi or PI3Ki (compared to those who had received >1 BTKi or PI3Ki).$^{159,160}$

Venetoclax monotherapy resulted in an ORR of 77% (21% CR and 49% PR) in patients with relapsed or refractory del(17p) CLL. The ORR was 63% in patients who had received prior BTKi (ibrutinib) or PI3Ki (idelalisib).$^{161}$ The median DOR was 39 months. After a median follow-up of 70 months, the median PFS and OS for the overall study population were 28 months and 63 months, respectively. The median PFS was 15 months for patients who had received prior BTKi or PI3Ki. The 5-year PFS and OS rates were 24% and 52%, respectively, for the overall study population.

VenR is included as a treatment option for second-line and subsequent therapy with a category 1 recommendation, irrespective of the del(17p)/TP53 mutation status. Venetoclax monotherapy is an option with a category 2A recommendation (a preferred regimen for CLL/SLL with del(17p)/TP53 mutation). The Panel consensus supported the inclusion of VenO as a preferred treatment option for second-line therapy based on the superior efficacy of obinutuzumab in first-line therapy compared to rituximab (CLL11 and GAIA/CLL13 studies) and the real world evidence demonstrating the efficacy of VenO in previously treated CLL/SLL.$^{25,148,162}$ The CLL11 and GAIA/CLL13 studies showed that obinutuzumab when used in combination with chlorambucil or venetoclax, respectively, as first-line therapy, resulted in better clinical outcomes (clinically meaningful PFS and TTNT benefit in CLL11 study; significantly higher PFS at 3 years in the GAIA/CLL13) compared to rituximab.$^{25,148}$ In a real-world study of 40

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patients with relapsed or refractory CLL/SLL (including CLL with TP53 mutation and/or del[17p] and CLL previously treated with BTKi), VenO was effective and well tolerated resulting in an ORF of 90% (63% CR) and the 2-year PFS rate was 81%.$^{162}$

The results of the phase II CLARITY study (n = 53) showed that treatment with venetoclax/ibrutinib was effective for relapsed or refractory CLL resulting in an ORR of 89% (51% CR), and this combination also resulted in higher rates of uMRD4.$^{103}$ This study included patients with relapsed or refractory CLL/SLL after prior chemoimmunotherapy or idelalisib and patients with relapsed or refractory CLL after prior BTKi or venetoclax were excluded. The Panel consensus was to include venetoclax/ibrutinib as an option (other recommended regimens; irrespective of del(17p)/TP53 mutation) with a category 2B recommendation based on the results of the CLARITY study.$^{103}$

Treatment with venetoclax-containing regimens (venetoclax ± anti-CD20 mAb [VenO is preferred] or irbutinib) is also included as an option for disease relapse after a period of remission following a time-limited treatment with venetoclax-containing regimen, irrespective of del(17p)/TP53 mutation status.$^{163-168}$ The results of retrospective analyses suggest that treatment with the venetoclax-containing regimen (Ven2) is effective for patients with CLL/SLL previously treated with a venetoclax-containing regimen (Ven1).$^{163,164}$ An international retrospective study showed that this approach is effective in any line of therapy.$^{163}$ Among 46 patients with CLL retreated with the venetoclax-containing regimen (response data were available for 39 patients; a median of 16 months between the completion of Ven1 and initiation of Ven2), Ven2 resulted in an ORR of 80% (33% CR). At a median follow-up of 10 months, the median PFS was 25 months. In the subgroup analysis of the MURANO trial (n = 25), retreatment with VenR resulted in an ORR of 72% and the median PFS was 23 months.$^{164}$ Retreatment with VenR was also effective

for disease progression while off treatment after achieving response to time-limited treatment with VenR.$^{165}$ Interim analysis of the ReVenG study demonstrated the efficacy of treatment with VenO in patients with disease relapse >2 years (n = 25) after completing first-line therapy with fixed-duration venetoclax-based regimens.$^{166}$ The feasibility of treatment with venetoclax-based regimens in CLL without del(17p)/TP53 mutation was also confirmed in the GAIA/CLL13 study, resulting treatment-free survival rates of more than 80%.$^{167}$ Longer follow-up are needed to confirm these preliminary results.

Covalent BTK Inhibitors

Acalabrutinib, ibrutinib, and zanubrutinib are also approved for treatment of relapsed or refractory CLL/SLL based on the results of phase III randomized studies (ASCEND, ELEVATE-RR, RESONATE, and ALPINE trials).$^{136,169-171}$ The PFS benefit compared to chemoimmunotherapy was seen across all patient subgroups including those with del(17p) or TP53 mutation.

In the ASCEND study, at a median follow-up of 47 months, the median PFS was 46 months and the 42-month PFS rate was 62% for patients with del(17p)/TP53 mutation assigned to acalabrutinib.$^{169}$ The phase III ELEVATE-RR trial demonstrated that acalabrutinib is noninferior to ibrutinib in terms of PFS and was also associated with a more favorable safety profile in patients with relapsed or refractory del(17p) or del(11q) CLL.$^{136}$

The final analysis of the RESONATE study showed that the presence of del(17p)/TP53 mutation or CK was not associated with inferior PFS outcomes to ibrutinib.$^{170}$ In an exploratory analysis that combined data from patients with del(17p) and TP53 mutation, the median PFS was 41 months for patients with del(17p) and/or TP53 mutation versus 57 months for those without del(17p) or TP53 mutation. Similarly, the median PFS

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was 41 months for patients with CK compared to 45 months for those without CK. The phase II RESONATE-17 study established the efficacy and safety of ibrutinib in patients with relapsed or refractory del(17p) CLL (n = 145), demonstrating an ORR of 83% (as assessed by the independent review committee).$^{172}$

The randomized phase III study (ALPINE) showed that zanubrutinib resulted in a significantly higher ORR and significantly longer PFS in patients with relapsed or refractory CLL/SLL.$^{171}$ Zanubrutinib also resulted in a higher ORR and longer PFS across the major subgroups of patients, including those with a del(17p) and/or TP53 mutation. Among patients with del(17p) and/or TP53 mutation, the 36-month PFS rate was 59% for zanubrutinib and 39% for ibrutinib. The corresponding 36-month OS rates were 83% and 80%, respectively. The 6-year follow-up data confirmed the durable PFS benefit for zanubrutinib.$^{173}$ After a median follow-up of 74 months, the median PFS was 53 months and the 60-month PFS rate was 47% for all patients. Among patients with del17p, the median PFS and 60-month PFS rate were 50 months and 38%, respectively.

Acalabrutinib, ibrutinib, or zanubrutinib are recommended options for second-line and subsequent therapy with a category 1 recommendation, irrespective of the del(17p)/TP53 mutation status. Acalabrutinib and zanubrutinib are listed as options for preferred regimens. Ibrutinib is included as an option under other recommended regimens based on the toxicity profile.

Non-Covalent BTK Inhibitors

Pirtobrutinib was approved for the treatment of patients with relapsed or refractory CLL/SLL who received at least two prior lines of therapy, including a BTKi and BCL2i based on the results of the BRUIN phase I–II study.$^{174,175}$

In this study, pirtobrutinib resulted in an ORR of 73% (82% including PR-L) with a median PFS of 20 months in patients previously treated with a BTKi (n = 247). At a median follow-up of 23 months, the estimated 18-month OS rate was 81% for patients previously treated with a BTKi. In the subgroup of patients previously treated with the BTKi and venetoclax-containing regimen (n = 100), the ORR was 70% (79% including PR-L) and the median PFS was 17 months.$^{174}$ The estimated median PFS was 17 months and 19 months, respectively, for patients with del(17p) or TP53 mutation and those with IGHV-unmutated CLL. The ORR (including PR-L) was higher irrespective of the status of prior therapy with BCL2is (83% for BCL2i-naïve and 80% for BCL2i-exposed); however, PFS was longer in the BCL2i-naïve group than in the BCL2i-exposed group (23 months and 16 months, respectively).$^{175}$ The 24-month OS rates were 83% and 61%, respectively.

The phase III randomized BRUIN CLL-321 study evaluated pirtobrutinib (n = 119) and investigator's choice of treatment (BR, n = 37 or idelalisib + rituximab [IdR], n = 82) in patients with CLL/LSLL previously treated with cBTKi with or without prior therapy with venetoclax (all patients had received prior cBTKi and 50% of patients had received prior therapy with venetoclax-containing regimens; cBTKi was discontinued either due to disease progression or intolerance).$^{176}$ At a median follow-up of 17 months, pirtobrutinib resulted in significant improvement in PFS compared to BR/IdR (independent review committee [IRC] assessed PFS was 14 months for pirtobrutinib vs. 9 months for BR/IdR) and the PFS benefit was observed across all subgroups of patients including those with CLL previously treated with venetoclax-containing regimens (HR, 0.54), unmutated IGHV (HR, 0.61), TP53 mutation and/or del(17p) (HR, 0.59), and CK (HR, 0.37). The 18-month OS rate was 73% and 71% for pirtobrutinib and BR/IdR, respectively. The OS rate, however, was confounded by a high effective crossover rate of 76%.

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Based on the results of BRUIN CLL-321 study, the Panel consensus was to include pirtobrutinib as a preferred treatment option with a category 1 recommendation (irrespective of del[17p]/TP53 mutation) for patients with intolerance to prior cBTKi or for those with disease that is resistant to cBTKi. Pirtobrutinib is also included as preferred option with a category 1 recommendation (if not previously used; irrespective of del[17p]/TP53 mutation) for relapsed or refractory disease after prior therapy with BTKi-based regimens and venetoclax-containing regimens.$^{174,175}$

Chimeric Antigen Receptor T-Cell Therapy

The TRANSCEND CLL 004 study evaluated the safety and efficacy of lisocabtagene maraleucel in patients with relapsed or refractory CLL/SLL after ≥2 prior lines of therapy (N = 137; 117 patients received infusion with lisocabtagene maraleucel and all had received prior BTKi).$^{177,178}$ A subset of 70 patients also received venetoclax-containing regimens after disease progression on BTKi. The primary efficacy analysis (49 patients including those who had received prior venetoclax-containing regimens after disease progression on BTKi) reported an ORR of 43% (18% CR) as assessed by an independent review committee.$^{177}$ Among the 30 patients with del(17p) and/or TP53 mutation, the ORR was 47% (23% CR).

The DOR was longer in patients achieving a CR. At a median follow-up of 20 months, the DOR was 35 months for all patients with responding disease (not reached for patients achieving a CR and 24 months for patients achieving a PR).$^{177}$ The median PFS and OS were 12 months and 30 months, respectively. The median PFS was not reached in patients achieving a CR compared to 26 months for those achieving a PR and 4 months for those with non-responding disease. The uMRD4 rate was 63% in blood and 59% in bone marrow.$^{177,178}$ The median PFS was longer in patients who had uMRD (26 vs. 3 months for those with detectable MRD).$^{177}$ The 24-month follow-up data confirmed the high uMRD rates (64% in blood and 60% in the bone marrow) and longer DOR among

patients achieving CR.$^{178}$ The median DOR was 30 months for all patients with responding disease and it was not reached for patients achieving a CR.

Results from the combination cohort of the TRANSCEND CLL004 study (n = 56) showed that ibrutinib in combination with lisocabtagene maraleucel also resulted in high ORR (86%; 45% CR) and uMRD rate (86% in blood and 84% in bone marrow).$^{179}$ The median DOR for CR was not reached. The median PFS and OS were 31 months and not reached, respectively. Ibrutinib was either initiated or continued through leukapheresis and for up to 90 days after the infusion of lisocabtagene maraleucel.

Lisocabtagene maraleucel is a one-time infusion that does not require continuous treatment and is approved for relapsed or refractory CLL/SLL after at least two prior lines of therapy, including a BTKi and a BCL2i (venetoclax).

Lisocabtagene maraleucel ± ibrutinib is included as a preferred option for relapsed or refractory disease after prior therapy with BTKi-based regimens and venetoclax-containing regimens [irrespective of del(17p)/TP53 mutation].

PI3K Inhibitor-Based Regimens

Idelalisib and duvelisib also demonstrated efficacy (in terms of median PFS) in randomized phase III studies for patients with relapsed or refractory CLL/SLL.$^{180}$⁻$^{186}$

In a phase III randomized trial (220 patients; CIRS >6, decreased renal function, or cumulative marrow toxicity from prior therapy; randomized to receive IdR or rituximab + placebo), IdR demonstrated efficacy in patients with relapsed or refractory CLL/SLL with and without del(17p).$^{181}$ IdR significantly prolonged survival in patients with del(17p) or TP53 mutation

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compared with those treated with rituximab + placebo and there was no difference in survival benefit compared to those without del(17p).$^{181}$ The median OS was 29 months following treatment with IdR compared to 15 months following treatment with rituximab + placebo. IdR is FDA approved for relapsed or refractory CLL based on the results of this study and is available for clinical use with a black box warning regarding the risks of fatal and serious toxicities including hepatotoxicity, diarrhea, colitis, pneumonitis, and intestinal perforation. In the BRUIN CLL-321 study that evaluated pirtobrutinib in patients with previously treated CLL/SLL, IdR (n = 82) was the control arm (based on investigator's choice) along with BR (n = 37).$^{176}$ At a median follow-up of 12 months, the IRC-assessed median PFS was 9 months in the IdR/BR control arm and the estimated 18-month OS rate was 71%.

Idelalisib monotherapy also demonstrated activity in relapsed or refractory SLL.$^{182}$ The indication for idelalisib monotherapy in relapsed or refractory SLL was withdrawn by the manufacturer as they are unable to complete the required confirmatory studies following the FDA accelerated approval. While the Panel acknowledged the change in the regulatory status of idelalisib, the Panel consensus was to continue listing idelalisib monotherapy as an option for relapsed or refractory SLL, given demonstrated efficacy.$^{182}$

In the phase DUO trial (N = 319; 160 patients were randomized to duvelisib and 159 patients were randomized to ofatumumab), duvelisib significantly extended median PFS (17 vs. 9 months) compared to ofatumumab and the PFS benefit was seen across all the subgroup of patients including those with del(17p).$^{183}$ In the final analysis, after a median follow-up of 63 months, the median OS was 52 months for patients assigned to duvelisib and 63 months for patients assigned to ofatumumab (including 90 patients who crossed over to duvelisib).$^{184}$ In the DUO crossover extension study (that evaluated the efficacy and safety)

of duvelisib monotherapy in patients with disease progression while receiving ofatumumab in the DUO trial), the ORR was 77% (61% PR) for the subset of 26 patients with del(17p) and/or TP53 mutations.$^{185}$

Duvelisib and idelalisib ± rituximab are included as options for relapsed or refractory disease after prior therapy with BTKi-based regimens and venetoclax-containing regimens, irrespective of del(17p)/TP53 mutation status).

Other Systemic Therapy Regimens

FCR and BR have demonstrated activity in patients with relapsed or refractory disease and are included as options for relapsed or refractory CLL/SLL without del(17p) or TP53 mutation after prior therapy with BTKi-based regimens and venetoclax-containing regimens.$^{187-189}$

HDMP + rituximab was effective in patients with heavily pretreated CLL (including fludarabine-refractory disease), although it was associated with infectious complications (including opportunistic fungal infections) in about 30% of patients, which may necessitate adequate anti-infective prophylaxis and close monitoring for early signs of infections.$^{190,191}$ Lenalidomide ± rituximab also demonstrated activity in patients with relapsed or refractory disease.$^{192-194}$ However, the ORR was lower for lenalidomide + rituximab in the subgroup of patients with fludarabine-refractory CLL compared with those with fludarabine-sensitive CLL. Growth factors and/or dose adjustment may be needed to address cytopenias, without necessitating holding treatment. Obinutuzumab (as monotherapy) also demonstrated activity in patients with relapsed or refractory CLL/SLL.$^{147}$

HDMP + anti-CD20 mAb (category 2B for CLL/SLL without del(17p)/TP53 mutation), lenalidomide ± rituximab and obinutuzumab are included as options for relapsed or refractory CLL/SLL (with or without

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del(17p)/TP53 mutation) after prior therapy with BTKi-based regimens and venetoclax-containing regimens.

Alemtuzumab + rituximab results in a higher ORR than that observed with alemtuzumab monotherapy.$^{195,196}$ However, it should be noted that bulky lymphadenopathy does not typically respond well to alemtuzumab monotherapy in patients with refractory CLL.$^{197}$ Alemtuzumab ± rituximab is included as an option for relapsed or refractory CLL/SLL with del(17p)/TP53 mutation after prior therapy with BTKi-based regimens and venetoclax-containing regimens.

Chemoimmunotherapy or immunotherapy are not recommended for patients who received these as first-line therapy. The recommendations for other systemic therapy regimens as listed above for CLL/SLL with del(17p)/TP53 mutation are based on results from retrospective analyses or subgroup analyses from prospective clinical trials that had included patients with del(17p) or TP53 mutation. However, it should be noted that these studies were not sufficiently powered to evaluate the efficacy and safety of regimens in patients with del(17p) or TP53 mutation.

