（2026.V1）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

*Jeremy S.Abramson, MD,MMSc+t$\&$Mass General Cancer Center

Farrukh Awan, MD t+$P UT Southwestern Simmons Comprehensive Cancer Center

Greg Bociek,MD,MSc+\ξ Fred& Pamela Buffett Cancer Center

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

Matthew Cortese, MD, MPH+t≠p Roswell Park Comprehensive Cancer Center

Larry Cripe, MD $\ddagger$ Indiana University Melvin and Bren Simon Comprehensive Cancer Center

Randall S. Davis, MD $\ddagger$ ONeal Comprehensive Cancer Center at UAB

Herbert Eradat,MD,MS++UCLA Jonsson Comprehensive Cancer Center

Naseem Esteghamat, MD, MS $\pm$ $\xi$ UC Davis Comprehensive Cancer Center

Lindsey Fitzgerald, MD †b Huntsman Cancer Institute at the University of Utah Christopher D. Fletcher, MD $\ddagger$ University of Wisconsin Carbone Cancer Center

Carbone Cancer Center Same of Wisconsin Moffitt Cancer Center

Scott Huntington, MD, MPH, MSc $+$ Yale Cancer Center/Smilow Cancer Hospital

Brad Kahl,MD‡Stitem Cancer Center at Barnes-Jewish Hospital and Washington

Manali Kamdar,MD‡University of Colorado Cancer Center

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

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

Claudio A. Mosse, MD, PhD $\ddagger$

Vanderbilt-Ingram Cancer Center

Shazia Nakhoda,MD‡

Fox Chase Cancer Center

Sameer A. Parikh, MBBS $\ddagger$

Mayo Clinic Comprehensive Cancer Center

Peter Riedell,MD $\ddagger$ 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$\ddagger$City of Hope National Medical Center

Andrea Sitlinger, MD †Duke Cancer Institute

Meghan Thompson, MD $+$ Memorial Sloan Kettering Cancer Center

Chaitra Ujjani, MD $\ddagger$ Fred Hutchinson Cancer Center

Nina Wagner-Johnston, MD ↑s Johns Hopkins Kimmel Cancer Center

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

NCCN Mary Dwyer,MS Hema Sundar,PhD

$\xi$ Bone marrow transplantation $\ddagger$ Hematology/Hematology oncology $\dagger$ Internal medicine $\dagger$ Medical oncology $\dagger$ Medical oncology $\neq$ Pathology/Hematopathology $\neq$ Patient advocacy $\because$ Patient advocacy $\quad$ Discussion Writing Committee Member

NCCN Guidelines Panel Disclosures

NCCN Guidelines Version 1.2026

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Version 1.2026, 10/10/25 © 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 1.2026

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.

NCCN Guidelines Version 1.2026

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 1.2026

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 Index Table of Contents Discussion

UPDATES

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 1.2026

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 1.2026 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.

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

CLL diagnosis requires the presence of monoclonal B lymphocytes 25 x 109/L in peripheral blood based on flow cytometrya

●Adequate immunophenotyping to establish diagnosis by flow cytometryb: 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;14); t(11q;v) to exclude mantle cell lymphoma (MCL).

Clonality of B cells should be confirmed by flow cytometry

SLL diagnosis requires presence of lymphadenopathy and/or splenomegal with monoclonal B lymphocytes≤5 x 109/L in peripheral blood. SLL diagnosis should be confirmed by histopathology evaluation of lymph node biopsy

◆ 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.

$\diamond$ 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,SOX11c

●Absolute monoclonal B lymphocyte counta

INFORMATIVE FOR PROGNOSTIC AND/OR THERAPY DETERMINATIONd:

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

●TP53 sequencing

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

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

●Beta-2-microglobulin

NCCN Guidelines Version 1.2026

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 1.2026

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)

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

NCCN Guidelines Index Table of Contents Discussion

PRESENTATIONJ

![SLL/Localized(Lugano Stage I)*\nInterface(ISRT)(if indicated)\nEvaluate for indications for treatment[M]:\n● Eligible for clinical trial\n● Significant disease-related symptoms:!\nDrenching night sweats\n● Drenching night sweats\n● Unintentional weight loss(≥10% in previous 6 months)\n● Fever without infection)\n● Threatened end-organ function\n● Progressive,symptomatic,or bulky disease(spleen>6 cm below cost margin, lymph nodes>10 cm)\nProgressive thrombocytopenia,n\n● Progressive anemia\n● Progressive of hydroxopenian,o\nIndication\nNo indication\n200\n](2/aj0YEe4oUhYkBdfpda0fYP/figure0d7eb7556a5d4487bf60f17b20341b72_0_5.png) ![#######SLL (Lugano Stages II-IV)^k\n######Lengano Stages II-IV)^k\n#######IF I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I\n](2/aj0YEe4oUhYkBdfpda0fYP/figure572c74dec50d4cb78b3500e542fb35e4_0_6.png)

Histologic transformation(Richter)

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).