Allogeneic Hematopoietic Cell Transplant

Long-term results from several prospective studies showed that allogeneic hematopoietic cell transplant (HCT) can provide long-term disease control and also overcome the poor prognosis associated with del(17p) and TP53 mutations.$^{67,198-204}$ Available data suggest that CK (≥5 abnormalities) is associated with inferior OS and EFS following allogeneic HCT with reduced-intensity conditioning in patients with high-risk interphase cytogenetics.$^{205,206}$

It is understood that studies involving allogeneic HCT are subject to significant selection biases. Nonetheless, at the present time, given the favorable outcome of patients with del(17p) or TP53 mutation treated with cBTKi as first-line therapy and the availability of venetoclax-based

regimens as an effective treatment option for relapsed or refractory CLL, allogeneic HCT can be considered for relapsed or refractory disease after prior therapy with BTKi-based regimens and venetoclax-containing regimens in patients without significant comorbidities.$^{207}$ HCT-specific comorbidity index (HCT-CI) could be used for the assessment of comorbidities prior to HCT and to predict the risks of non-relapse mortality and the probabilities of survival after HCT.$^{208,209}$

Special Considerations for Treatment

Precautions and considerations when initiating treatment or transitioning to next therapy for disease progression while on treatment are outlined in the Supportive Care section of the algorithm (CSLL-C 2 of 6).

Management of Resistance to Small-Molecule Inhibitors

BTK Inhibitors

Acquired resistance to BTKis is predominantly mediated by BTK and PLCG2 mutations.$^{57,210-214}$ BTK and/or PLCG2 mutations were detected at an estimated median of 9 months before progression in patients with CLL treated with ibrutinib, and these mutations were also detected in patients with progressive CLL during ibrutinib therapy up to 15 months before the manifestation of clinical progression.$^{57,210}$ In the randomized ELEVATE-RR trial, acquired BTK mutations were detected at the time of disease progression in 66% of patients with CLL treated with acalabrutinib and in 37% of patients with CLL treated with ibrutinib.$^{213}$ BTK C481S mutations were most common with both ibrutinib and acalabrutinib whereas the detection of other BTK mutations was variable (T474I and E41V mutations were detected in the acalabrutinib group; L528W and A428D were detected in the ibrutinib group). The median VAF was not significantly different (16% and 15.6% for acalabrutinib and ibrutinib, respectively). PLCG2 mutations were detected in 6% of patients with CLL acalabrutinib and 20% of patients with CLL treated with ibrutinib, with a median VAF of 2% and 10% for acalabrutinib and ibrutinib, respectively.

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VAF are variable, with low VAF often associated with disease progression on ibrutinib, leading to speculation that these mutations do not fully explain clinical resistance.$^{57,210,213}$ In the ALPINE trial, BTK C481S, L528W, A428D mutations were detected in patients with progressive disease on zanubrutinib whereas PLCG2 mutations were not detected in patients with CLL treated with zanubrutinib.$^{214}$ BTK A428D, T474I, and L528W mutations also confer resistance to ncBTKi.$^{211}$

Alternative cBTKi is not a reasonable treatment option for patients with a mutation in either BTK C481 or PLCG2. Pirtobrutinib (ncBTKi) is an effective treatment option for the management of resistance to cBTKi, including in patients with BTK C481 mutations.$^{174,175}$ In the BRUIN study, mutations in BTK, TP53, and PLCG2 were detected at baseline in 53%, 48%, and 14% of patients, respectively. Among the patients with BTK C481 mutation, decrease in BTK C481 VAF or complete clearance of BTK C481 clone was observed in 86% and 55% of patients, respectively.$^{215}$ The use of pirtobrutinib for relapsed or refractory CLL following BCL2i-containing regimens without prior exposure to cBTKi has not been evaluated. Venetoclax is an also an appropriate treatment option for relapsed or refractory CLL after prior treatment with irbutinib or idelalisib,$^{153-156,158-160}$

Switching to alternate therapy (ncBTKi or BCL2i-containing regimen) is recommended at the time of disease progression while on treatment with a cBTKi. Treatment-free interval should be as short as possible to minimize tumor flare reactions. In patients with disease progression on cBTKi, it is recommended to continue cBTKi through venetoclax dose ramp-up to reduce the risk of tumor flare when transitioning from cBTKi to BCL2i.

Testing for BTK and PLCG2 mutations may be useful to confirm resistance to BTKis in patients with disease progression or no response while on BTKi therapy, including if poor treatment adherence is considered as a possible cause. BTK and PLCG2 mutation status alone is not an

indication to change treatment in absence of disease progression. Testing for BTK, PLCG2, or BCL2 mutations as screening for resistance to BTKi or venetoclax is not currently recommended.

BTKis are available in different formulations, dosage forms, and strengths that are subject to different administration instructions. The choice of cBTKi should be made by the treating clinician based on patient-specific factors (eg, age, functional status, comorbid conditions) and the agent's toxicity profile. These products are not interchangeable.

BCL2 Inhibitors

Acquisition of BCL2 mutations (G101V and D103Y) was implicated in resistance to venetoclax.$^{216}$,$^{217}$ BCL2 G101V mutation (low VAF) was identified in patients with progressive CLL during venetoclax therapy up to 25 months before clinical progression.$^{216}$ BCL2 mutations are uncommonly associated with clinical resistance to venetoclax; therefore, other resistance mechanisms must be important. Upregulation of MCL1 due to amplification of chromosome 1 as well as NOTCH1 and SF3B1 mutations detected during venetoclax therapy have also been associated with resistance to venetoclax.$^{218}$,$^{219}$

Mutation analysis in patients with progressive disease after fixed duration treatment with venetoclax/ibrutinib in the CAPTIVATE study revealed the absence of BTK, PLCG2, and BCL2 mutations that confer resistance to BTKi and venetoclax, suggesting that combination therapy may also mitigate the development of resistance to targeted therapies as single agents.$^{220}$

Limited available data suggest that subsequent treatment with cBTKi or retreatment with venetoclax-containing regimens is effective in patients with relapsed CLL after a period of remission following time-limited treatment with venetoclax-containing regimen, whereas PI3Ki following time-limited treatment with venetoclax-containing regimens does not

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appear to result in durable remissions.$^{163,221-223}$ Pirtobrutinib also has demonstrated efficacy for the treatment of CLL/SLL previously treated with cBTKi and venetoclax.$^{176}$

Switching to cBTKi is recommended for disease progression while on treatment with BCL2i + anti-CD20 mAb. Switching to a ncBTKi is recommended for disease progression while on treatment with BCL2i + cBTKi.

Management of Treatment-Emergent Adverse Events

BTK Inhibitors

Diarrhea, fatigue, arthralgia, infections, cytopenias, bleeding, and cardiovascular toxicities (including atrial fibrillation, ventricular arrhythmias, and hypertension) are the most common TEAEs associated with BTKis. BTKi therapy also causes mobilization of lymphocytes into blood early during treatment initiation, resulting in a significant transient lymphocytosis (increase in ALC) in most patients, which does not signify disease progression.$^{82,83}$

TEAEs associated with BTKi are discussed below and are summarized in Table 4.

Acalabrutinib and zanubrutinib both have a more favorable toxicity profile than ibrutinib due to the more selective/specific inhibition of BTK. In the ELEVATE-RR head-to-head trial of acalabrutinib versus ibrutinib, treatment discontinuation due to TEAEs was lower with acalabrutinib (15% vs. 21% for ibrutinib).$^{136,224}$ The incidences of adverse events of special interest (AESI) were also lower with acalabrutinib compared to ibrutinib: atrial fibrillation (9% vs. 16%), hypertension (9% vs. 23%), and bleeding (38% vs. 51%).$^{136,224}$ The incidences of atrial fibrillation and hypertension were also lower for acalabrutinib when used in combination with venetoclax ± obinutuzumab in the AMPLIFY trial.$^{33}$ Atrial fibrillation (any grade) was reported in <1% of patients in the acalabrutinib + venetoclax

arm and in 2% of patients in the acalabrutinib + venetoclax + obinutuzumab arm. Hypertension (grade ≥3) was reported in 3% and 2% of patients, respectively.

Acalabrutinib was associated with a higher rate of headache (35% vs. 20% for ibrutinib), with only 2% of patients experiencing grade ≥3 headache.$^{136}$ Headache is commonly observed with acalabrutinib early in the treatment course and can generally be managed with analgesics (eg, acetaminophen) and caffeine supplements and typically subsides with time on treatment.

Zanubrutinib was also associated with lower rates of cardiac events (26% vs. 36%) and lower incidence of atrial fibrillation (7% vs. 17%) compared to ibrutinib in the ALPINE trial, with no cardiac deaths reported with zanubrutinib compared to 6 cardiac deaths reported with ibrutinib.$^{171}$ In contrast, neutropenia of any grade was more frequent with zanubrutinib (32% vs. 30% for ibrutinib); however, this did not translate into a higher rate of infection (71% with zanubrutinib vs. 73% for ibrutinib). The incidences of grade ≥3 infections were 27% and 28%, respectively.

Pirtobrutinib has a favorable toxicity profile (low incidences of atrial fibrillation, major hemorrhage, and hypertension) due to more selective inhibition of BTK and the relative absence of off-target inhibition.$^{174-176}$ Longer-term follow-up data are needed to assess the incidence of these TEAEs.

The benefit and risk of BTKis should be evaluated in patients requiring anti-platelet or anticoagulant therapies. Patients requiring the use of anticoagulants including warfarin were excluded from clinical trials evaluating acalabrutinib and ibrutinib, while the use of anticoagulants including warfarin was not restricted in clinical trials evaluating zanubrutinib (except in the ALPINE trial). Zanubrutinib can be

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coadministered with anticoagulants including warfarin. Concomitant administration of ibrutinib or acalabrutinib with warfarin should be avoided.

A baseline assessment of cardiac function should be done prior to initiation of cBTKi.$^{225,226}$ Hypertension should be managed with antihypertensives as appropriate. Monitoring for signs of bleeding, atrial fibrillation, and hypertension along with appropriate management is recommended for patients receiving BTKis.

Acalabrutinib (tablets) and zanubrutinib can be coadministered with gastric acid-reducing agents (eg, antacids, proton pump inhibitors [PPIs], H2-receptor antagonists). Acalabrutinib tablets are the primary formulation and distribution of acalabrutinib capsules was discontinued.

Acalabrutinib and zanubrutinib were shown to be effective for the management of disease in patients with ibrutinib intolerance.$^{139,227,228}$ Pirtobrutinib is also an acceptable option for the management of intolerance to cBTKi.$^{174,175}$ Data from real-world studies suggest that dose modification of ibrutinib may resolve intolerance without compromising efficacy.$^{229-231}$ In patients with no intolerance, ibrutinib can be continued until disease progression while following recommended dose modification guidance as needed. However, the efficacy of dose modification of ibrutinib was not confirmed in prospective studies.

Switching to alternate cBTKi or ncBTKi or BCL2i-based regimen can be considered in the setting of intolerance to therapy, especially in patients with atrial fibrillation or hypertension that is not medically controllable. Alternate cBTKi should be considered for intolerance only in the absence of disease progression. Patients with CLL/SLL without del(17p)/TP53 mutation who discontinue a cBTKi for intolerance can remain off treatment (if there is no disease progression) for an extended period of time and alternate BTKi can be reinitiated when symptomatic. When transitioning from cBTKi to BCL2i or ncBTKi in the setting of disease progression,

treatment-free interval should be as short as possible to avoid a tumor flare reaction. It is recommended to continue cBTKi through venetoclax dose ramp-up to reduce the risk of tumor flare when transitioning from cBTKi to BCL2i.

BCL2 Inhibitor

TLS was an important TEAE of venetoclax in early clinical trials. Several trials including AMPLIFY suggest that debulking with a BTKi is effective in reducing the risk of TLS prior to venetoclax.$^{232}$ In the AMPLIFY trial, the incidences of grade ≥3 TLS were lower (<1%) for acalabrutinib + venetoclax and acalabrutinib + venetoclax + obinutuzumab compared to FCR/BR (3%).$^{33}$ Similarly, debulking with obinutuzumab prior to initiation of venetoclax has been suggested as a safe and effective strategy to reduce the risk of TLS in patients with previously untreated CLL, although obinutuzumab itself can also lead to TLS.$^{233}$

Other TEAEs associated with BCL2i-containing regimens are summarized in Table 5. In the AMPLIFY trial, AVO was associated with higher rates of infections compared to other two treatment arms.$^{33}$ Growth factor support should be considered for patients with neutropenia. Dose reduction may be necessary for patients with persistent neutropenia and limited bone marrow involvement.

Initiation at lower dose (20 mg for 1 week) and gradual step-wise ramp-up over 5 weeks to target dose (400 mg daily) along with TLS prophylaxis is recommended to mitigate the risk and frequency of TLS.$^{234}$ Initiation and accelerated dose escalation (20-400 mg over 3 weeks) with close inpatient monitoring for TLS can be done in patients with high tumor burden and concern for rapid disease progression on or following BTKi therapy.$^{153,235,236}$ Administration of obinutuzumab prior to initiation of venetoclax should be considered for further cytoreduction. Switching to a cBTKi is recommended for patients with intolerance to BCL2i.

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CAR T-Cell Therapy

In the primary safety analysis of the TRANSCEND CLL 004 study, cytokine release syndrome (CRS) and neurologic events were the AESI reported in 85% (grade 3, 9%) and 45% (grade 3, 18%) of patients, respectively.$^{177}$ Headache (29%), confusional state (26%), and dizziness (25%) were the most common neurologic events. Tocilizumab and/or corticosteroids were used in 67% and 33% of patients respectively, for the management of CRS and neurologic events. Neutropenia (60%), anemia (52%), thrombocytopenia (41%), and infections (17%) were the other most common grade ≥3 AEs. Second primary malignancies were reported in 9% of patients, but none were related to treatment with lisocabtagene maraleucel. The safety results after 24-month follow-up were similar to those reported in the primary safety analysis.$^{178}$

The combination of lisocabtagene + ibrutinib was associated with lower incidences of grade ≥3 CRS (4% vs. 8%) and neurologic toxicity (11% vs.19%) compared to lisocabtagene maraleucel monotherapy.$^{179}$ Ilbrutinib-related TEAEs including hypertension and atrial fibrillation were observed in 7% and 2% of patients, respectively.

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 CAR T-Cell and Lymphocyte Engager-Related Toxicities (available at www.NCCN.org).

PI3K Inhibitors

Hepatotoxicity (transaminase elevations), severe diarrhea or colitis, pneumonitis, opportunistic infections, and febrile neutropenia were observed following treatment with idelalisib or duvelisib.

Hepatotoxicity is a major concern in younger patients with CLL treated with idelisib as first-line therapy.$^{237}$ Close monitoring of transaminase

levels is essential and concurrent administration of idelalisib or duvelisib with other hepatotoxic drugs should be avoided.

The addition of anti-CD20 mAb or chemoimmunotherapy to idelaisib increases the risk of febrile neutropenia.$^{238}$ Anti-infective prophylaxis for herpes simplex virus (HSV) and Pneumocystis jirovecii pneumonia (PJP), and monitoring for cytomegalovirus (CMV) reactivation are recommended for patients receiving idelaisib or duvelisib.

Anti-CD20 Monoclonal Antibodies

Rare complications such as mucocutaneous reactions including paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis can occur following treatment with anti-CD20 mAb. Consultation with a dermatologist is recommended for management of these complications.

A rapid infusion over 90 minutes can be used if no severe infusion-related reactions were experienced with the prior cycle of rituximab.

Obinutuzumab infusion-related reactions (initial reaction and reactions in patients with high ALC) can be severe and patients should be monitored closely. Premedication with a corticosteroid, antihistamine, and acetaminophen should be considered to mitigate infusion-related reactions. Monitoring and prophylaxis for TLS is recommended for patients with high ALC.

Re-challenge with the same anti-CD20 mAb is not recommended in patients experiencing aforementioned severe reactions to the chosen anti-CD20 mAb (rituximab or obinutuzumab). There are some data (based on clinical experience) showing that substitution with an alternative anti-CD20 mAb is tolerated in patients experiencing severe reactions to a specific anti-CD20 mAb.$^{239}$,$^{240}$ However, it is unclear if such a substitution poses the same risk of recurrence.

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Rituximab and hyaluronidase human injection for subcutaneous use is approved by the FDA for the treatment of patients with CLL based on the results of the SAWYER trial in which subcutaneous rituximab (rituximab with recombinant human hyaluronidase) had similar pharmacokinetic characteristics as IV rituximab when used in combination with fludarabine and cyclophosphamide.$^{241}$ Rituximab and hyaluronidase human injection for subcutaneous use may be substituted for intravenous rituximab in patients who received at least one full dose of intravenous rituximab without experiencing severe TEAEs.

Histologic Transformation

Histologic transformation of CLL/SLL to diffuse large B-cell lymphoma (DLBCL; also known as Richter transformation) or Hodgkin lymphoma (HL) occurs in about 2% to 10% of patients during the course of their disease and treatment.$^{242-244}$

Richter transformation has a poor prognosis with a pattern of no response to minimal responses to chemoimmunotherapy and a median survival of 5 to 12 months from diagnosis, although the median survival was significantly better for patients with previously untreated CLL.$^{245-249}$ Histologic transformation to HL is clinically less aggressive than Richter transformation but it is associated with a poorer prognosis than de novo HL.$^{250-253}$ Accelerated CLL or CLL with expanded proliferation centers may be diagnosed when proliferation centers in CLL are expanded or fused together and show a high Ki-67 proliferative rate (>40%). Progression to CLL with increased prolymphocytes may occur when there are increased prolymphocytes in the blood (>15%). Neither of these findings is considered as Richter transformation, but rather as progression of CLL, associated with a more aggressive disease course and poorer outcomes and optimal management has not been established.$^{243,244,254,255}$

Diagnosis

The diagnosis of histologic transformation should be confirmed by excisional or incisional biopsy of the suspected lymph node/lesion with an increased standardized uptake value (SUV) on PET scan (particularly if discordant with the remaining disease). Core needle biopsy (multiple biopsies may be required) in conjunction with appropriate ancillary techniques may be sufficient for diagnosis when lymph node/lesion is not accessible for excisional or incisional lymph node biopsy. CD19, CD20, CD22, PAX5, MUM1, and LEF1 are the most commonly expressed immunohistochemical markers, whereas CD5 and CD23 are variable.$^{256,257}$

PET/CT scans are recommended to identify the optimal site for nodal biopsy, and biopsies should be directed to lesions with highest FDG uptake on PET scans.$^{128,258-260}$ A maximum standardized uptake value ($SUV_{max}$) ≥10 on PET scan has been shown to be a valid marker to distinguish Richter transformation from CLL among patients mostly treated with chemoimmunotherapy or chemotherapy.$^{261,262}$ Among patients who developed Richter transformation after irbutinib therapy, the median $SUV_{max}$ was 15 for patients who developed Richter transformation compared with an $SUV_{max}$ of 8 for those who did not develop Richter transformation.$^{262}$ However, other studies have reported that $SUV_{max}$ ≥10 alone lacks both sensitivity and specificity to distinguish Richter transformation from CLL in patients who develop Richter transformation while on irbutinib.$^{263,264}$ In both these studies, biopsy-proven Richter transformation was diagnosed in patients who had an $SUV_{max}$ between 5 and 10, suggesting that PET alone is insufficient and lymph node biopsy is required for the definitive diagnosis of Richter transformation. Biopsy of lesions with SUV ≥5 is recommended if there is high clinical suspicion, or the lesion has a differentially higher uptake than the remaining disease.

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Workup

The workup of patients with histologic transformation should include history and physical exam with attention to node-bearing areas, including Waldeyer's ring, and the size of liver and spleen, whole-body PET/CT scan, or chest/abdomen/pelvis CT with contrast of diagnostic quality.

Epstein-Barr virus (EBV) infection has been reported in 16% of patients with Richter transformation and is associated with a poor outcome.$^{265}$ EBV infection of CLL can produce Reed-Sternberg (RS)-like proliferations, and presence of morphologic RS cells in a CLL background should not be considered as Richter transformation. However, RS-like cells in a background of CLL may progress to classical HL in some patients.$^{266}$ Biopsy specimen should be evaluated for EBV infection using LMP1 staining or EBV-encoded RNA in situ hybridization (EBER-ISH).

Richter Transformation

Richter transformation is characterized by immunoblastic morphology and non-germinal center B-cell immunophenotype; however, cell of origin does not seem to have prognostic implications.$^{256}$ The exact mechanism of Richter transformation is not well understood; however, it has been associated with molecular characteristics of the underlying CLL/SLL. The following molecular characteristics have been associated with the risk of developing Richter transformation and may be linked to the pathogenesis of the disease$^{267}$⁻$^{276}$:

$\bullet$ IGHV-unmutated;

$\bullet$ Stereotyped B-cell receptor (BCR) subset 8 combined with IGHV4-39 usage;

$\bullet$ Cytogenetic abnormalities detected by FISH such as del(17p) and CK (≥3 clonal chromosome abnormalities); and

$\bullet$ Genetic abnormalities such as TP53 and NOTCH1 mutations, C-MYC activation, or inactivation of CDKN2A/B.

The incidence of Richter transformation increases with the number of prior chemoimmunotherapy (CIT) regimens, and the rate is higher following treatment with a combination of purine nucleoside analogues and alkylating agents.$^{274}$ Richter transformation has also been reported following treatment with ibrutinib and venetoclax.$^{262,277-280}$ Richter transformation developing after treatment with ibrutinib lacked resistance to BTK and PLCG2 mutations.$^{279}$ Age <70 years, progression on treatment, TP53 aberrations (del[17p] or TP53 mutation), elevated LDH, and lymphadenopathy without lymphocytosis were independent prognostic variables for Richter transformation at progression in patients who received treatment with ibrutinib for CLL.$^{262,280}$ Lymph node biopsy should be considered to rule out Richter transformation in patients with disease progression on ibrutinib, an elevated LDH, or disease progression with lymphadenopathy without lymphocytosis.$^{262}$ While the rate of Richter transformation during venetoclax therapy was significantly higher among patients with heavily pretreated del(17p) CLL, it was less common among a broader group of patients with less heavily pretreated CLL/SLL.$^{278}$ Further studies are needed to determine the exact risk profile and mechanism of Richter transformation following treatment with targeted therapies.

Richter transformation can either be clonally related (78%) or clonally unrelated to underlying CLL/SLL (22%).$^{246}$,$^{249}$,$^{273}$,$^{276}$,$^{281}$⁻$^{284}$ The majority of patients with clonally related Richter transformation carry unmutated IGHV and have more heavily pretreated CLL/SLL.$^{281}$,$^{284}$ Clonally unrelated Richter transformation is a de novo DLBCL that, at least in one study, has been found to carry mutations associated more with clonally related RT, such as TP53, MYC, ATM, and NOTCH1, in the absence of mutations frequently involved in de novo DLBCL.$^{283}$ The prevalence of TP53 mutation, however, was significantly lower in clonally unrelated Richter transformation (23% vs. 60%).$^{273}$ Clonally unrelated Richter transformation has a significantly longer median survival than clonally related Richter

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transformation (62 vs.14 months).$^{273,283}$ Although clonally related Richter transformation has inferior OS compared to clonally unrelated Richter transformation,$^{249,273,276,282-284}$ clonal relatedness has not been established as an independent predictor of clinical outcomes in multivariate analysis.$^{285}$ Clonal relatedness retained its prognostic significance (along with TP53 mutation status, international prognostic index and double-hit status of DLBCL) for OS in one series (n = 58),$^{284}$ however, in another series (n = 86), clonal relatedness lost its prognostic significance in multivariate analysis and only the lack of TP53 aberrations was associated with a significant survival advantage.$^{273}$ Another series also reported older age, elevated LDH, Richter transformation after previously treated CLL and CK in CLL/SLL as independent predictors of shorter OS in multivariate analysis.$^{249}$

Molecular analysis is useful to determine if there is a clonal relationship between baseline CLL/SLL tumor cells and histologically transformed tumor cells. IGHV gene rearrangement studies of CLL and histologically transformed tissue are used to establish the clonal relationship between CLL and transformed DLBCL.$^{273,281}$ Comparative clonality testing for IGHV gene rearrangement should be done on prior defined CLL sample and biopsy specimen of transformed tissue to establish clonal relatedness between CLL/SLL and DLBCL cells, using a lab-based assay for IGHV clonality. However, initiation of therapy should not be delayed for clonality testing. If the clonal relation is unknown or if clonality testing is not feasible, treatment as described for clonally unrelated Richter transformation should be considered in patients with previously untreated CLL/SLL.

Treatment Options

Enrollment in a clinical trial is recommended for all patients with Richter transformation to DLBCL. PET/CT scan is required for response assessment and should be interpreted via the 5-Point Scale (5-PS).

CIT regimens recommended for DLBCL typically result in poor responses.$^{245}$ In the absence of a suitable clinical trial, the following CIT regimens used at the NCCN Member Institutions are mostly based on data from single-arm phase I/II studies as summarized in Table 6.

Elevated platelet counts, higher hemoglobin levels, lower beta-2-microglobulin levels and LDH levels have been identified as independent predictors of higher response rates to CIT.$^{245}$ However, the use of these prognostic variables for the selection of optimal CIT for Richter transformation has not been established.

Although there are limited published data supporting the use of non-CIT regimens in patients with Richter transformation (and additional data will be forthcoming), given the unmet clinical need and the lack of effective treatment options, the Panel acknowledged that inclusion of non-CIT regimens as treatment options is reasonable for Richter transformation.

Immune check point inhibitor (ICI)-based regimens (nivolumab or pembrolizumab ± irutinib, zanubrutinib + tisleizumab, venetoclax + atezolizumab + obinutuzumab), BTKis (acalabrutinib [category 2B] and pirtobrutinib), and bispecific antibodies (epcoritamab and glofitamab) are included as options for non-CIT regimens. Chimeric antigen receptor (CAR) T-cell therapy (axicabtagene ciloleucel, tisagencleucel, and lisocabtagene maraleucel) is an option for eligible patients who have received at least one prior systemic therapy regimen.

ICI-based regimens nivolumab and pembrolizumab (either as monotherapy or in combination with ibrutinib) have demonstrated activity in patients with Richter transformation in phase II clinical trials and ORR are higher when used in combination with ibrutinib.$^{286-290}$

In a phase II study of 24 patients with Richter transformation, nivolumab + ibrutinib resulted in an ORR of 42%. The median DOR and median OS

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were 15 months and 13 months, respectively.$^{289}$ In a phase II trial of 26 patients with Richter transformation, pembrolizumab monotherapy resulted in an ORR of 23% (8% CR and 15% PR) with a median DOR of 3 months and the median PFS was 4 months.$^{290}$ In an expanded analysis of 15 patients who received ibrutinib combination with pembrolizumab, the ORR was 63% (25% CR and 38% PR). The median DOR and PFS were 4.5 and 8 months, respectively. After a median follow-up of 50 months, the median OS and the 2-year OS rate for all 26 patients with RT was 12 months and 27%, respectively.

In a phase II trial of (N= 57; 48 patients included in the full efficacy analysis), zanubrutinib + tisleizumab was also effective resulting in an ORR of 58% (19% CR) in patients with Richter transformation.$^{291}$ After the median follow-up of 26 months, the median DOR and PFS were 17 months and 10 months, respectively. The median OS was not reached, and the estimated 24-month OS rate was 63%.

In another multicenter phase II trial of 24 patient with Richter transformation, venetoclax in combination with atezolizumab, and obinutuzumab resulted in an ORR of 68%.$^{292}$ The 12-month PFS and OS rates were 43% and 64% respectively. In the post-hoc subgroup analyses, number of prior therapies for CLL/SLL and prior treatment with BTKi were predictors of OS.

BTKi Monotherapy

In a phase I/II trial of 25 patients with Richter transformation (treatment naïve or previously treated), acalabrutinib (cBTKi) resulted in an ORR of 40% and the median PFS was 3 months.$^{293}$

In the BRUIN phase I/II study that included 82 patients with heavily pretreated Richter transformation (including prior therapy with chemoimmunotherapy and cBTKi), pirtobrutinib (ncBTKi) resulted in an ORR of 50% (13% CR and 37% PR) and pirtobrutinib was also effective

as a bridge to transplant in eight patients with ongoing response who discontinued treatment to receive HCT.$^{294}$

Bispecific Antibody Therapy

In the EPCORE CLL-1 trial (n = 42; majority of patients had received ≥1 prior lines of therapy with BTKi and/or BCL2 inhibitor for CLL or Richter transformation), after a median follow-up of 23 months, epcoritamab (subcutaneous CD3 x CD20 bispecific antibody) resulted in an ORR of 48% (40% CR) and the median duration of CR was 10 months.$^{295}$ The median PFS and OS were 3 months and 13 months respectively for the overall study population.

In a phase I/II study of 11 patients (majority of the patients had Richter transformation that is refractory to prior therapy with anti-CD20 mAb containing regimens), fixed-duration treatment with glofitamab (CD3 x CD20 bispecific antibody) induced durable complete remissions, resulting in an ORR of 64% (46% CR).$^{296}$

CAR T-Cell Therapy

In a real-world analysis of 30 patients with Richter transformation, at median follow-up of 12 months, lisocabtagene maraleucel resulted in an ORR of 76%; the median DOR, PFS, and OS were not reached.$^{297}$ The estimated rates of DOR, PFS, and OS were 77%, 54%, and 67%, respectively. Lisocabtagene maraleucel was also well tolerated with low incidences of grade ≥3 CRS and immune effector cell-associated neurotoxicity syndrome (ICANS).

In an international multicenter retrospective analysis (N= 69; 58 patients had received prior lines of therapy with BTKi and/or BCL2 inhibitor for CLL and/or Richter transformation), CAR T-cell therapy resulted in an ORR of 63% (46% CR) with a median duration of response of 28 months in patients achieving CR.$^{298}$ Axicabtagene ciloleucel, tisagenlecleucel, and lisocabtagene maraleucel were administered in 64% (n = 44), 25% (n =

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17), and 10% (n = 7) of patients, respectively. After a median follow-up of 24 months, the median PFS and OS were 5 months and 9 months, respectively. The 2-year PFS and OS rates were 29% and 38%, respectively.

HCT

In a non-randomized comparative analysis, the estimated cumulative 3-year survival rate was significantly higher for patients who underwent allogeneic HCT after achieving a CR or PR compared with those with treatment-sensitive disease who did not undergo allogeneic HCT, or who underwent allogeneic HCT for relapsed or refractory Richter transformation (75% vs. 27% and 21%, respectively; P = .019).$^{245}$

In a retrospective analysis that evaluated the outcome after autologous or allogeneic HCT in 59 patients with Richter transformation, the 3-year estimated OS, relapse-free survival (RFS), and cumulative incidences of relapse and non-relapse mortality rates were 36%, 27%, 47%, and 26%, respectively, for allogeneic HCT and 59%, 45%, 43%, and 12%, respectively, for autologous HCT.$^{299}$ In a multivariate analysis, treatment-sensitive disease and reduced-intensity conditioning were found to be associated with superior RFS after allogeneic HCT. In a Center for International Blood and Marrow Transplant Research registry study evaluating outcomes after HCT (autologous HCT, n = 53; allogeneic HCT, n = 118), the 3-year PFS and OS rates were 43% and 52%, respectively, for patients who underwent allogeneic HCT.$^{300}$ The corresponding 3-year PFS and OS rates were 48% and 57%, respectively, for patients who underwent autologous HCT.

Treatment-sensitive disease and ≤3 previous lines of therapy were associated with superior PFS and OS outcomes following allogeneic HCT with reduced-intensity conditioning.$^{301}$ Deeper remissions at the time of transplant was associated with better survival outcomes after allogeneic HCT.$^{300}$

Allogeneic HCT can be considered for patients with disease responding to treatment and autologous HCT may also be appropriate for patients with who are not candidates for allogeneic HCT (due to age, comorbidities, or lack of a suitable donor).$^{245}$,$^{299}$⁻$^{303}$

Richter Transformation from Untreated CLL or Clonally Unrelated Richter Transformation

CIT is recommended for all patients. It is reasonably safe to combine cBTKi (given continuously for disease control in patients with previously treated CLL/SLL) with CIT when given without the addition of other targeted agents.

Observation is appropriate for patients achieving CR to CIT. CAR T-cell therapy or other non-CIT regimens (as discussed above) are recommended for patients achieving a PR, refractory or progressive disease. Allogeneic HCT can be considered for patients achieving a CR to non-CIT regimens.

Richter Transformation from Previously Treated CLL (Clonally Related or Clonal Relation Unknown)

CIT or non-CIT regimens (other than CAR T-cell therapy, preferred) are included as treatment options. In patients with previously treated CLL, the selection of treatment for Richter transformation depends on treatment received for CLL/SLL prior to transformation:

$\bullet$ ncBTKi, ICI-based combination regimens or bispecific antibody therapy are appropriate options for transformation after prior therapy with a cBTKi and/or BCL2i-based regimens.

$\bullet$ cBTKi is an appropriate option for transformation after prior therapy with BCL2i-based regimens.

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$\bullet$ ICI-based combination regimens with cBTki used for prior therapy for CLL/SLL are not appropriate for patients who are intolerant to or have disease progression on the same cBTKi.

Allogeneic HCT can be considered for patients achieving a CR to any regimen. Continuation of treatment until progression is recommended for patients achieving CR to non-CIT regimens. Observation may also be appropriate for patients achieving CR, although allogeneic HCT is typically considered for patients who are appropriate candidates.

CAR T-cell therapy or other non-CIT regimens (not previously used) are recommended for patients achieving a PR. Continuation of non-CIT regimen until progression or switching to an alternate non-CIT regimens is recommended if they are not a candidate for HCT or CAR T-cell therapy.