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

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/ $\mu L$ are typically not associated with clinical risk.

°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.

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

NCCN National Cancer Network®

NCCN Guidelines Version 1.2026 Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

NCCN Guidelines Index Table of Contents Discussion

![FIRST-LINE THERAPYr,s\nTHIRD-LINE THERAPYr,s,v,z,aa\nSuggested Regimens (CSLL-D 2 of 6)\nTime-limited treatment\nBCL2i intolerancev\nBCLTi\nResponse after completion of treatment\ncBTKi\nor\ncregimens\ncBTKi\nSuggested Regimens\n(CSLL-D 1 of 6)\nRelapsed or Refractory disease after prior therapy with cBTKi-or nbcTki-based BCL2i-containing regimens\nCBSLL-5A\nor nbcTki\nCalventv\nCBTKi\nBCL2 inhibitor (BCL2i) + anti-CD20 mAb See Suggested Regimens (CSLL-D 1 of 6)\nBCL2 inhibitor (BCL2i) + anti-CD20 mAb See Suggested Regimens (CSLL-D 1 of 6)\nResponse after completion of treatment\nBCKTi\nNoRevalent\ncBTKi\nCBTKi\nBCL2i intolerance\nObserve until relapse with indication for treatment\ncBTKi\nTHERAPYr,s,v,z,aa\nSuggested Regimens (CSLL-D 2 of 6)\nTime-limited treatment\nRelapsed or Refractory disease after prior therapy with cBTKi-or nbcTki and BCL2i-containing regimens are options for relapse after a period of remission or progression on treatment. See CSLL-D 2 of 6 for suggested regimens\nCSLL-5A\nTHERAPYr,s,v,z,aa\nS S S\nConderent.1.2026,10/10/25 © 2025 National Comprehensive Cancer Network (NCCN).All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.\n](2/aj0YEe4oUhYkBdfpda0fYP/figurefcf0338197cd4b3fa638b15d48788e1d_0_4.png) NCCN授权医师脉通提供NCCN指南全文下载。wmIsyy于2025/10/21,23:30在脉医通平台下载，仅供个人使用，严禁分发。2025美国国家综合癌症网络版权所有。

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NCCN Guidelines Version 1.2026 Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

NCCN Guidelines Index Table of Contents Discussion

![FIRST-LINE THERAPYr,s\nRESPONSE TO STHERAPYr,s,v,z,aa,bb\n THERAPYr,s,v,z,aa,bb\nSuggested Regimens (CSLL-D 2 of 6)\n](2/aj0YEe4oUhYkBdfpda0fYP/figurede22a2e191ef43f38fa7729dc7ab64fc_0_4.png) ![Continuous treatment\nCovalt BTK inhibitor\(cBTKi-based regimens)\n\nanti-CD20 mAb\nSee Suggested Regimens\n\nResponse\nIntroduction\nLololeranceV\nBCL2i-containing or BCL2i-containing regimens\n\nncBTKi\n\nProgression while on treatment ${w},{x},{y}$\nBCL2i-containing regimens\nor ncBTKi\nncBTKi\n](2/aj0YEe4oUhYkBdfpda0fYP/figure60d9edb055504bb68f49ac41352b2a92_0_5.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 $\underline{CSLL}$-D 2 of 6 for suggested treatment regimens for second-line and subsequent therapy.

Footnotes on CSLL-5A

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NCCN Guidelines Version 1.2026 Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

NCCN Guidelines Index Table of Contents Discussion

RELAPSED OR REFRAFACTORY THERAPYr,s or Clinical trial or Refractory disease CAR T-cell Therapy (CSLL-D 2 of 6)or ncTKi (if not previously given) (CSLL-D 2 of 6)with cBTKi or ncBTKi-y or Other Recommended Regimens (CSLL-D 2 of 6; Therapy for relapsed or refractory disease after BTKi- and BCL2i-containing or after BTKi- and BCL2i-containing regimens)or Consider allogeneic hematopoietic cell transplant (HCT) if without significant comorbidities

FOOTNOTES FOR CSLL-4 and CSLL-5

r Clinical trial is preferred when available.

sSupportive Care for Patients with CLL2i+ cBTKi± CD20 mAb may be fixed-duration or MRD-guided(based on undetectable MRD

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).

uSee Discussion for iwCLL response criteria.

vAdverse 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.