Clinical trial, CAR T-cell therapy or other non-CIT regimens are recommended for patients with refractory or progressive disease.

Histologic Transformation to Hodgkin Lymphoma

ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) was the most commonly used regimen resulting in an ORR of 68%, and achievement of CR to the ABVD regimen was the most important factor predicting survival of patients with Richter transformation to HL.304-306

Richter transformation to HL should be treated as outlined in the NCCN Guidelines for Hodgkin Lymphoma (available at www.NCCN.org).

Supportive Care

Infections

Infectious complications are influenced by the progressive reduction in immunoglobulin levels (hypogammaglobulinemia) and are more common in patients with previously treated CLL.$^{307,308}$ Patients with heavily

pretreated fludarabine-refractory CLL have high susceptibility to developing serious infections.$^{309}$

IVIG is associated with a significant decrease in the occurrence of infections but with no improvement in OS outcome.$^{310-314}$ Monitoring IVIG levels and monthly administration of IVIG (0.3–0.5 g/kg to maintain nadir levels of approximately 500 mg/dL) is recommended for selected patients with serum IVIG <500 mg/dL and recurrent sinopulmonary infections requiring intravenous antibiotics or hospitalization.

Anti-infective prophylaxis is also appropriate for the management of infections in patients who may be susceptible to certain infections due to a given treatment regimen. Antiinfective prophylaxis (herpes virus prophylaxis with acyclovir or equivalent), PJP prophylaxis with sulfamethoxazole trimethoprim, or equivalent is recommended for patients receiving purine-analog or bendamustine-based chemoimmunotherapy, idelalisib, corticosteroids, and/or alemtuzumab during treatment and thereafter.

Hepatitis B Virus Reactivation

Hepatitis B virus (HBV) reactivation was reported following treatment with chemotherapy ± immunotherapy agents.$^{315,316}$ HBV carriers have a high risk of HBV reactivation. Fulminant hepatitis, hepatic failure, and death associated with HBV reactivation occurred in patients receiving anti-CD20 mAb-containing regimens. Patients receiving IVIG may be HBcAb positive as a consequence of IVIG therapy.$^{317}$

Antiviral prophylaxis and monitoring are recommended for patients receiving anti-CD20 mAb, alemtuzumab, purine analogs, and idelalisib. Prophylactic antiviral therapy with entecavir is recommended for patients who are HBsAg positive and undergoing anti-lymphoma therapy. Entecavir is more effective than lamivudine in preventing rituximab-associated HBV reactivation.$^{318}$,$^{319}$ Lamivudine prophylaxis

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should be avoided due to the risks for the development of resistance. 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 treatment.$^{320}$

HBV reactivation and invasive fungal infections were rarely reported in following treatment with ibrutinib.$^{321,322}$ There currently are no sufficient data to recommend routine screening and prophylaxis.

Cytomegalovirus Reactivation

Clinicians should be aware of the high risk of CMV reactivation in patients receiving fludarabine-based chemoimmunotherapy, idelalis, or alemutuzumab. Monitoring for the presence of CMV viremia using quantitative PCR (at least 2–3 weeks) is an effective approach to the management of CMV reactivation.$^{323}$ Current practices include the use of prophylactic ganciclovir if CMV viremia is present or the use of ganciclovir if the viral load is found to be increasing during therapy.$^{324,325}$ Consultation with an infectious disease expert may be necessary.

Autoimmune Cytopenias

Autoimmune hemolytic anemia (AIHA), immune-mediated thrombocytopenia (also known as immune thrombocytopenic purpura [ITP]), and PRCA are the most frequent autoimmune cytopenias in patients with CLL.$^{326,327}$ Bone marrow evaluation is recommended to confirm the diagnosis of autoimmune cytopenias.

Although the direct antiglobulin test (DAT) was used for the diagnosis of AIHA, some patients with AIHA have a negative DAT; additional markers such as low haptoglobin and elevated reticulocyte and LDH are required to confirm the diagnosis of AIHA.$^{328}$ Patients with advanced disease, IGHV-unmutated, increased serum beta-2 microglobulin level, and high expression of ZAP-70 are also at a higher risk of developing AIHA.$^{328-331}$

Purine analog-based therapy was associated with AIHA. Higher incidence of AIHA was reported following treatment with fludarabine or chlorambucil compared to those who received fludarabine-based combination regimens.$^{328,332}$ AIHA should not preclude the use of regimens containing fludarabine. However, patients should be observed carefully and fludarabine therapy should be avoided in those where a history of fludarabine-associated AIHA is suspected.

ITP in patients with CLL is associated with poorer survival independent of common clinical prognostic variables.$^{333}$ High white blood cell (WBC) count, IGHV-unmutated, positive DAT, and ZAP-70 positivity are associated with the development of ITP in patients with CLL.$^{333}$

AIHA and ITP can be managed with corticosteroids in most cases. IVIG, cyclosporine,$^{334}$ and splenectomy should be used in steroid-refractory cases. Rituximab was also effective for the treatment of patients with autoimmune cytopenias.$^{335}$-$^{339}$ Eltrombopag and romiplostim are FDA-approved for the treatment of thrombocytopenia in patients with ITP that is refractory to steroids, IVIG, and splenectomy and were also shown to be effective in the management of CLL-associated ITP that is refractory to standard therapies.$^{340}$-$^{344}$

PRCA is less common in patients with CLL. PRCA can be managed with corticosteroids, cyclophosphamide, cyclosporine, or anti-thymocyte globulin.$^{327}$ Corticosteroids tend to be less effective in PRCA than in ITP or AIHA. In very refractory cases, allogeneic HCT may be necessary. Evaluation of parvovirus B19 is also recommended for all patients with PRCA since patients with evidence of parvovirus B19 infection usually respond well to IVIG.$^{327}$

Tumor Flare Reactions

Tumor flare reaction associated with lenalidomide is typically observed as painful enlargement of lymph nodes, and may be accompanied by

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lymphocytosis, spleen enlargement, low-grade fever, rash, and/or bone pain.$^{345}$ In patients with relapsed or refractory CLL, the 25-mg initial dose of lenalidomide used in patients with multiple myeloma resulted in excessive toxicity (tumor flare, tumor lysis, and myelosuppression).$^{346}$ Initiation of lenalidomide at lower doses (5, 10, or 15 mg/day) with subsequent dose escalation by 5 mg up to a maximum of 25 mg/day is associated with an acceptable tolerability profile in patients with relapsed or refractory CLL.$^{347}$

The Panel recommends the use of steroids to manage lymph node enlargement and inflammation, and antihistamines to manage rash/pruritus in patients who experience tumor flare reactions. Tumor flare prophylaxis with steroids may be considered for the first 10 to 14 days of therapy in patients with bulky lymph nodes (>5 cm). Severe tumor flare reaction is generally rare if an anti-CD20 mAb is initiated at least 1 week prior to the start of lenalidomide in patients with CLL treated with combination regimen.

Venous Thromboembolism

Lenalidomide may also be associated with venous thromboembolism (VTE) in patients with CLL/SLL. Prophylaxis with daily low-dose aspirin (81 mg daily) may be considered in patients with extremely high platelet counts at baseline. Patients already on anticoagulants, such as warfarin, do not need aspirin. However, it should be noted that these recommendations may differ from the NCCN Guidelines for Cancer-Associated Venous Thromboembolic Disease (available at www.NCCN.org) in which the recommendations for VTE associated with lenalidomide pertain only to patients with multiple myeloma.

Tumor Lysis Syndrome

Patients with bulky lymph nodes, progressive disease after small-molecule inhibitor therapy, and receiving chemoimmunotherapy, venetoclax,

lenalidomide, and obinutuzumab are considered to be at high risk for TLS. TLS prophylaxis as noted in the Supportive Care section of the algorithm should be considered for these patients.

Immunizations

All live vaccines including live attenuated influenza vaccine should be avoided. Protein and conjugate vaccines were shown to induce better responses than plain polysaccharide vaccines.$^{348,349}$ Studies that evaluated the safety and efficacy of mRNA-based vaccines against the SARS-CoV-2 infection (COVID-19) in patients with hematologic malignancies reported lower seroconversion rates and decreased antibody responses in patients with CLL/SLL, regardless of their treatment status.$^{350-354}$ The correlation, if any, between antibody titers against spike protein and the protective immunity in this population was not established, and the duration of any protection is unknown. Therefore, no recommendations can be made regarding antibody testing or actions based on antibody test results. Furthermore, tests are not available to assess cellular immunity post-COVID-19 vaccination.

Annual influenza vaccine, pneumococcal vaccine, and COVID-19 vaccine are recommended for all patients as recommended by the CDC Guidelines. Zoster vaccine recombinant, adjuvanted is recommended for all patients with CLL treated with BTKi. Respiratory syncytial virus (RSV) vaccine (single dose) is recommended for all patients, including patients <60 years.

Patients with CLL tend to have poor response to influenza vaccine and should be counseled to exercise care during influenza season even with vaccination. In the absence of laboratory testing to confirm immune response to mRNA-based vaccines, patients with CLL/SLL who received COVID-19 vaccines should take precautions recommended for unvaccinated individuals, such as mask wearing, social distancing, and

diligent hand hygiene, until additional data are available to further clarify their risk.

Summary

The choice of first-line treatment for CLL/SLL should be based on the

disease stage, presence or absence of del(17p) or TP53 mutation, IGHV mutation status, patient’s age, PS, comorbid conditions, duration of

treatment (continuous or time-limited) and the agent’s toxicity profile. In

addition to these factors, the type of prior first-line therapy, duration of

remission, and acquired resistance to treatment are also important factors in the selection of treatment for relapsed or refractory CLL/SLL.

The benefit/risk of a continuous versus time-limited (fixed duration or

MRD-guided) treatment approach should also be carefully evaluated.

Venetoclax-containing regimens are time-limited, whereas BTKis are given continuously until disease progression or intolerance.

Chemoimmunotherapy regimens can be considered for first-line therapy

only when cBTKi and BCL2i are not available or treatment with these

targeted therapies are not feasible. Testing for BTK and PLCG2 mutations may be useful to confirm resistance to BTKis in patients with disease

progression or no response while on BTKi therapy.

Histologic transformation to DLBCL or HL is associated with a poor

prognosis. Precise diagnosis and enrollment in clinical trials evaluating

novel targeted agents will improve the clinical outcomes of patients with

histologic transformation.

Careful monitoring of AEs after initiation of treatment and supportive care for the treatment-related complications should be an integral part in the

treatment of patients with CLL/SLL and histologic transformation.

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|Trial|Regimen|No. of Patients|Patient Characteristics|Median Follow-up|Undetectable MRD (≤$10^{-4},$ uMRD4)|MRD Detection| |---|---|---|---|---|---|---| |GLOW (Phase III; Fixed duration)$^{27}$|Venetoclax/lbrutinib|106|≥65 years or <65 years who also had CIRS >6 or CrCl <70 mL/min|34 months|EOT+3 (BM): 67% among patients with a CR; 64% among patients with a PR)|NGS| |GLOW (Phase III; Fixed duration)$^{27}$|Chlorambucil + Obinutuzumab|105|≥65 years or <65 years who also had CIRS >6 or CrCl <70 mL/min|34 months|EOT+3 (BM): 31% among patients with a CR; 21% among patients with a PR|NGS| |FLAIR (Phase III; MRD-guided)$^{29,a}$|Ibrutinib|263|Median age, 62 years (>65 years, 31%) [without del(17p)]|62 months|60 months: 4% (blood); 0% (BM)|MRD-flow| |FLAIR (Phase III; MRD-guided)$^{29,a}$|Venetoclax/lbrutinib|260|Median age, 62 years (>65 years, 31%) [without del(17p)]|62 months|60 months: 93% (blood); 72% (BM)|MRD-flow| |FLAIR (Phase III; MRD-guided)$^{29,a}$|Fludarabine, Cyclophosphamide + Rituximab (FCR)|263|Median age, 62 years (>65 years, 31%) [without del(17p)]|62 months|60 months: 69% (blood); 55% (BM)|MRD-flow| |CAPTIVATE (Phase II; MRD cohort)$^{101}$|Venetoclax/lbrutinib|164|≤70 years; ECOG PS 0-1 (Prandomization)|31 months|75% (blood); 68% (BM)|MRD-flow| |CAPTIVATE (Phase II; MRD cohort)$^{101}$|Venetoclax/lbrutinib|32|≤70 years; ECOG PS 0-1 (Randomization; uMRD not confirmed)|31 months|69% (blood); 66% (BM)|MRD-flow| |CAPTIVATE (Phase II; MRD cohort)$^{101}$|Ibrutinib|31|≤70 years; ECOG PS 0-1 (Randomization; uMRD not confirmed)|31 months|45% (blood); 42% (BM)|MRD-flow| |CAPTIVATE (Phase II; Fixed duration)$^{31}$|Venetoclax/lbrutinib|159|≤70 years; ECOG PS 0-1|69 months|Cycle 7: 54% (blood) EOT: 69% (blood and BM)|MRD-flow| |Phase II (MRD-guided)$^{32,b}$|Venetoclax/lbrutinib|80|≥65 years (18 patients with del(17p) and/or TP53 mutation)|39 months|Cycle 12 (BM): 56% (69% for those with del(17p) and/or TP53 mutation) Cycle 24 (BM): 66% (77% for those with del(17p) and/or TP53 mutation)|MRD-flow NGS| |CLL14 (Phase III; Fixed duration)$^{45}$|Venetoclax + Obinutuzumab (Veno)|216|≥65 years (CIRS >6; CrCl <70 mL/min)|65 months|EOT+2: 75% (blood)|ASO-PCR; MRD-flow; NGS| |CLL14 (Phase III; Fixed duration)$^{45}$|Chlorambucil + Obinutuzumab|216|≥65 years (CIRS >6; CrCl <70 mL/min)|65 months|EOT+2: 33% (blood)|ASO-PCR; MRD-flow; NGS|

BM, bone marrow; EOT, end of treatment; EOT+2, 2 months of end of treatment; EOT+3, 3 months after end of treatment; MRD, measurable residual disease; NGS, next-generation sequencing; PS, performance status;

a. The duration of combined venetoclax/ibrutinib was determined based on serial MRD monitoring and treatment discontinuation in patients meeting with the uMRD-guided stopping criteria.

b. Discontinuation of treatment was allowed for patients achieving uMRD4 after 24 cycles.

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|Trial|Regimen|No. of Patients|Patient Characteristics|Median Follow-up|Undetectable MRD (≤$10^{-4},$ uMRD4)|MRD Detection| |---|---|---|---|---|---|---| |AMPLIFY (Phase III; Fixed duration)$^{33}$|Venetoclax/Acalabrutinib|291|Median age, 61 years [without del(17p) or TP53 mutation])|41 months|EOT: 45% (blood); EOT+3: 38% (blood)|MRD-flow| |AMPLIFY (Phase III; Fixed duration)$^{33}$|Venetoclax/Acalabrutinib + Obinutuzumab (AVO)|286|Median age, 61 years [without del(17p) or TP53 mutation])|41 months|EOT: 95% (blood); EOT+3: 94% (blood)|MRD-flow| |AMPLIFY (Phase III; Fixed duration)$^{33}$|FCR or Bendamustine + Rituximab (BR)|290|Median age, 61 years [without del(17p) or TP53 mutation])|41 months|EOT: 73% (blood); EOT+3: 78% (blood)|MRD-flow| |Phase II (MRD-guided)$^{34,c}$|Venetoclax/Acalabrutinib + Obinutuzumab (AVO)|72 (n = 45, TP53 aberration)|≥18 years; ECOG PS 0-1|55 months|Cycle 16 (BM): 78% (71% for those with TP53 aberration) Cycle 16 (blood): 83% (82% for those with TP53 aberration)|NGS; MRD-flow| |SEQUOIA (Phase III; ARM D; MRD-guided)$^{92,d}$|Venetoclax/Zanubrutinib (Non-Randomized Cohort)|66 (TP53 aberration)|≥65 years of age OR unsuitable for FCR (CIRS >6; CrCl <70 mL/min or a history of severe/multiple infections within 2 years)|31 months|59% (blood)|MRD-flow| |SEQUOIA (Phase III; ARM D; MRD-guided)$^{92,d}$|Venetoclax/Zanubrutinib (Non-Randomized Cohort)|47 (without TP53 aberration)|≥65 years of age OR unsuitable for FCR (CIRS >6; CrCl <70 mL/min or a history of severe/multiple infections within 2 years)|31 months|60% (blood)|MRD-flow|

BM, bone marrow; EOT, end of treatment; EOT+2, 2 months of end of treatment; EOT+3, 3 months after end of treatment; MRD, measurable residual disease; PS, performance status; NGS, next-generation sequencing; PS, performance status

c. Patients could discontinue treatment if CR with uMRD in the bone marrow was achieved at the start of cycle 16.