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

y 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 $\pm$ 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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NCCN Guidelines Version 1.2026 Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

NCCN Guidelines Index Table of Contents Discussion

1

Table 1: Cytogenetics and gene mutations

|Method of Detection|Prognostic Variable|Clinical Associationa| |---|---|---| |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|IGHVC' mutated:>2% 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 mutationd 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 mutationd 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

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

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NCCN Guidelines Index Table of Contents Discussion

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|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 models30,31 ●Elevated levels9 are associated with overall response, treatment free intervals, and OS in patients treated with frontlinetherapy32 ●Reduction in levels associated with prolonged PFS in patients treated with ibrutinib33,34|

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.

cIGHV 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 method to detect specific chromosomal abnormalities that may have prognostic significance.CpG oligonucleotide stimulation can be utilized to enhance metaphase cytogenetics.

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

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PROGNOSTIC VARIABLES IN PATIENTS WITH CLL/SLL

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 WT ●May 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 WT ●Shorter OS in historical cohorts ●Correlated 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 cBTKi ●BTK L528 or T474 mutations have been detected in patients with disease progressing on cBTKi and noncovalent (reversible) BTKi (ncBTKi)| |CARD1147|●Identified in patients with disease progressing on BTK inhibitors| |PLCG227,44-47|●Identified in patients with disease progressing on BTK inhibitors| |BCL2 (G101V and D103Y) 48,49|●Identified in patients with disease progressing on venetoclax|

Note: All recommendations are category 2A unless otherwise indicated. NCCN Guidelines Index Table of Contents Discussion CSLL-A 4 OF 5 PROGNOSTIC VARIABLES IN PATIENTS WITH CLL/SLL

References

Abstract

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

References

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NCCN Guidelines Index Table of Contents Discussion

CLL STAGING SYSTEMS

Rai Systema

|Stage|Description|Modified Risk Status| |---|---|---| |0|Lymphocytosis, lymphocytes in blood >5 x 109/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 System$^{b}$

|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.

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SLL STAGING SYSTEM

Lugano Modification of Ann Arbor Staging Systemc(for primary nodal lymphomas)

|Staged|Involvement|Extranodal (E) Status| |---|---|---| |Limited||| |Stage I|One node or a group of adjacent nodes|Single extranodal lesions without nodal involvement| |Stage II|Two or more nodal groups on the same side of the diaphragm|Stage I or ll by nodal extent with limited contiguous extranodal involvement| |Stage II bulkye|Il as above with "bulky" disease|Not applicable| |Advanced||| |Stage III|Nodes on both sides of the diaphragm|Not applicable| |Nodes above the diaphragm 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.

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

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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 aletemuzumab Herpes virus prophylaxis with acyclovir or equivalent

Pneumocystis jirocevi pneumonia (PJP) prophylaxis with sulfamethoxazole/trimethoprim or equivalent

●Consider PJP and varcella 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.

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

Viral Reactivation

HBV:

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

is positive

●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.

Entecavir is preferred.a Avoid lamivudine due to risks of resistance development.

Other antirivals including adefovir, telbivudine, and tenofovir are proven active treatments and are acceptable alternatives.

Viral Reactivation (continued)

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

If viral load is consistently undetectable, treatment is considered prophylactic.

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

◆ 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.

Low-grade B-cell NHL

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 alemutumab. 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):

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

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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

Chronic Lymphocytic Lymphoma

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Discussion

SUPPORTIVE CARE FOR PATIENTS WITH CLL/SLL

Tumor Lysis Syndrome (TLS)

●Laboratory hallmarks of TLS:

High serum creatinine

▶High potassium

High uric acid

High phosphorous

Low calcium

High LDH

●Symptoms of TLS:

Nausea and vomiting, shortness of breath, irregular heartbeat,clouding of urine, lethargy, and/or joint discomfort

●TLS features

Consider TLS prophylaxis for patients with the following risk factors:

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

Progressive disease after small-molecule inhibitor therapy

Bulky (>5 cm) lymph nodes

◆ Spontaneous TLS

Elevated white blood cell (WBC) count

Pre-existing elevated uric acid

Renal disease or renal involvement by tumor

\* Treatment of TLS:

For BCL2i-associated TLS, see venetoclax prescribing information

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

Centerpiece of treatment includes:

◆Rigorous hydration Management of hyperuricemia

Management of hyperuricemia

◆Frequent monitoring of electrolytes and aggressive correction(essential)

First-line and atretreatment for hyperuricemia

◆Alloporinol,febuxostat,and rasburicase according to prescribing information and institutional standards

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.

Rasparicase is indicated for patients with any of the following risk factors (Doses of 3-6 mg are usually effective.8 One dose of rasparicase is frequently adequate. Re-dosing should be individualized):

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

◆ Situations where adequate hydration may be difficult or impossible

$\diamond$ Acute renal failure

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

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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.

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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 1.2026

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 1.2026

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 1.2026

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

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 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.

bSupportive Care for Patients with CLL/SLL(CSL-C).

$^{[1]}$ 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 myosulpression 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)/TP53 mutation(Thompson P,et al. Blood 2016;127:303-309).

cRituximab 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.

dRe-challenge with the same mAb is not recommended in patients experiencing rare complications(eg, mucocutaneous reactions including paraneoplasmic phemphs, Stevens-Johnson syndrome, lichenoid dermatitis,vesviculobullous dermatitis, and toxic epidermal necrolysis). It is unclear whether re-challenge with alternative anti-CD20 mAb poses the same risk of recurrence.

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.

1 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).

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

fPlease 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.

v 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 CSL-E.

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).

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

x Acalabrutinib or zanubrutinib has been shown to be effective for brinuxib-refractory CLLW BTK C481S mutations. Patients with brinuxibutin intolerance have been successfully treated with acalabrutinib or zanubrutinib without recurrence of symptoms.

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

iThe choice of cBTKi should be based on patient-specific factors (eg, age,functional status,cormbord conditions) and the agent's toxicity profile.

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

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

Z venetoclax containing combinations with brutinib are not appropriate for patients who are intolerant to or have disease progression on brutinib.

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

k 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).

I 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.

The Panel consensus to not list brutinib 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/m2 in cycle 1 with escalation to 90 mg/m2 if tolerated.

9 Not recommended for patients who are frail.

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. With 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 alemutuzumab 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).

National Comprehensive Cancer Network®

NCCN Guidelines Index Table of Contents Discussion

SUGGESTED TREATMENT REGIMENS REFERENCES

Acaulrabutinib obutinutumab

Sharman JP, Egedy M, Jurczak W, et al. Acalabrutinob-utinuzubatum improves survival vs chemoimmunotherapy in treatment-naive cl in the 6-year follow-up of ELEVATE-TN. Blood 2025.146:1276-1285.

Byrd JC, Hilmson P, Ghia P, et al. Acalbrutinib versus Irbinutin 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.ACROEND: Phase III, randomized trial of acalabrutin versus idelalisib plus rituximab or bendamustine plus rituximab in relapsed or refractory chronic lymphocytic lymphocyte. J. Clin Oncol 2010;38:2849-2861.

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

Rogers KA, Thompson PA, Allan JN, et al. Phase II study of acalbrutinib inbritin-intolerant patients with relapsed/refractory chronic lymphocytic leukemia. Haematologica 2021:106:234-2373.

Alemtuzumab 38 rituximab

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

Faderf 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 obutinuzubama

Eichorth B, Fink AM, Bahlo J. et al. First-line chemomutherapy with bendamustine and rituximab versus fludabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia(CLLL: 10): 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 Leukemia Study Group. J Clin Oncol 2011;29:3559-3566.

Stilgenbauer S, Bosch F, Ilhan O, et al. Safety and efficacy of obutunizabum alone or with chemotherapy in previously untreated or relapsed/refractory chronic lymphocytic lymphocytic lymphocytic phenology patients. Final analysis of the Phase IIb GREEN study. Br 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 of atfumabum 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.

Eichorth B,Fink AM,Bahlo J,et al.First-line chemoimmunotherapy with bendamustine and rituximab versus glutarabine, cyclophosphamide, and rituximab 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,B'enrich 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 et al. Fludarabine, cyclophosphamide, and rituximab commotherapy is highly effective treatment for relapsed patients with PLL. Blood 2011;117:3016-3024.

HDMP (high-dose methylprednisolone) + rituximab or inbutizumab

Boweren DA,Call TG, Jenkins GD,et M. alhytromadis-orbiturizumab in an effective salvage therapy for patients with relapsed chronic lymphocytic leukemia including those with unfavorable cytogenetic features.Leukum lymphoma 2007;48:2412-2417.

Castro J,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 emissions in CLL

Castro JE,Amaya-Chanaga Cl,Velez Lujan J,et al.Obutizumuzabum(Gazyva) and High-Dose Blutirunolischolene(DHMP) Combination for Patients with Chronic Lymphocytic Leukemia(CLII)-a Phase Ib/Study[abstract]. Blood 2017;130:Abstract 1730.