d. Discontinuation of treatment (venetoclax after a minimum of 12 cycles or zanubrutinib after a minimum of 27 cycles) was allowed in patients meeting with the uMRD-guided stopping criteria

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NCCN Guidelines Version 2.2026

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

|Trial|Regimen|No. of Patients|Patient Characteristics|Median Follow-up|ORR|PFS|OS| |---|---|---|---|---|---|---|---| |ELEVATE-TN20|Acalabrutinib|179 [del(17p) and/or mutated TP53, n = 23]|≥65 years or <65 years with comorbidities (CIRS >6; CrCl <70 mL/min); ECOG PS of ≤2 and adequate hematologic, hepatic, and renal function|75 months|90% (19% CR)|Median, Not reached (72-month, 62%)|Median, Not reached (72-month, 76%)| |ELEVATE-TN20|Acalabrutinib + Obinutuzumab|179 [del(17p) and/or mutated TP53, n = 25]|≥65 years or <65 years with comorbidities (CIRS >6; CrCl <70 mL/min); ECOG PS of ≤2 and adequate hematologic, hepatic, and renal function|75 months|96% (37% CR)|Median, Not reached (72-month, 78%)|Median, Not reached (72-month, 84%)| |ELEVATE-TN20|Chlorambucil + Obinutuzumab|177 [del(17p) and/or mutated TP53, n = 25]|≥65 years or <65 years with comorbidities (CIRS >6; CrCl <70 mL/min); ECOG PS of ≤2 and adequate hematologic, hepatic, and renal function|75 months|83% (14% CR)|Median, 28 months (72-month, 17%)|Median, Not reached (72-month, 75%)| |RESONATE-218|Ibrutinib|136|≥65 years [without del(17p)]|8 years|92% (34% CR)|Median, Not reached (7-year, 59%)|Median, Not reached (7-year, 78%)| |RESONATE-218|Chlorambucil|133|≥65 years [without del(17p)]|8 years|37%|Median, 15 months (7-year, 9%)|Not reported| |Alliance North American Intergroup (A041202)43|Ibrutinib|182|≥65 years|55 months|93% (7% CR)|4-year, 76%|4-year, 85%| |Alliance North American Intergroup (A041202)43|Ibrutinib + Rituximab|182|≥65 years|55 months|94% (12% CR)|4-year, 76%|4-year, 86%| |Alliance North American Intergroup (A041202)43|Bendamustine + Rituximab|183|≥65 years|55 months|81% (26% CR)|4-year, 47%|4-year, 84%| |E1912 study23|Ibrutinib + Rituximab|354|≤70 years|70 months|96% (17% CR)|5-year, 78%|5-year, 95%| |E1912 study23|Fludarabine, Cyclophosphamide + Rituximab (FCR)|175|≤70 years|70 months|81% (30% CR)|5-year, 51%|5-year, 89%| |SEQUOIA [without del(17p)]2122|Zanubrutinib|241 (mutated TP53, n = 15)|≥65 years of age OR unsuitable for treatment with CFR (CIRS >6; CrCl <70 mL/min or a history of severe/multiple infections within 2 years)|61 months|95% (7% CR)|Median, Not reached (60-month, 76%; P < .0001)|Median,: Not reached (60-month, 86%)| |SEQUOIA [without del(17p)]2122|Bendamustine + Rituximab|238 (mutated TP53, n = 13)|≥65 years of age OR unsuitable for treatment with CFR (CIRS >6; CrCl <70 mL/min or a history of severe/multiple infections within 2 years)|61 months|85% (15% CR)|Median, 44 months (60-month, 40%)|Median, Not reached (60-month, 85%)| |SEQUOIA (ARM C) [with del(17p)]137,151|Zanubrutinib (Non-Randomized Cohort)|111|≥65 years of age OR unsuitable for treatment with CFR (CIRS >6; CrCl <70 mL/min or a history of severe/multiple infections within 2 years)|77 months|97% (18% CR)*|72-month, 64%|72-month, 83%| |SEQUOIA (ARM D)92|Venetoclax/Zanubrutinib (Non-Randomized Cohort)|66 (TP53 aberration)|≥65 years of age OR unsuitable for treatment with CFR (CIRS >6; CrCl <70 mL/min or a history of severe/multiple infections within 2 years)|39 months|99% (47% CR)|24-month, 94% 36-month, 88%|Median, Not reached (24 month, 96%)| |SEQUOIA (ARM D)92|Venetoclax/Zanubrutinib (Non-Randomized Cohort)|47 (without TP53 aberration)|≥65 years of age OR unsuitable for treatment with CFR (CIRS >6; CrCl <70 mL/min or a history of severe/multiple infections within 2 years)|30 months|96% (49% CR)|24-month, 89%|Median, Not reached (24 month, 96%)|

CR, complete response; ORR, overall response rate; OS, overall survival; PS, performance status; PFS, progression-free survival *5-year follow-up: Tam CSL et al. J Clin Oncol 2025;43:Abstract 7011.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 2.2026

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

|Trial|Regimen|No. of Patients|Patient Characteristics|Median Follow-up|ORR|PFS|OS| |---|---|---|---|---|---|---|---| |CLL1424,45|Venetoclax + Obinutuzumab|216 [del(17p), n = 17; deleted or mutated TP53, n = 25]|≥65 years with comorbidities (CIRS >6; CrCl <70 mL/min)|76 months|85% (50% CR)|Median, 76 months 6-year, 53% (P < .0001)|6-year, 79%| |CLL1424,45|Chlorambucil + Obinutuzumab|216 [del(17p), n = 14; deleted or mutated TP53, n = 24]|≥65 years with comorbidities (CIRS >6; CrCl <70 mL/min)|76 months|71% (23% CR)|Median, 36 months 6-year, 22%|6-year, 69%| |AMPLIFY33|Venetoclax/Acalabrutinib + Obinutuzumab (AVO)|286|Median age, 61 years [without del(17p) or TP53 mutation])|41 months|93%|36-month, 83%|36-month, 88%| |AMPLIFY33|Venetoclax/Acalabrutinib|291|Median age, 61 years [without del(17p) or TP53 mutation])|41 months|93%|36-month, 77%|36-month, 94%| |AMPLIFY33|Fludarabine/Cyclophosphamide + Rituximab (FCR) or Bendamustine + Rituximab (BR)|290|||75%|36-month, 67%|36-month, 86%| |GLOW27,28|Venetoclax/ibrutinib|106 (mutated TP53, n = 7)|≥65 years or <65 years who also had CIRS >6 or CrCl <70 mL/min|64 months|87% (39% CR)|60-month, 60%|60-month, 82%| |GLOW27,28|Chlorambucil + Obinutuzumab|105 (mutated TP53, n = 2)|≥65 years or <65 years who also had CIRS >6 or CrCl <70 mL/min|64 months|36% (11% CR)|60-month, 18%|60-month, 61%| |FLAIR29|Ibrutinib|263|Median age, 62 years (>65 years, 31%) [without del(17p)]|62 months|87% (87%)|5-year, 79%|5-year, 91%| |FLAIR29|Venetoclax/ibrutinib|260|Median age, 62 years (>65 years, 31%) [without del(17p)]|62 months|88%|5-year, 94%|5-year, 96%| |FLAIR29|FCR|263|Median age, 62 years (>65 years, 31%) [without del(17p)]|62 months|78%|5-year, 58%|5-year, 87%| |GAIA/CLL1325,26|Venetoclax/ibrutinib + Obinutuzumab|231|≤65 years or >65 years [without del(17p) or TP53 mutation]|51 months|94% (62% CR)|4-year, 86%|4-year, 95%| |GAIA/CLL1325,26|Venetoclax + Obinutuzumab|229|≤65 years or >65 years [without del(17p) or TP53 mutation]|51 months|96% (57% CR)|4-year, 82%|4-year, 95%| |GAIA/CLL1325,26|Venetoclax + Rituximab (VenR)|237|≤65 years or >65 years [without del(17p) or TP53 mutation]|51 months|93% (49% CR)|4-year, 70%|4-year, 96%| |GAIA/CLL1325,26|Chemoimmunotherapy (FCR ≤65 Years; BR >65 Years)|229|≤65 years or >65 years [without del(17p) or TP53 mutation]|51 months|81% (31% CR)|4-year, 62%|4-year, 94%|

CR, complete response; ORR, overall response rate; OS, overall survival; PS, performance status; PFS, progression-free survival

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 2.2026

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

|Trial|Regimen|No. of Patients|Patient Characteristics|Median Follow-up|ORR|PFS|OS| |---|---|---|---|---|---|---|---| |ASCEND169|Acalabrutinib|155[del(17p), n = 28; mutated TP53, n = 39]|Median age, 67-68years with ECOG PS≤2 and adequate hematologic, hepatic, and renal function|47 months|83%|Median, Not reached42-month, 62%(HR, 0.28; P<.0001)|Median, Not reached42-month, 78%| |ASCEND169|Idelalisib + Rituximab (IdR) orBendamustine + Rituximab (BR)|155[ldR, n = 119; BR, n = 36);[del(17p), n = 21; mutated TP53, n = 34]|Median age, 67-68years with ECOG PS≤2 and adequate hematologic, hepatic, and renal function|47 months|84%|Median, 17 months42-month, 23%|Median, Not reached42-month, 65%| |ELEVATE-RR136|Acalabrutinib|268|≥18 years; ECOG PS≤2 and the presence of del(17p) and/or del(11q)|41 months|81%(3% CR)|Median, 38 months (forboth treatment arms)|Median, Not reached42-month, 65%| |ELEVATE-RR136|Ibrutinib|265|≥18 years; ECOG PS≤2 and the presence of del(17p) and/or del(11q)|41 months|77%(4% CR)|Median, 38 months (forboth treatment arms)|Median, Not reached42-month, 65%| |RESONATE170|Ibrutinib|195[del(17p), n = 63; mutated TP53, n = 79]|Median age, 67 years|74 months|91%(11% CR)|Median, 44 months60-month, 40%|Median, 68 months| |RESONATE170|Ofatumumab|196[del(17p), n = 64; mutated TP53, n = 68]|Median age, 67 years|74 months|-|Median, 8 months60-month, 3%|Median, 65 months| |ALPINE171|Zanubrutinib|327[del(17p) and/or mutated TP53, n = 41]|Median age, 67 years; ECOG PS≥1;relapsed or refractory disease after≥1 priorsystemic therapy|42.5 months|86%(12% CR)|36-month, 65%(HR, 0.67; P =.002)|36-month, 83%| |ALPINE171|Ibrutinib|325[del(17p) and/or mutated TP53, n = 38]|Median age, 67 years; ECOG PS≥1;relapsed or refractory disease after≥1 priorsystemic therapy|42.5 months|75%(8% CR)|36-month, 54%|36-month, 80%| |MURANO98,100|Venetoclax + Rituximab|194[del(17p), n = 46; mutated TP53, n = 48]|≥18 years; ECOG PS0-1;relapsed or refractory diseaserequiring therapy andadequate bonemarrow, liver, andkidney function|59 months|92%(8% CR)|Median, 54 months(HR, 0.19; P<.0001)|5-year, 82%(HR, 0.40; P<.0001)| |MURANO98,100|Bendamustine + Rituximab|195[del(17p), n = 46; mutated TP53, n = 51]|≥18 years; ECOG PS0-1;relapsed or refractory diseaserequiring therapy andadequate bonemarrow, liver, andkidney function|59 months|72%(4% CR)|Median, 17 months|5-year, 62%|

CR, complete response; ORR, overall response rate; OS, overall survival; PS, performance status; PFS, progression-free survival

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 2.2026

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

|TEAEs|Treatment-Naïve CLL|Treatment-Naïve CLL|Treatment-Naïve CLL|Relapsed or Refractory CLL||||| |---|---|---|---|---|---|---|---|---| |TEAEs|ELEVATE-TN19,20|RESONATE-21|SEQUOIA21|ELEVATE-RR136|ELEVATE-RR136|ALPINE171|ALPINE171|BRUIN174,176| |TEAEs|Acalabrutinib|Ibrutinib|Zanubrutinib|Acalabrutinib|Ibrutinib|Zanubrutinib|Ibrutinib|Pirtobrutinib| |Most common TEAEs (all grades)||||||||| |Diarrhea|43%|50%|14%|35%|46%|19%|26%|16%*| |Headache|39%|-|11%|35%|20%|NR|NR|17%| |Cough|25%|36%|11%|29%|21%|NR|NR|24%| |Fatigue|24%|36%|11%|20%|17%|11%|15%|32%| |Arthralgia|27%|26%|14%|16%|23%|17%|19%|-| |Anemia|-|26%|4%|22%|19%|17%|19%|21%*| |Neutropenia|13%|13% (Grade ≥3)|16%|21%|25%|32%|30%|16%*| |Adverse events of special interest (AESI)||||||||| |Atrial fibrillation/Flutter||||||||| |Any grade|9%|16%|3%|9%|16%|7%|17%|3%*| |Grade ≥3|2%|5%|<1%|5%|3%|3%|5%|<1%| |Bleeding|Bleeding|Bleeding|Bleeding|||||| |Any grade|45%|NR|45%|38%|51%|20%|22%|43%| |Grade ≥3|5%|NR|4%|-|-|-|-|1%| |Major bleeding|Major bleeding|Major bleeding|Major bleeding|||||| |Any grade|6%|11%|5%|-|-|-|-|21%| |Grade ≥3|5%|7%|4%|-|-|-|-|1%| |Hypertension|Hypertension|Hypertension|Hypertension|||||| |Any grade|11%|23%|14%|9%|23%|27%|25%|6%*| |Grade ≥3|5%|8%|6%|4%|9%|17%*|16%*|<1%| |Infections|Infections|Infections|Infections|||||| |Any grade|80%|26%|62%|-|-|29%*|20%*|71%| |Grade ≥3|28%|-|16%|-|-|2%|1%|4%|

*Data from BRUIN CLL-321 study

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NCCN Guidelines Version 2.2026

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

|TEAEs (All Grades)|Treatment-Naïve CLL|Treatment-Naïve CLL|Treatment-Naïve CLL|Treatment-Naïve CLL|Treatment-Naïve CLL|Relapsed or Refractory CLL|| |---|---|---|---|---|---|---|---| |TEAEs (All Grades)|CLL14^{132}|GAIA/CLL13^{25}|FLAIR2^{9}|AMPLIFY3^{33}|AMPLIFY3^{33}|MURANO^{152}|M13-982^{161}| |TEAEs (All Grades)|VenO|VenO|Venetoclax/ Ibrutinib*|AVO|Venetoclax/ Acalabrutinib|VenR|Venetoclax| |Neutropenia|58%|49%|12%|40%|31%|61%|46%| |Thrombocytopenia|24%|18%|21%|5%|9%|13%|23%| |Anemia|17%|8%|24%|5%|7%|16%|27%| |Infusion-related reaction|45%|51%|<1%|20%|0%|8%|NR| |Diarrhea|28%|33%|44%|36%|33%|40%|44%| |Nausea|19%|NR|36%|22%|15%|22%|38%| |Constipation|13%|NR|11%|8%|7%|14%|13%| |Pyrexia|23%|24%|NR|16%|6%|15%|19%| |Fatigue|15%|NR|38%|14%|15%|18%|27%| |Cough|16%|NR|9%|NR|NR|18%|19%| |Headache|11%|NR|15%|28%|35%|11%|18%|

*Grade 1-2 TEAE; NR, Not reported

National Comprehensive Cancer Network®

NCCN Guidelines Version 2.2026

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

|Regimen|No. of Patients|Median Follow-up|ORR|Median PFS|OS| |---|---|---|---|---|---| |CHOP (Cyclophosphamide/Doxorubicin/Vincristine/Prednisone) + Rituximab355|15|69 months|67% (7% CR)|10 months|Median, 21 months| |CHOP/Venetoclax + Rituximab356|42|15 months|71% (52% CR)|16 months|Median, NR; 63% at 2 years| |Dose-adjusted EPOCH (Etoposide/Prednisone/Vincristine/Cyclophosphamide/Doxorubicin) + Rituximab357|46|39 months|39%|4 months|Median, 6 months| |HyperCVAD (Cyclophosphamide/Vincristine/Liposomal Daunorubicin/Dexamethasone) + Rituximab alternating with Cytarabine + High-dose Methotrexate358|30|8 months|43% (27% CR)|—|1-year, 28%| |OFA (Oxaliplatin/Fludarabine/Cytarabine + Rituximab)359|20|9 months|50%|—|6-month, 53%| |Modified OFA + Rituximab360|35|26 months|39% (7% CR)|—|Median, 7 months 2-year: 20%|

CR, complete response; ORR, overall response rate; OS, overall survival; PS, performance status; PFS, progression-free survival

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NCCN Guidelines Version 2.2026

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

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NCCN Guidelines Version 2.2026 Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

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Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

58. Ramakrishnan V, Xu L, Paik JC, et al. Broad superiority of zanubrutinib (Zanu) over bendamustine + rituximab (BR) across multiple high-risk factors: Biomarker subgroup analysis in the phase 3 SEQUOIA study in patients with treatment-naive (TN) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) without del(17p) [abstract]. Blood 2023;142:Abstract 1902. Available at: https://doi.org/10.1182/blood-2023-174543.