Ibrutinib

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

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

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

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

Brown JR, Davis MS, Chang JE,et al. Outcomes of brutinib (lbr) therapy in lbr-naive patients) pts with chronic lymphocytic leukemia (CLL) progressing after venetolaxcl (ven) [abstract]. Blood 2019,134:Abstract 4320.

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 venetoclax discontinuation in CLL reveals BTK inhibition as an effective strategy. Clin Cancer Res 2020;26:3589-3596.

Irbutinib + rituximab

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

Munir 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 brutinib regimens for older adults with CLL. Blood 2024;143:1616-1627.

National Cancer Network

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

NCCN Guidelines Index Table of Contents Discussion

SUGGESTED TREATMENT REGIMENS REFERENCES

Ibrutinib+ obinutuzumab

Moreno C, Greil R, Dermikan F, et al. First-line treatment of chronic lymphocytic leukemia with brinitinib plus obutinuzumab versus chalbrucium plus obutinuzumab: final analysis of the randomized, phase III ILLUMINATE trial. Haematologica 2022;107:2108-2120.

Idealisab 2 rituximab

Sharman JP, Coutre SE, Furman RR, et al. Final results of a randomized, phase II study of rituximab with or without idealisbel followed by open-label idealisib in patients with relapsed chronic lymphocytic leukemia. J Clin Oncol 2019;37:1391-1402.

Gopal AK, Kahl BS,De Vos S,et al.P13KO inhibition by idelisib in patients with relapsed indolent lymphoma. N Engl J Med 2014:370:1008-1018.

Lenalidomide± rituximab

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.

Ferrajol A, Lee BN, Schlette EJ, et al. Lenalidomide induces complete and partial remissions in patients with relapsed and refractory chronic lymphocytic leukemia. Blood 2008;11:5291-5297.

Badoux XC, Keating MJ, Wen S, et al. Phase II modelalidenitom and imaxubutum as salvage as therapy for patients with relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol 2013;31:584-591.

Lisocabtage $\pm$ ibritin

Siddigl T, Maloney DG, Kenderian SS, et al. Liscosabatene maraleucel (liso-cel) in R/R CLL/SLL:24-month median follow-up of TRANSCEND CLL 004 [abstract]. Blood 2023;142:Abstract 330.

Werda WG, Dorritie K, Gauthier J,et al. Liscobatagene maraleucel(liso-cel) combined with ibritun (br) for patients (pts) with relapsed or refractory (RR) chronic lymphocytic leukemia(LCL)/small lymph oclymphytic lymphoma (SLL): Primary results from the open-label, phase 1/2 Transcend CLL 004 study [abstract]. Blood 2024;144:Abstract 887.

Obinutuzumab & chlorambucius

Byrd JC, Flynn JM, Kipts TJ,et al. Randomized phase 2 study of obutinuzumab monotherapy in symptomatic, previously untreated chronic lymphocytic leukemia. Blood 2016;127:79-86.

Cartron G, de Güert S, Diluydy 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,Engeke A,et al.Obutivutumab as frontline treatment of chronic lymphocytic leukemia: updated results of the CLL11 study.Leukemia 2015;29:1602-1604.

Moreno C, Greil R, Derimkan F, et al. First-line treatment of chronic lymphocytic ibutrinib plus obutinuzum as verchlorucam plus obutinuzumab: final analysis of the randomized, phase III iLLUMINATE trial. Haematologica 2022;107:2108-2120.

Pirtobutin

Sharman JP, Munir T, Grosicki S, et al. Phase III Trial of Pirtobrutinib Versus Idelisabif/ 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 retreatment/crossover substudy results of VenR for patients with relapsed/refractory CLL. Blood 2025;145:2733-279.

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-Ns: All recommendations are category 2A unless otherwise indicated.

REFERENCES

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

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

Venetoclax/Acaularbutin 8±obutinuzumab

Brown JR, Seymour JF, Jurczak W, et al. Fixed-duration acalrabutin combinations in untreated chronic lymphocytic leukemia, N Engl J Med 2025;392:348:7892.

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

Venetoclax+ ibrutinib

Allan Jin, Fln II W, Siddiqi T, et al. Outcomes in patients with high-risk features after fixed-duration britolunib versus elotaxion: Phase II CAPTIVATE study in first-line chronic lymphocytic leukemia. Clin Cancer Res 2023;2959-2601.

Gia P,Bar P,Jan L,et al. Final analysis of fixed-duration britolunib+ 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-1inbrutin ibin plus venetoclax vs charamocbluis plus venotubinum or or comborid 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 A, Brock K, et al. Brulinitus ben quotrasel in relapsed/refractory chronic lymphocytic lymphocyticity: The CLARITY study.J Clin Oncol 2019;37:2722-2729.