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Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

86. Aw A, Kim HT, Fernandes SM, et al. Minimal residual disease detected by immunoglobulin sequencing predicts CLL relapse more effectively than flow cytometry. Leuk Lymphoma 2018;59:1986–1989. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29164966.

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100. Kater AP, Seymour JF, Hillmen P, et al. Fixed duration of venetoclax-rituximab in relapsed/refractory chronic lymphocytic leukemia eradicates minimal residual disease and prolongs survival: Post-treatment follow-up of the MURANO Phase III Study. J Clin Oncol 2019;37:269–277. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30523712.

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238. Zelenetz AD, Barrientos JC, Brown JR, et al. Idelisib or placebo in combination with bendamustine and rituximab in patients with relapsed or refractory chronic lymphocytic leukaemia: interim results from a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Oncol 2017;18:297–311. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28139405.

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259. Noy A, Schoder H, Gonen M, et al. The majority of transformed lymphomas have high standardized uptake values (SUVs) on positron emission tomography (PET) scanning similar to diffuse large B-cell lymphoma (DLBCL). Ann Oncol 2009;20:508–512. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19139176.

260. Papajik T, Myslivecek M, Urbanova R, et al. 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography examination in patients with chronic lymphocytic leukemia may reveal Richter transformation. Leuk Lymphoma 2014;55:314–319. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23656196.

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281. Mao Z, Quintanilla-Martinez L, Raffeld M, et al. IgVH mutational status and clonality analysis of Richter's transformation: diffuse large B-cell lymphoma and Hodgkin lymphoma in association with B-cell chronic lymphocytic leukemia (B-CLL) represent 2 different pathways of disease evolution. Am J Surg Pathol 2007;31:1605-1614. Available at: https://www.ncbi.nlm.nih.gov/pubmed/17895764.

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286. Ding W, LaPlant BR, Call TG, et al. Pembrolizumab in patients with CLL and Richter transformation or with relapsed CLL. Blood 2017;129:3419-3427. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28424162.

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288. Armand P, Murawski N, Molin D, et al. Pembrolizumab in relapsed or refractory Richter syndrome. Br J Haematol 2020;190:e117-e120. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32544980.

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292. Tedeschi A, Frustaci AM, Condoluci A, et al. Atezolizumab, venetoclax, and obinutuzumab combination in Richter transformation diffuse large B-cell lymphoma (MOLTO): a multicentre, single-arm, phase 2 trial. Lancet Oncol 2024;25:1298–1309. Available at: https://www.ncbi.nlm.nih.gov/pubmed/39270702.

293. Eyre TA, Schuh A, Wierda WG, et al. Acalabrutinib monotherapy for treatment of chronic lymphocytic leukaemia (ACE-CL-001): analysis of the

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294. Wierda WG, Shah NN, Cheah CY, et al. Pirtobrutinib, a highly selective, non-covalent (reversible) BTK inhibitor in patients with B-cell malignancies: analysis of the Richter transformation subgroup from the multicentre, open-label, phase 1/2 BRUIN study. Lancet Haematol 2024;11:e682-e692. Available at: https://www.ncbi.nlm.nih.gov/pubmed/39033770.

295. Kater A, Janssens A, Eradat H, et al. Epcoritamab monotherapy demonstrates promising efficacy in patients with Richter transformation (RT): 2-year follow-up results from arm 2A of the phase 1b/2 EPCORE CLL-1 trial [abstract]. Blood 2025;146:Abstract 1017. Available at: https://doi.org/10.1182/blood-2025-1017.

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300. Herrera AF, Ahn KW, Litovich C, et al. Autologous and allogeneic hematopoietic cell transplantation for diffuse large B-cell lymphoma-type Richter syndrome. Blood Adv 2021;5:3528–3539. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34496026.

301. Lahoud OB, Devlin SM, Maloy MA, et al. Reduced-intensity conditioning hematopoietic stem cell transplantation for chronic lymphocytic leukemia and Richter's transformation. Blood Adv 2021;5:2879-2889. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34297048.

302. Kharfan-Dabaja MA, Kumar A, Stingo FE, et al. Allogeneic hematopoietic cell transplantation for Richter syndrome: A single-center experience. Clin Lymphoma Myeloma Leuk 2018;18:e35-e39. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29126867.

303. Kim HT, Baker PO, Parry E, et al. Allogeneic hematopoietic cell transplantation outcomes in patients with Richter's transformation. Haematologica 2021;106:3219-3222. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34435483.

304. Parikh SA, Habermann TM, Chaffee KG, et al. Hodgkin transformation of chronic lymphocytic leukemia: Incidence, outcomes, and comparison to de novo Hodgkin lymphoma. Am J Hematol 2015;90:334–338. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25581025.

305. Mauro FR, Galieni P, Tedeschi A, et al. Factors predicting survival in chronic lymphocytic leukemia patients developing Richter syndrome transformation into Hodgkin lymphoma. Am J Hematol 2017;92:529–535. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28295527.

306. Stephens DM, Boucher K, Kander E, et al. Hodgkin lymphoma arising in patients with chronic lymphocytic leukemia: outcomes from a large multi-center collaboration. Haematologica 2021;106:2845-2852. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33054118.

307. Tsai HT, Caporaso NE, Kyle RA, et al. Evidence of serum immunoglobulin abnormalities up to 9.8 years before diagnosis of chronic lymphocytic leukemia: a prospective study. Blood 2009;114:49284932. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19828698.

308. Morrison VA. Infectious complications of chronic lymphocytic leukaemia: pathogenesis, spectrum of infection, preventive approaches. Best Pract Res Clin Haematol 2010;23:145–153. Available at: https://www.ncbi.nlm.nih.gov/pubmed/20620978.

309. Perkins JG, Flynn JM, Howard RS, Byrd JC. Frequency and type of serious infections in fludarabine-refractory B-cell chronic lymphocytic leukemia and small lymphocytic lymphoma: implications for clinical trials in this patient population. Cancer 2002;94:2033-2039. Available at: https://www.ncbi.nlm.nih.gov/pubmed/11932906.

310. Chapel H, Dicato M, Gamm H, et al. Immunoglobulin replacement in patients with chronic lymphocytic leukaemia: a comparison of two dose regimes. Br J Haematol 1994;88:209-212. Available at: https://www.ncbi.nlm.nih.gov/pubmed/7803248.

311. Cooperative Group for the Study of Immunoglobulin in Chronic Lymphocytic L, Gale RP, Chapel HM, et al. Intravenous immunoglobulin for the prevention of infection in chronic lymphocytic leukemia. A randomized, controlled clinical trial. N Engl J Med 1988;319:902–907. Available at: https://www.ncbi.nlm.nih.gov/pubmed/2901668.

312. Boughton BJ, Jackson N, Lim S, Smith N. Randomized trial of intravenous immunoglobulin prophylaxis for patients with chronic lymphocytic leukaemia and secondary hypogammaglobulinaemia. Clin Lab Haematol 1995;17:75-80. Available at: https://www.ncbi.nlm.nih.gov/pubmed/7621634.

313. Molica S, Musto P, Chiurazzi F, et al. Prophylaxis against infections with low-dose intravenous immunoglobulins (IVIG) in chronic lymphocytic leukemia. Results of a crossover study. Haematologica 1996;81:121–126. Available at: https://www.ncbi.nlm.nih.gov/pubmed/8641639.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 2.2026

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

314. Raanani P, Gafter-Gvili A, Paul M, et al. Immunoglobulin prophylaxis in chronic lymphocytic leukemia and multiple myeloma: systematic review and meta-analysis. Leuk Lymphoma 2009:50:764–772. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19330654.

315. Yeo W, Chan PK, Zhong S, et al. Frequency of hepatitis B virus reactivation in cancer patients undergoing cytotoxic chemotherapy: a prospective study of 626 patients with identification of risk factors. J Med Virol 2000;62:299–307. Available at: https://www.ncbi.nlm.nih.gov/pubmed/11055239.

316. Lau GK. Hepatitis B reactivation after chemotherapy: two decades of clinical research. Hepatol Int 2008;2:152–162. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19669300.

317. Arnold DM, Crowther MA, Meyer RM, et al. Misleading hepatitis B test results due to intravenous immunoglobulin administration: implications for a clinical trial of rituximab in immune thrombocytopenia. Transfusion 2010;50:2577-2581. Available at: https://www.ncbi.nlm.nih.gov/pubmed/20576011.

318. Huang YH, Hsiao LT, Hong YC, et al. Randomized controlled trial of entecavir prophylaxis for rituximab-associated hepatitis B virus reactivation in patients with lymphoma and resolved hepatitis B. J Clin Oncol 2013;31:2765-2772. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23775967.

319. Kim SJ, Hsu C, Song YQ, et al. Hepatitis B virus reactivation in B-cell lymphoma patients treated with rituximab: analysis from the Asia Lymphoma Study Group. Eur J Cancer 2013;49:3486–3496. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23910494.

320. Liang R. How I treat and monitor viral hepatitis B infection in patients receiving intensive immunosuppressive therapies or undergoing hematopoietic stem cell transplantation. Blood 2009;113:3147–3153. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19144986.

321. Hammond SP, Chen K, Pandit A, et al. Risk of hepatitis B virus reactivation in patients treated with irutinib. Blood 2018;131:1987–1989. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29490923.

322. Ghez D, Calleja A, Protin C, et al. Early-onset invasive aspergillosis and other fungal infections in patients treated with irbutinib. Blood 2018;131:1955–1959. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29437588.

323. O'Brien SM, Keating MJ, Mocarski ES. Updated guidelines on the management of cytomegalovirus reactivation in patients with chronic lymphocytic leukemia treated with alemtuzumab. Clin Lymphoma Myeloma 2006;7:125–130. Available at: https://www.ncbi.nlm.nih.gov/pubmed/17026823.

324. Laurenti L, Piccioni P, Cattani P, et al. Cytomegalovirus reactivation during alemtuzumab therapy for chronic lymphocytic leukemia: incidence and treatment with oral ganciclovir. Haematologica 2004;89:1248–1252. Available at: https://www.ncbi.nlm.nih.gov/pubmed/15477211.

325. Visani G, Mele A, Guiducci B, et al. An observational study of once weekly intravenous ganciclovir as CMV prophylaxis in heavily pre-treated chronic lymphocytic leukemia patients receiving subcutaneous alemtuzumab. Leuk Lymphoma 2006;47:2542–2546. Available at: https://www.ncbi.nlm.nih.gov/pubmed/17169798.

326. Dearden C. Disease-specific complications of chronic lymphocytic leukemia. Hematology Am Soc Hematol Educ Program 2008;2008:450–456. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19074125.

327. Zent CS, Kay NE. Autoimmune complications in chronic lymphocytic leukaemia (CLL). Best Pract Res Clin Haematol 2010;23:47–59. Available at: https://www.ncbi.nlm.nih.gov/pubmed/20620970.

328. Borthakur G, O'Brien S, Wierda WG, et al. Immune anaemias in patients with chronic lymphocytic leukaemia treated with fludarabine, cyclophosphamide and rituximab--incidence and predictors. Br J Haematol 2007;136:800-805. Available at: https://www.ncbi.nlm.nih.gov/pubmed/17341265.

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NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 2.2026

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

329. Barcellini W, Capalbo S, Agostinelli R, et al. Relationship between autoimmune phenomena and disease stage and therapy in B-cell chronic lymphocytic leukemia. Haematologica 2006;91:1689-1692. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17145607.

330. Zanotti R, Frattini F, Ghia P, et al. ZAP-70 expression is associated with increased risk of autoimmune cytopenias in CLL patients. Am J Hematol 2010;85:494-498. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20575031.

331. Moreno C, Hodgson K, Ferrer G, et al. Autoimmune cytopenia in chronic lymphocytic leukemia: prevalence, clinical associations, and prognostic significance. Blood 2010;116:4771-4776. Available at: https://www.ncbi.nlm.nih.gov/pubmed/20736453.

332. Dearden C, Wade R, Else M, et al. The prognostic significance of a positive direct antiglobulin test in chronic lymphocytic leukemia: a beneficial effect of the combination of fludarabine and cyclophosphamide on the incidence of hemolytic anemia. Blood 2008;111:1820-1826. Available at: https://www.ncbi.nlm.nih.gov/pubmed/18055869.

333. Visco C, Ruggeri M, Laura Evangelista M, et al. Impact of immune thrombocytopenia on the clinical course of chronic lymphocytic leukemia. Blood 2008;111:1110-1116. Available at: https://www.ncbi.nlm.nih.gov/pubmed/17986663.

334. Cortes J, O'Brien S, Loscertales J, et al. Cyclosporin A for the treatment of cytopenia associated with chronic lymphocytic leukemia. Cancer 2001;92:2016–2022. Available at: https://www.ncbi.nlm.nih.gov/pubmed/11596014.

335. Hegde UP, Wilson WH, White T, Cheson BD. Rituximab treatment of refractory fludarabine-associated immune thrombocytopenia in chronic lymphocytic leukemia. Blood 2002;100:2260-2262. Available at: https://www.ncbi.nlm.nih.gov/pubmed/12200396.

336. Ghazal H. Successful treatment of pure red cell aplasia with rituximab in patients with chronic lymphocytic leukemia. Blood 2002;99:1092–1094. Available at: https://www.ncbi.nlm.nih.gov/pubmed/11807020.

337. Gupta N, Kavuru S, Patel D, et al. Rituximab-based chemotherapy for steroid-refractory autoimmune hemolytic anemia of chronic lymphocytic leukemia. Leukemia 2002;16:2092–2095. Available at: https://www.ncbi.nlm.nih.gov/pubmed/12357362.

338. D'Arena G, Laurenti L, Capalbo S, et al. Rituximab therapy for chronic lymphocytic leukemia-associated autoimmune hemolytic anemia. Am J Hematol 2006;81:598–602. Available at: https://www.ncbi.nlm.nih.gov/pubmed/16823816.

339. Godeau B, Porcher R, Fain O, et al. Rituximab efficacy and safety in adult splenectomy candidates with chronic immune thrombocytopenic purpura: results of a prospective multicenter phase 2 study. Blood 2008;112:999–1004. Available at: https://www.ncbi.nlm.nih.gov/pubmed/18463354.

340. Bussel JB, Provan D, Shamsi T, et al. Effect of elrombopag on platelet counts and bleeding during treatment of chronic idiopathic thrombocytopenic purpura: a randomised, double-blind, placebo-controlled trial. Lancet 2009;373:641–648. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19231632.

341. Kuter DJ, Rummel M, Boccia R, et al. Romiplostim or standard of care in patients with immune thrombocytopenia. N Engl J Med 2010;363:1889-1899. Available at: https://www.ncbi.nlm.nih.gov/pubmed/21067381.

342. D'Arena G, Cascavilla N. Romiplostim for chronic lymphocytic leukemia-associated immune thrombocytopenia. Leuk Lymphoma 2011;52:701–704. Available at: https://www.ncbi.nlm.nih.gov/pubmed/21171868.

343. Sinisalo M, Sankelo M, Itala-Remes M. Thrombopoietin receptor agonists can be used temporarily with patients suffering from refractory chronic lymphocytic leukemia-associated immunologic thrombocytopenia. Leuk Lymphoma 2011;52:724-725. Available at: https://www.ncbi.nlm.nih.gov/pubmed/21323511.

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 2.2026

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

344. Paul S, Jain N, Ferrajoli A, et al. A phase II trial of elrombopag for patients with chronic lymphocytic leukaemia (CLL) and thrombocytopenia. Br J Haematol 2019;185:606–608. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30406944.

345. Chanan-Khan A, Miller KC, Lawrence D, et al. Tumor flare reaction associated with lenalidomide treatment in patients with chronic lymphocytic leukemia predicts clinical response. Cancer 2011;117:2127–2135. Available at: https://www.ncbi.nlm.nih.gov/pubmed/21523725.

346. Andritsos LA, Johnson AJ, Lozanski G, et al. Higher doses of lenalidomide are associated with unacceptable toxicity including life-threatening tumor flare in patients with chronic lymphocytic leukemia. J Clin Oncol 2008;26:2519-2525. Available at: https://www.ncbi.nlm.nih.gov/pubmed/18427150.

347. Wendtner CM, Hallek M, Fraser GA, et al. Safety and efficacy of different lenalidomide starting doses in patients with relapsed or refractory chronic lymphocytic leukemia: results of an international multicenter double-blinded randomized phase II trial. Leuk Lymphoma 2016;57:1291-1299. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26763349.

348. Sinisalo M, Aittoniemi J, Kayhty H, Vilpo J. Vaccination against infections in chronic lymphocytic leukemia. Leuk Lymphoma 2003;44:649-652. Available at: https://www.ncbi.nlm.nih.gov/pubmed/12769342.