Munir TG, Siran Curs A, et al. Measurable residual disease-guided therapy for chronic lymphocytic leukemia.N Engl J Med 2025:Online ahead of print.

Venetoclax + obutinuzabum

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

Fursenau M, Kater P, Rabrecht S, et al. First-line venetoclax combinations versus chemoinmuther therapy in fit and chronic lymphocytic leukaemia(GAIA/CLL13): 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. Venetoclax 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/Sulflar output:after fixed-venetoclonet arxivithumab. Blood 2022;144:2706-839-850.

Zanubutinib

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

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

Tam CSL, Ghia P, Shadman M, et al. SEQUOIA 5-year follow-up in arm C: Frontline zanubutin monotherapy in patients with del(17p) and treatment-naive chronic lymphocytic leukemia/small lymphocytic lymphoma(SCL/Lled). J Clin Oncol 2025;43:Abstract 7011.

Venetoclax + Zanubrutinib

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

NCCN Guidelines Index

Abstract

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

Abstract

Table of Contents Discussion CSLL-E 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 1.2026 Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

NCCN Guidelines Index Table of Contents Discussion

MEASURABLE RESIDUAL DISEASE (MRD) ASSESSMENT

Table 1: MRD-guided treatment regimens

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

mDavids MS, Ryan CE, Lampson BL, et al. Phase II study of acalabrutin, venetoclax, and obinutuzumab in a treatment-naive chronic lymphocytic leukemia population

$^{n}$ 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.

°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.

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 1.2026 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

●LDH, uric acid

●Molecular analysis to establish clonal relatedness between CLL and DLBCL cells

●Assess for distress9

USEFUL IN SELECTED CASES:

●Unilateral bone marrow aspirate and biopsy

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

●Hepatitis Bh 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

●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 of CLL and histologically transformed tissue may be performed to establish the clonal relationship.Comparative clality 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).

9 Refer to the NCCN Distress Thermometer and Problem List, which includes social determinants of health. See NCCN Guidelines for Distress Management(DIS-A).Hepatitis B testing is indicated because of the risk of reactivation during treatment(eg,immunotherapy,CIT,chemotherapy,targeted therapy).See Viral Reactivation(CSLL-C 1 of 6).Tests include HBsAg and core antibody for a patient with no risk factors. For patients with risk factors or previous history of hepatitis B,add e-antigen. If positive, check viral load and consult with gastroenterologist.

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

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

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Histologic Transformation (Richter)

NCCN Guidelines Index Table of Contents Discussion

![CLINICAL PRESENTATION\nTREATMENT\nRESP\nComplete response\nObservation\nClonally unrelated\nClinical trial or or CIT regimens (HT-A)\nPartial response or Refractory disease or progression while on treatment\nTREATMENTJ\nComplete response\nObservation\nClinical trial or CIT regimens (HT-A)\nPartial response or Refractory disease or progression while on treatment\nNot 4\n](2/aj0YEe4oUhYkBdfpda0fYP/figure0570ee1e4abb41aa9e92ca8deaacd528_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).

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

kRichter 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.

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Histologic Transformation (Richter)

NCCN Guidelines Index Table of Contents Discussion

![CLINICAL PRESENTATION\nTREATMENT\nRESPSESSMENT\nCase\nRecognition\n or or on CIT regimens (other or on CIT regimens (HT-A) or CIT regimens (HT-A)\nComplete response\n Partial response\nReforcement on CIT R�1\nTCL-It therapy (HT-A) (if eligible, after at least 1 prior systemic therapy regimen) or Non-CIT regimens (other than CAR T-cell therapy)→If CR, consider allogeneic HCT n (not previously used)→(HT-A)\nInfrared therapy (HT-A) or Progression while on treatment\nRFactory disease or treatment with non-CIT regimens (other other modimens therapy)\nAC DIT response\n6333\nADDITIONAL THERAPYj\nObservation\nor or on CIT regimens (not previously used)→(HT-A)\nIf CR, consider allogeneic HCTn (not previously used)→(HT-A)\n·Continue the same non-CIT regimen until or progression or switch to an alternate non-CIT regimen (HT-A)\nClinical 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](2/aj0YEe4oUhYkBdfpda0fYP/figure6b071b8d73f740f7a83b32a0d800c4f5_0_4.png) 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.$^{m} PET/CT\,scan$ 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.

kRichter 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.

${}^{n}$ 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.

NCCN

NCCN Guidelines Version 1.2026

NCCN Guidelines Index Table of Contents Discussion

SUGGESTED TREATMENT REGIMENS

RICHTER TRANSFORMATIONa,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）+ Rituximab ●HyperCVAD（Cyclophosphamide/Vincristine/Doxorubicin/Dexamethasone）+ Rituximab alternating with Cytarabine/High-Dose Methotrexate ●OFA (Oxaliplatin/Fludarabine/Cytarabine) + Rituximab|||| |●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 $^{d}$|||| |---|---|---|---| |ICI-based regimens$|BTKi (monotherapy)|Bispecific Antibody Therapy|CAR T-cell Therapy (CD19-directed; after at least 1 prior systemic therapy regimen) ${}^{1}$| |● Venetoclax${}^{*}$ Atezolizumab ${}^{*}$ Acolarbrutin${}^{**}$ (category 2B)|- Pirtobrutinib ${}^{**}$ ● Acalbrutinib ${}^{+}$ (category 2B)|● Epcoritamab-bysp ● Glofitamab-gxbm|● Axicabtagene ciloleucel ● Lisocabtagene maraleucel ● Tisagenlecleucel| |●Nivolumb${}^{t}$ + Islebrurinib ${}^{+}$||||

$$\begin{array}{l}\text{*BCL-2-inhibitor(BCL2i)}\\ \text{*Noncovalent(reversible)BTKi(ncBTKi)\\ \end{array}$$

** Noncovalent(reversible) BTKi(ncBTKi)

Footnotes

References

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 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.

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

dThe 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.

fICI-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.

g 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.

iSee also CAR T-Cell-Related Toxicities in the NCCN Guidelines for Management of Immunotherapy-Related Toxicities for the management of cytokine release syndrome(RCS) and neurologic toxicity.

REFERENCES

Richter Transformation

HyperCVAD+ Rituximab

Chemoimmunotherapy

CHOP+ Rituximab± Venetoclax

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 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.

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.

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

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.

Dose-adjusted-EPOCH-R

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

Continued

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

National National NCCN 推prehensive NCCN Guidelines Version 1.2026 Cancer Cancer Histologic Transformation(Richter)

NCCN Guidelines Index Table of Contents Discussion

SUGGESTED TREATMENT REGIMENS REFERENCES

Richter Transformation(continued)

ICL-based regimens

Venetoclax/Atezolizumab+ Obinutuzumab

Tedeschi A, Frustaci AM, Condoluci A, et al. Atezolizumab, venetolaxc, 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 brutibin 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 2021;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

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. Single-agent epcorbitamab leads to deep responses in patients(pts) with richer's transformation(RT): primary results from the EPCORE CLL-1 trial[abstract]. European Hematology Association 2024:Abstract S163.

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

Pirtobrutinib

Wierda WG, Shah NN, Cheah CY,et al. Pirtobutrinit, 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 cilleuleet

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 lioscabagene marileoclus(lecil-iso) at 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.

Tisagenlecleucel

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.

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

NCCN Guidelines Index Table of Contents Discussion

|AIHA|autoimmune hemolytic anemia| |---|---| |ALC|absolute lymphocyte count| |ANC|absolute neutrophil count| |ASO-PCR|allele-specific oligonucleotide polymerase chain reaction| |BCL2i|BCL2-inhibitor| |BTKi|BTK inhibitor| |C/A/P|chest/abdomen/pelvis| |CAR|chimeric antigen receptor| |CBC|complete blood count| |cBTKi|covalent BTK inhibitor| |CHL|classic Hodgkin lymphoma| |CIT|chemoimmunotherapy| |CK|complex karyotype| |CMV|cytotegalovirus| |CrCI|creatinine clearance| |CRS|cytokine release syndrome| |DAA|direct-acting antiviral| |DLBCL|diffuse large B-cell lymphoma|

EBER Epstein-Barr virus-encoded RNA in situ hybridization

EBV Epstein-Barr virus EF流动ERIC European Research Initiative on CLL

FISH fluorescence in situ hybridization(NHL

G6PD glucose-6-phosphate dehydrogenase GVHD graft-versus-host disease

ABBREVIATIONS

|HBcAb|hepatitis B core antibody|| |---|---|---| |HBsAg|hepatitis B surface antigen|| |HBV|hepatitis B virus|| |HCT|hematopoietic cell transplant|| |HCV|hepatitis C virus|| |HLA|human leukocyte antigen|| |HR|hazard ratio|qPCR| |HR|immunohistochemistry|| |ISRT|involved-site radiation therapy|| |ITP|immune thrombocytopenic purpura|RT-PCR| |IVF|in vitro fertilization|| |IVIG|intravenous immunoglobulin|| |SCIG|SCIG|subcutaneous immunoglobulin| |JSPE|SIFE|serum immunofixation electrophoresis| |LVEF|left ventricular ejection fraction|SPEP| |SUV|SUV|standardized uptake value|