349. Mauro FR, Giannarelli D, Galluzzo CM, et al. Response to the conjugate pneumococcal vaccine (PCV13) in patients with chronic lymphocytic leukemia (CLL). Leukemia 2021;35:737–746. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32555297.

350. Bergman P, Blennow O, Hansson L, et al. Safety and efficacy of the mRNA BNT162b2 vaccine against SARS-CoV-2 in five groups of immunocompromised patients and healthy controls in a prospective open-label clinical trial. EBioMedicine 2021;74:103705. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34861491.

351. Herishanu Y, Avivi I, Aharon A, et al. Efficacy of the BNT162b2 mRNA COVID-19 vaccine in patients with chronic lymphocytic leukemia.

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352. Parry H, McIlroy G, Bruton R, et al. Antibody responses after first and second Covid-19 vaccination in patients with chronic lymphocytic leukaemia. Blood Cancer J 2021;11:136. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34330895.

353. Haggenburg S, Lissenberg-Witte BI, van Binnendijk RS, et al. Quantitative analysis of mRNA-1273 COVID-19 vaccination response in immunocompromised adult hematology patients. Blood Adv 2022;6:1537–1546. Available at: https://www.ncbi.nlm.nih.gov/pubmed/35114690.

354. Herishanu Y, Rahav G, Levi S, et al. Efficacy of a third BNT162b2 mRNA COVID-19 vaccine dose in paties with CLL who failed standard 2-dose vaccination. Blood 2022;139:678-685. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34861036.

355. Langerbeins P, Busch R, Anheier N, et al. Poor efficacy and tolerability of R-CHOP in relapsed/refractory chronic lymphocytic leukemia and Richter transformation. Am J Hematol 2014;89:E239-243. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25196783.

356. Davids MS, Ryan CE, Tyekucheva S, et al. Primary endpoint evaluation of a multicenter phase 2 study of venetoclax in combination with R-CHOP (VR-CHOP) for patients with Richter syndrome [abstract]. Hematological Oncology 2025;43:e73_70093. Available at: https://onlinelibrary.wiley.com/doi/abs/10.1002/hon.70093_73.

357. Rogers KA, Huang Y, Ruppert AS, et al. A single-institution retrospective cohort study of first-line R-EPOCH chemoimmunotherapy for Richter syndrome demonstrating complex chronic lymphocytic leukaemia karyotype as an adverse prognostic factor. Br J Haematol 2018;180:259–266. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29193006.

358. Tsimberidou AM, Kantarjian HM, Cortes J, et al. Fractionated cyclophosphamide, vincristine, liposomal daunorubicin, and dexamethasone plus rituximab and granulocyte-macrophage-colony stimulating factor (GM-CSF) alternating with methotrexate and cytarabine

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表 1
Method of Detection	Prognostic Variable	Clinical $Association^{a}$
Interphase cytogenetics (FISH)	Del(13q) as a sole abnormality	Favorable prognosis: longest median overall survival (OS) in patients treated with chemoimmunotherapy (CIT).$^{1}$
Interphase cytogenetics (FISH)	Trisomy 12	Intermediate prognosis for time-to-first treatment (TTFT) in patients with newly diagnosed CLL; and intermediate OS in patients treated with chemoimmunotherapy.$^{1}$
Interphase cytogenetics (FISH)	None	Intermediate prognosis for TTFT in patients with newly diagnosed CLL; and intermediate OS in patients treated with chemoimmunotherapy.$^{1}$
Interphase cytogenetics (FISH)	Del(11q)	Shortened TTFT, and shorter median OS with chemoimmunotherapy.$^{1}$
Interphase cytogenetics (FISH)	Del(17p)$^{b}$	Inferior response, shorter treatment-free interval, and inferior survival with chemoimmunotherapy.$^{1-3}$ Good responses but shorter progression-free survival (PFS) and OS with both time-limited venetoclax-based regimens$^{4,5}$ and covalent BTK inhibitor (cBTKi).$^{6-10}$
DNA sequencing	$IGHV^{c}$ Mutated: >2% mutation or <98% homology with germline gene sequence Unmutated: ≤2% of mutation or ≥98% homology with germline gene sequence)	Unmutated IGHV is associated with shorter TTFT and PFS with chemoimmunotherapy and time-limited venetoclax-based regimens, compared to mutated IGHV.$^{3,5,11-15}$.Overall response rates are not correlated with IGHV mutation status in patients treated with cBTKi or time-limited venetoclax-based regimens.$^{6-10}$.PFS and OS are not correlated with IGHV mutation status in patients treated with cBTKi.$^{6,7,16}$
DNA sequencing	$TP53 mutation^{d}$ with del(17p)	Shorter PFS and OS with chemoimmunotherapy,$^{e,17-20}$ time-limited venetoclax-based regimens$^{4,5}$ and cBTKi.$^{6-10}$ Increased resistance to chemoimmunotherapy and targeted therapies; significantly shortened TTFT and time-to-next treatment (TTNT) and potentially increased risk for Richter transformation. Low burden variant allele frequencies (VAF, <10%) may behave similar to wild type (WT).$^{21,22}$
DNA sequencing	$TP53 mutation^{d}$ without del(17p)	TP53 mutation in the absence of del(17p) is associated with shortened PFS and OS. However, PFS and OS outcomes on treatment with TP53 mutation but in absence of del(17p) may be more favorable than with concurrent TP53 mutation and del(17p).$^{18,23}$
DNA sequencing	Other Significant Mutations	See Table 2 and Table 3 (CSLL-A 3 of 5)
CpG-stimulated metaphase $karyotype^{f}$	Complex karyotype (CK) (≥3 unrelated clonal chromosome abnormalities in more than one cell on karyotype)	Inferior survival and shorter time to disease progression with chemoimmunotherapy, time-limited venetoclax based regimens, and cBTKi.$^{24-27}$ High CK (≥5 unrelated chromosomal abnormalities) is an adverse prognostic factor independent of clinical stage, IGHV mutation status, del(17p) and/or TP53 mutation.$^{28,29}$
Serum test	Beta-2 Microglobulin (B2M) (can be affected by renal dysfunction in a CLL- independent manner)	Correlates with CLL/SLL disease burden and retains independent prognostic significance in multivariate $models^{30,31}$ Elevated $levels^{9}$ are associated with overall response, treatment free intervals, and OS in patients treated with frontline chemoimmunotherapy^{32}$ Reduction in levels associated with prolonged PFS in patients treated with ibrutinib$^{33,34}$

表 3
Mutated Gene	Clinical Association
ATM35-38	Shorter TTFT, PFS, TTNT and OS with CIT compared to WT
BIRC336,39,40	Shorter TTNT, PFS with CIT compared to WTMay be more sensitive to BCL2i-containing regimens
NOTCH14,36,41,42	Shorter TTFT and PFS irrespective of the IGHV mutation status and shorter TTNT with CIT compared to WTShorter OS in historical cohortsCorrelated with higher risk for Richter transformation
SF3B136,43	Shorter TTFT and OS with CIT compared to WT
TP53	See Table 1 (CSLL-A 1 of 5)
BTK (C481, L528, A428D, and T474)$^{27,44-46}$	BTK C481 and BTK A428D mutations have been detected in patients with disease progressing on cBTKiBTK L528 or T474 mutations have been detected in patients with disease progressing on cBTKi and noncovalent (reversible) BTKi (ncBTKi)
$CARD11^{47}$	Identified in patients with disease progressing on BTK inhibitors
$PLCG2^{27,44-47}$	Identified in patients with disease progressing on BTK inhibitors
BCL2 (G101V and $D103Y$)$^{48,49}$	Identified in patients with disease progressing on venetoclax

表 5
Stage	Description	Modified Risk Status
0	Lymphocytosis, lymphocytes in blood >5 x 10°/L clonal B cells and/or >40% lymphocytes in the bone marrow	Low
I	Stage 0 with enlarged node(s)	Intermediate
II	Stage 0-I with splenomegaly, hepatomegaly, or both	Intermediate
III	Stage 0-II with hemoglobin <11.0 g/dL or hematocrit <33%	High
IV	Stage 0-III with platelets <100,000/mm³	High

表 6
Stage	Description
A	Hemoglobin ≥10 g/dL and Platelets ≥100,000/mm³ and <3 enlarged areas
B	Hemoglobin ≥10 g/dL and Platelets ≥100,000/mm³ and ≥3 enlarged areas
C	Hemoglobin <10 g/dL and/or Platelets <100,000/mm³ and any number of enlarged areas

表 7
$Stage^{d}$	$Involvement^{f}$	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 $bulky^{e}$	Il 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

表 8
Trial	First-line Therapy	Regimen
$FLAIR^{k}$	CLL/SLL without del(17p) or TP53 mutation	Venetoclax/lbrutinib^{n} (category 1; other recommended)
$SEQUOIA$ (Arm $D^{l}$)	CLL/SLL without del(17p) or TP53 mutation	Venetoclax/Zanubrutinib^{o} (category 2A; useful in certain circumstances)
$SEQUOIA$ (Arm $D^{l}$)	CLL/SLL with del(17p) or TP53 mutation	Venetoclax/Zanubrutinib^{o} (category 2A; preferred)
Phase II $study^{m}$	CLL/SLL with del(17p) or TP53 mutation	Venetoclax/Acalabrutinib + Obinutuzumab^{p} (category 2A; preferred)

表 9
Chemoimmunotherapy (CIT)$^{e}$
CHOP (Cyclophosphamide/Doxorubicin/Vincristine/Prednisone) + Rituximab ± Venetoclax* (category 2B with Venetoclax)Dose-Adjusted EPOCH (Etoposide/Prednisone/Vincristine/Cyclophosphamide/Doxorubicin) + RituximabHyperCVAD (Cyclophosphamide/Vincristine/Doxorubicin/Dexamethasone) + Rituximab alternating with Cytarabine/High-Dose MethotrexateOFA (Oxaliplatin/Fludarabine/Cytarabine) + RituximabPatients who are frail or patients with poor left ventricular ejection fraction (LVEF): See NCCN Guidelines for B-Cell Lymphomas (First-line therapy for DLBCL (BCEL-C): Patients with Poor LVEF or Very Frail Patients and Patients >80 Years of Age with Comorbidities)

表 10
NON-CIT BASED REGIMENS
ICI-based $regimens^{f}$	BTKi (monotherapy)	Bispecific Antibody Therapy	CAR T-cell Therapy (CD19-directed; after at least 1 prior systemic therapy $regimen^{i}$)
Venetoclax* + Atezolizumab^{g} + Obinutuzumab^{Nivolumab^{h}} ± Ibrutinib^{†}Pembrolizumab ± Ibrutinib^{†}Zanubrutinib^{†} + Tislelizumab.jsgr	Pirtobrutinib**Acalabrutinib† (category 2B)	Eporitamab-byspGlofitamab-gxbm	Axicabtagene ciloleucelLiscabtagene maraleucelTisagenlecleucel

表 11
AIHA	autoimmune hemolytic anemia	HBcAb	hepatitis B core antibody	PFS	progression-free survival
ALC	absolute lymphocyte count	HBsAg	hepatitis B surface antigen	PI3Ki	PI3K inhibitor
ANC	absolute neutrophil count	HBV	hepatitis B virus	PJP	pneumocystis jirovecii pneumonia
ASO-PCR	allele-specific oligonucleotide polymerase chain reaction	HCT	hematopoietic cell transplant	PML	progressive multifocal leukoencephalopathy
BCL2i	BCL2-inhibitor	HLA	human leukocyte antigen	PRCA	pure red cell aplasia
BTKi	BTK inhibitor	HR	hazard ratio	qPCR	quantitative RT-PCR
C/A/P	chest/abdomen/pelvis	IHC	immunohistochemistry	RS	Reed-Sternberg
CAR	chimeric antigen receptor	ISRT	involved-site radiation therapy	RSV	respiratory syncytial virus
CBC	complete blood count	ITP	immune thrombocytopenic purpura	RT-PCR	reverse transcriptase polymerase chain reaction
cBTKi	covalent BTK inhibitor	IVF	in vitro fertilization
CHL	classic Hodgkin lymphoma	IVIG	intravenous immunoglobulin
CIT	chemoimmunotherapy	JCV	SCIG	subcutaneous immunoglobulin
CK	complex karyotype	JCV	John Cunningham virus	SIFE	serum immunofixation electrophoresis
CMV	cytomegalovirus	LDH	lactate dehydrogenase
CRCl	creatinine clearance	LVEF	left ventricular ejection fraction	SPEP	serum protein electrophoresis
CRS	cytokine release syndrome	LVEF	left ventricular ejection fraction	SUV	standardized uptake value
DAA	direct-acting antiviral
DLBCL	diffuse large B-cell lymphoma	mb	monoclonal antibody	TLS	tumor lysis syndrome
EBER	Epstein-Barr virus-encoded RNA	MBL	monoclonal B-cell lymphocytosis	TTFT	time-to-first treatment
EBER-ISH	Epstein-Barr virus-encoded RNA in situ hybridization	MCL	mantle cell lymphoma	TTNT	time-to-next treatment
EBV	Epstein-Barr virus	MRD	minimal residual disease	uMRD	undetectable MRD
ERIC	European Research Initiative on CLL	MUGA	multigated acquisition
FISH	fluorescence in situ hybridization	ncBTKi	noncovalent BTK inhibitor	VAF	variant allele frequency
FNA	fine-needle aspiration	NGS	next-generation sequencing	VZV	varicella zoster virus
G6PD	glucose-6-phosphate dehydrogenase	NHL	non-Hodgkin lymphoma	WBC	white blood cell
GVHD	graft-versus-host disease	OS	overall survival	WT	wild type

表 12
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.

表 13
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).

表 14
Trial	Regimen	No. of Patients	Patient Characteristics	Median Follow-up	Undetectable MRD (≤$10^{-4},$ uMRD4)	MRD Detection
GLOW (Phase III; Fixed duration)$^{27}$	Venetoclax/lbrutinib	106	≥65 years or <65 years who also had CIRS >6 or CrCl <70 mL/min	34 months	EOT+3 (BM): 67% among patients with a CR; 64% among patients with a PR)	NGS
GLOW (Phase III; Fixed duration)$^{27}$	Chlorambucil + Obinutuzumab	105	≥65 years or <65 years who also had CIRS >6 or CrCl <70 mL/min	34 months	EOT+3 (BM): 31% among patients with a CR; 21% among patients with a PR	NGS
FLAIR (Phase III; MRD-guided)$^{29,a}$	Ibrutinib	263	Median age, 62 years (>65 years, 31%) [without del(17p)]	62 months	60 months: 4% (blood); 0% (BM)	MRD-flow
FLAIR (Phase III; MRD-guided)$^{29,a}$	Venetoclax/lbrutinib	260	Median age, 62 years (>65 years, 31%) [without del(17p)]	62 months	60 months: 93% (blood); 72% (BM)	MRD-flow
FLAIR (Phase III; MRD-guided)$^{29,a}$	Fludarabine, Cyclophosphamide + Rituximab (FCR)	263	Median age, 62 years (>65 years, 31%) [without del(17p)]	62 months	60 months: 69% (blood); 55% (BM)	MRD-flow
CAPTIVATE (Phase II; MRD cohort)$^{101}$	Venetoclax/lbrutinib	164	≤70 years; ECOG PS 0-1 (Prandomization)	31 months	75% (blood); 68% (BM)	MRD-flow
CAPTIVATE (Phase II; MRD cohort)$^{101}$	Venetoclax/lbrutinib	32	≤70 years; ECOG PS 0-1 (Randomization; uMRD not confirmed)	31 months	69% (blood); 66% (BM)	MRD-flow
CAPTIVATE (Phase II; MRD cohort)$^{101}$	Ibrutinib	31	≤70 years; ECOG PS 0-1 (Randomization; uMRD not confirmed)	31 months	45% (blood); 42% (BM)	MRD-flow
CAPTIVATE (Phase II; Fixed duration)$^{31}$	Venetoclax/lbrutinib	159	≤70 years; ECOG PS 0-1	69 months	Cycle 7: 54% (blood) EOT: 69% (blood and BM)	MRD-flow
Phase II (MRD-guided)$^{32,b}$	Venetoclax/lbrutinib	80	≥65 years (18 patients with del(17p) and/or TP53 mutation)	39 months	Cycle 12 (BM): 56% (69% for those with del(17p) and/or TP53 mutation) Cycle 24 (BM): 66% (77% for those with del(17p) and/or TP53 mutation)	MRD-flow NGS
CLL14 (Phase III; Fixed duration)$^{45}$	Venetoclax + Obinutuzumab (Veno)	216	≥65 years (CIRS >6; CrCl <70 mL/min)	65 months	EOT+2: 75% (blood)	ASO-PCR; MRD-flow; NGS
CLL14 (Phase III; Fixed duration)$^{45}$	Chlorambucil + Obinutuzumab	216	≥65 years (CIRS >6; CrCl <70 mL/min)	65 months	EOT+2: 33% (blood)	ASO-PCR; MRD-flow; NGS
AMPLIFY (Phase III; Fixed duration)$^{33}$	Venetoclax/Acalabrutinib	291	Median age, 61 years [without del(17p) or TP53 mutation])	41 months	EOT: 45% (blood); EOT+3: 38% (blood)	MRD-flow
AMPLIFY (Phase III; Fixed duration)$^{33}$	Venetoclax/Acalabrutinib + Obinutuzumab (AVO)	286	Median age, 61 years [without del(17p) or TP53 mutation])	41 months	EOT: 95% (blood); EOT+3: 94% (blood)	MRD-flow
AMPLIFY (Phase III; Fixed duration)$^{33}$	FCR or Bendamustine + Rituximab (BR)	290	Median age, 61 years [without del(17p) or TP53 mutation])	41 months	EOT: 73% (blood); EOT+3: 78% (blood)	MRD-flow
Phase II (MRD-guided)$^{34,c}$	Venetoclax/Acalabrutinib + Obinutuzumab (AVO)	72 (n = 45, TP53 aberration)	≥18 years; ECOG PS 0-1	55 months	Cycle 16 (BM): 78% (71% for those with TP53 aberration) Cycle 16 (blood): 83% (82% for those with TP53 aberration)	NGS; MRD-flow
SEQUOIA (Phase III; ARM D; MRD-guided)$^{92,d}$	Venetoclax/Zanubrutinib (Non-Randomized Cohort)	66 (TP53 aberration)	≥65 years of age OR unsuitable for FCR (CIRS >6; CrCl <70 mL/min or a history of severe/multiple infections within 2 years)	31 months	59% (blood)	MRD-flow
SEQUOIA (Phase III; ARM D; MRD-guided)$^{92,d}$	Venetoclax/Zanubrutinib (Non-Randomized Cohort)	47 (without TP53 aberration)	≥65 years of age OR unsuitable for FCR (CIRS >6; CrCl <70 mL/min or a history of severe/multiple infections within 2 years)	31 months	60% (blood)	MRD-flow

表 16
Trial	Regimen	No. of Patients	Patient Characteristics	Median Follow-up	ORR	PFS	OS
ELEVATE-TN20	Acalabrutinib	179 [del(17p) and/or mutated TP53, n = 23]	≥65 years or <65 years with comorbidities (CIRS >6; CrCl <70 mL/min); ECOG PS of ≤2 and adequate hematologic, hepatic, and renal function	75 months	90% (19% CR)	Median, Not reached (72-month, 62%)	Median, Not reached (72-month, 76%)
ELEVATE-TN20	Acalabrutinib + Obinutuzumab	179 [del(17p) and/or mutated TP53, n = 25]	≥65 years or <65 years with comorbidities (CIRS >6; CrCl <70 mL/min); ECOG PS of ≤2 and adequate hematologic, hepatic, and renal function	75 months	96% (37% CR)	Median, Not reached (72-month, 78%)	Median, Not reached (72-month, 84%)
ELEVATE-TN20	Chlorambucil + Obinutuzumab	177 [del(17p) and/or mutated TP53, n = 25]	≥65 years or <65 years with comorbidities (CIRS >6; CrCl <70 mL/min); ECOG PS of ≤2 and adequate hematologic, hepatic, and renal function	75 months	83% (14% CR)	Median, 28 months (72-month, 17%)	Median, Not reached (72-month, 75%)
RESONATE-218	Ibrutinib	136	≥65 years [without del(17p)]	8 years	92% (34% CR)	Median, Not reached (7-year, 59%)	Median, Not reached (7-year, 78%)
RESONATE-218	Chlorambucil	133	≥65 years [without del(17p)]	8 years	37%	Median, 15 months (7-year, 9%)	Not reported
Alliance North American Intergroup (A041202)43	Ibrutinib	182	≥65 years	55 months	93% (7% CR)	4-year, 76%	4-year, 85%
Alliance North American Intergroup (A041202)43	Ibrutinib + Rituximab	182	≥65 years	55 months	94% (12% CR)	4-year, 76%	4-year, 86%
Alliance North American Intergroup (A041202)43	Bendamustine + Rituximab	183	≥65 years	55 months	81% (26% CR)	4-year, 47%	4-year, 84%
E1912 study23	Ibrutinib + Rituximab	354	≤70 years	70 months	96% (17% CR)	5-year, 78%	5-year, 95%
E1912 study23	Fludarabine, Cyclophosphamide + Rituximab (FCR)	175	≤70 years	70 months	81% (30% CR)	5-year, 51%	5-year, 89%
SEQUOIA [without del(17p)]2122	Zanubrutinib	241 (mutated TP53, n = 15)	≥65 years of age OR unsuitable for treatment with CFR (CIRS >6; CrCl <70 mL/min or a history of severe/multiple infections within 2 years)	61 months	95% (7% CR)	Median, Not reached (60-month, 76%; P < .0001)	Median,: Not reached (60-month, 86%)
SEQUOIA [without del(17p)]2122	Bendamustine + Rituximab	238 (mutated TP53, n = 13)	≥65 years of age OR unsuitable for treatment with CFR (CIRS >6; CrCl <70 mL/min or a history of severe/multiple infections within 2 years)	61 months	85% (15% CR)	Median, 44 months (60-month, 40%)	Median, Not reached (60-month, 85%)
SEQUOIA (ARM C) [with del(17p)]137,151	Zanubrutinib (Non-Randomized Cohort)	111	≥65 years of age OR unsuitable for treatment with CFR (CIRS >6; CrCl <70 mL/min or a history of severe/multiple infections within 2 years)	77 months	97% (18% CR)*	72-month, 64%	72-month, 83%
SEQUOIA (ARM D)92	Venetoclax/Zanubrutinib (Non-Randomized Cohort)	66 (TP53 aberration)	≥65 years of age OR unsuitable for treatment with CFR (CIRS >6; CrCl <70 mL/min or a history of severe/multiple infections within 2 years)	39 months	99% (47% CR)	24-month, 94% 36-month, 88%	Median, Not reached (24 month, 96%)
SEQUOIA (ARM D)92	Venetoclax/Zanubrutinib (Non-Randomized Cohort)	47 (without TP53 aberration)	≥65 years of age OR unsuitable for treatment with CFR (CIRS >6; CrCl <70 mL/min or a history of severe/multiple infections within 2 years)	30 months	96% (49% CR)	24-month, 89%	Median, Not reached (24 month, 96%)
CLL1424,45	Venetoclax + Obinutuzumab	216 [del(17p), n = 17; deleted or mutated TP53, n = 25]	≥65 years with comorbidities (CIRS >6; CrCl <70 mL/min)	76 months	85% (50% CR)	Median, 76 months 6-year, 53% (P < .0001)	6-year, 79%
CLL1424,45	Chlorambucil + Obinutuzumab	216 [del(17p), n = 14; deleted or mutated TP53, n = 24]	≥65 years with comorbidities (CIRS >6; CrCl <70 mL/min)	76 months	71% (23% CR)	Median, 36 months 6-year, 22%	6-year, 69%
AMPLIFY33	Venetoclax/Acalabrutinib + Obinutuzumab (AVO)	286	Median age, 61 years [without del(17p) or TP53 mutation])	41 months	93%	36-month, 83%	36-month, 88%
AMPLIFY33	Venetoclax/Acalabrutinib	291	Median age, 61 years [without del(17p) or TP53 mutation])	41 months	93%	36-month, 77%	36-month, 94%
AMPLIFY33	Fludarabine/Cyclophosphamide + Rituximab (FCR) or Bendamustine + Rituximab (BR)	290			75%	36-month, 67%	36-month, 86%
GLOW27,28	Venetoclax/ibrutinib	106 (mutated TP53, n = 7)	≥65 years or <65 years who also had CIRS >6 or CrCl <70 mL/min	64 months	87% (39% CR)	60-month, 60%	60-month, 82%
GLOW27,28	Chlorambucil + Obinutuzumab	105 (mutated TP53, n = 2)	≥65 years or <65 years who also had CIRS >6 or CrCl <70 mL/min	64 months	36% (11% CR)	60-month, 18%	60-month, 61%
FLAIR29	Ibrutinib	263	Median age, 62 years (>65 years, 31%) [without del(17p)]	62 months	87% (87%)	5-year, 79%	5-year, 91%
FLAIR29	Venetoclax/ibrutinib	260	Median age, 62 years (>65 years, 31%) [without del(17p)]	62 months	88%	5-year, 94%	5-year, 96%
FLAIR29	FCR	263	Median age, 62 years (>65 years, 31%) [without del(17p)]	62 months	78%	5-year, 58%	5-year, 87%
GAIA/CLL1325,26	Venetoclax/ibrutinib + Obinutuzumab	231	≤65 years or >65 years [without del(17p) or TP53 mutation]	51 months	94% (62% CR)	4-year, 86%	4-year, 95%
GAIA/CLL1325,26	Venetoclax + Obinutuzumab	229	≤65 years or >65 years [without del(17p) or TP53 mutation]	51 months	96% (57% CR)	4-year, 82%	4-year, 95%
GAIA/CLL1325,26	Venetoclax + Rituximab (VenR)	237	≤65 years or >65 years [without del(17p) or TP53 mutation]	51 months	93% (49% CR)	4-year, 70%	4-year, 96%
GAIA/CLL1325,26	Chemoimmunotherapy (FCR ≤65 Years; BR >65 Years)	229	≤65 years or >65 years [without del(17p) or TP53 mutation]	51 months	81% (31% CR)	4-year, 62%	4-year, 94%
ASCEND169	Acalabrutinib	155[del(17p), n = 28; mutated TP53, n = 39]	Median age, 67-68years with ECOG PS≤2 and adequate hematologic, hepatic, and renal function	47 months	83%	Median, Not reached42-month, 62%(HR, 0.28; P<.0001)	Median, Not reached42-month, 78%
ASCEND169	Idelalisib + Rituximab (IdR) orBendamustine + Rituximab (BR)	155[ldR, n = 119; BR, n = 36);[del(17p), n = 21; mutated TP53, n = 34]	Median age, 67-68years with ECOG PS≤2 and adequate hematologic, hepatic, and renal function	47 months	84%	Median, 17 months42-month, 23%	Median, Not reached42-month, 65%
ELEVATE-RR136	Acalabrutinib	268	≥18 years; ECOG PS≤2 and the presence of del(17p) and/or del(11q)	41 months	81%(3% CR)	Median, 38 months (forboth treatment arms)	Median, Not reached42-month, 65%
ELEVATE-RR136	Ibrutinib	265	≥18 years; ECOG PS≤2 and the presence of del(17p) and/or del(11q)	41 months	77%(4% CR)	Median, 38 months (forboth treatment arms)	Median, Not reached42-month, 65%
RESONATE170	Ibrutinib	195[del(17p), n = 63; mutated TP53, n = 79]	Median age, 67 years	74 months	91%(11% CR)	Median, 44 months60-month, 40%	Median, 68 months
RESONATE170	Ofatumumab	196[del(17p), n = 64; mutated TP53, n = 68]	Median age, 67 years	74 months	-	Median, 8 months60-month, 3%	Median, 65 months
ALPINE171	Zanubrutinib	327[del(17p) and/or mutated TP53, n = 41]	Median age, 67 years; ECOG PS≥1;relapsed or refractory disease after≥1 priorsystemic therapy	42.5 months	86%(12% CR)	36-month, 65%(HR, 0.67; P =.002)	36-month, 83%
ALPINE171	Ibrutinib	325[del(17p) and/or mutated TP53, n = 38]	Median age, 67 years; ECOG PS≥1;relapsed or refractory disease after≥1 priorsystemic therapy	42.5 months	75%(8% CR)	36-month, 54%	36-month, 80%
MURANO98,100	Venetoclax + Rituximab	194[del(17p), n = 46; mutated TP53, n = 48]	≥18 years; ECOG PS0-1;relapsed or refractory diseaserequiring therapy andadequate bonemarrow, liver, andkidney function	59 months	92%(8% CR)	Median, 54 months(HR, 0.19; P<.0001)	5-year, 82%(HR, 0.40; P<.0001)
MURANO98,100	Bendamustine + Rituximab	195[del(17p), n = 46; mutated TP53, n = 51]	≥18 years; ECOG PS0-1;relapsed or refractory diseaserequiring therapy andadequate bonemarrow, liver, andkidney function	59 months	72%(4% CR)	Median, 17 months	5-year, 62%

表 19
TEAEs	Treatment-Naïve CLL	Treatment-Naïve CLL	Treatment-Naïve CLL	Relapsed or Refractory CLL
TEAEs	ELEVATE-TN19,20	RESONATE-21	SEQUOIA21	ELEVATE-RR136	ELEVATE-RR136	ALPINE171	ALPINE171	BRUIN174,176
TEAEs	Acalabrutinib	Ibrutinib	Zanubrutinib	Acalabrutinib	Ibrutinib	Zanubrutinib	Ibrutinib	Pirtobrutinib
Most common TEAEs (all grades)
Diarrhea	43%	50%	14%	35%	46%	19%	26%	16%*
Headache	39%	-	11%	35%	20%	NR	NR	17%
Cough	25%	36%	11%	29%	21%	NR	NR	24%
Fatigue	24%	36%	11%	20%	17%	11%	15%	32%
Arthralgia	27%	26%	14%	16%	23%	17%	19%	-
Anemia	-	26%	4%	22%	19%	17%	19%	21%*
Neutropenia	13%	13% (Grade ≥3)	16%	21%	25%	32%	30%	16%*
Adverse events of special interest (AESI)
Atrial fibrillation/Flutter
Any grade	9%	16%	3%	9%	16%	7%	17%	3%*
Grade ≥3	2%	5%	<1%	5%	3%	3%	5%	<1%
Bleeding	Bleeding	Bleeding	Bleeding
Any grade	45%	NR	45%	38%	51%	20%	22%	43%
Grade ≥3	5%	NR	4%	-	-	-	-	1%
Major bleeding	Major bleeding	Major bleeding	Major bleeding
Any grade	6%	11%	5%	-	-	-	-	21%
Grade ≥3	5%	7%	4%	-	-	-	-	1%
Hypertension	Hypertension	Hypertension	Hypertension
Any grade	11%	23%	14%	9%	23%	27%	25%	6%*
Grade ≥3	5%	8%	6%	4%	9%	17%*	16%*	<1%
Infections	Infections	Infections	Infections
Any grade	80%	26%	62%	-	-	29%*	20%*	71%
Grade ≥3	28%	-	16%	-	-	2%	1%	4%

表 20
TEAEs (All Grades)	Treatment-Naïve CLL	Treatment-Naïve CLL	Treatment-Naïve CLL	Treatment-Naïve CLL	Treatment-Naïve CLL	Relapsed or Refractory CLL
TEAEs (All Grades)	CLL14^{132}	GAIA/CLL13^{25}	FLAIR2^{9}	AMPLIFY3^{33}	AMPLIFY3^{33}	MURANO^{152}	M13-982^{161}
TEAEs (All Grades)	VenO	VenO	Venetoclax/ Ibrutinib*	AVO	Venetoclax/ Acalabrutinib	VenR	Venetoclax
Neutropenia	58%	49%	12%	40%	31%	61%	46%
Thrombocytopenia	24%	18%	21%	5%	9%	13%	23%
Anemia	17%	8%	24%	5%	7%	16%	27%
Infusion-related reaction	45%	51%	<1%	20%	0%	8%	NR
Diarrhea	28%	33%	44%	36%	33%	40%	44%
Nausea	19%	NR	36%	22%	15%	22%	38%
Constipation	13%	NR	11%	8%	7%	14%	13%
Pyrexia	23%	24%	NR	16%	6%	15%	19%
Fatigue	15%	NR	38%	14%	15%	18%	27%
Cough	16%	NR	9%	NR	NR	18%	19%
Headache	11%	NR	15%	28%	35%	11%	18%

表 21
Regimen	No. of Patients	Median Follow-up	ORR	Median PFS	OS
CHOP (Cyclophosphamide/Doxorubicin/Vincristine/Prednisone) + Rituximab355	15	69 months	67% (7% CR)	10 months	Median, 21 months
CHOP/Venetoclax + Rituximab356	42	15 months	71% (52% CR)	16 months	Median, NR; 63% at 2 years
Dose-adjusted EPOCH (Etoposide/Prednisone/Vincristine/Cyclophosphamide/Doxorubicin) + Rituximab357	46	39 months	39%	4 months	Median, 6 months
HyperCVAD (Cyclophosphamide/Vincristine/Liposomal Daunorubicin/Dexamethasone) + Rituximab alternating with Cytarabine + High-dose Methotrexate358	30	8 months	43% (27% CR)	—	1-year, 28%
OFA (Oxaliplatin/Fludarabine/Cytarabine + Rituximab)359	20	9 months	50%	—	6-month, 53%
Modified OFA + Rituximab360	35	26 months	39% (7% CR)	—	Median, 7 months 2-year: 20%

图示：NCCN

引用 / 出处

（2026.V2）NCCN临床实践指南：慢性淋巴细胞白血病／小淋巴细胞淋巴瘤. 2026.