LDH lactate dehydrogenase LVEF left ventricular ejection fraction

mAb monoclonal antibody MBL monoclonal B-cell lymphocytosis MTNT mantle cell lymphoma

MRD minimal residual disease MUGA multigated acquisition

ncBTKi noncovalent BTK inhibitor NGS next-generation sequencing NHLB non-Hodgkin lymphoma

OS overall survival

PFS

PI3Ki

PJP

PML

pleukencephalopathy

PRCA pure red cell aplasia

qPCR

RS Reed-Sternberg RSV respiratory syncytial virus

RT-PCR reverse transcriptase polymerase chain reaction

SCIG subcutaneous immunoglobulin

SIFE serum immunofixation electrophoresis

SPEP serum protein electrophoresis SUV standardized uptake value

TLS TFT tumor lysis syndrome TTFT time-to-first treatment

TTNT uMRD

uMRD

VAF variant allele frequency VZV varicella zoster virus

WBC white blood cell WT wild type

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

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.

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

This discussion corresponds to the NCCN Guidelines for Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma. Last updated: April 2, 2025.

Discussion

|Overview||| |---|---|---| |Guidelines Update Methodology||MS-2| |Literature Search Criteria||●MS-2| |Sensitive /Inclusive Language Usage||MS-2| |Staging.||MS-3| |Prognostic Factors|Discussion|MS-3| |Response Criteria||MS-8| |Minimal Residual Disease||MS-8| |Workup||MS-11| |First-Line Therapy||MS-12| |Second-Line and Subsequent Therapy||MS-13| |Special Considerations for the Use of Small-Molecule Inhibitors||MS-24| |Histologic Transformation||MS-27| |Supportive Care||MS-31| |Summary.||MS-35| |References||MS-43|

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

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 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.InCCN 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

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

Immunoglobulin Heavy Chain Variable Region (IGHV) Gene Mutation

A cut-off level of ≤2% deviation from germline IGHV sequence is routinely used in clinical practice to differentiate patients with IGHV-unmutated CLL from those with 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) in patients treated with the FCR (fludarabine, cyclophosphamide, and rituximab) regimen, suggesting that IGHV mutation percentage is a continuous variable.10

IGHV gene mutation status correlated with lower response rates and shorter time-to-first treatment (TTFT), PFS, and OS in patients treated with FCR.11-13 In the CLL10 study, the PFS benefit of FCR was significant in physically fit patients <65 years and in patients with mutated IGHV.12 Among patients with mutated IGHV gene, the median PFS was not reached with FCR compared to 55 months for bendamustine/rituximab(BR;P=.089). In a phase II study of 300 patients with previously untreated CLL, IGHV-mutated CLL (>2% mutation or <98% homology with germline gene sequence) was associated with long-term PFS, with a plateau on the PFS curve beyond 10 years following treatment with FCR(after a median follow-up of 19 years, the median PFS for patients with IGHV-mutated CLL was 15 years vs. 4 years for patients with IGHV-unmutated CLL).13 In a multivariable analysis, IGHV-unmutated status and del(17p) were independently associated with significantly shorter PFS.

IGHV-unmutated status(≤2% of mutation or≥98% homology with germline gene sequence) is associated with unfavorable prognosis and significantly shorter survival compared to mutated IGHV in patients

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treated with chemoimmunotherapy-based regimens, independent of the stage of the disease.14 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).15 IGHV-unmutated status and/or the VH3-21 gene usage was shown to be an independent predictor of shorter treatment-free interval and/or survival outcomes in patients treated with time-limited chemoimmunotherapy and venetoclax-containing regimens, even when high-risk genetic abnormalities were included in the multivariable regression models.16,17 PFS and OS were not correlated with IGHV mutation status in patients treated with continuous BTK inhibitor(BTKi)-based regimens.18-20

Continuous treatment with a covalent BTKi (cBTKi; ibrutinib, acalabrutinib, or zanubrutinib) results in high response rate and survival independent of the IGHV mutation status. 18,19,21-23

The ELEVATE-TN trial showed that acalabrutinib $\pm$ obinutuzumab resulted in greater PFS benefit compared to obinutuzumab + chlorambicil 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. ${ }^{19}$ In the ECOG-ACRIN Cancer Research Group (E1912) study, ibrutinib + rituximab resulted in superior PFS compared to FCR in patients with IGHV-unmutated CLL (HR, 0.27; P<.001) and IGHV-mutated CLL (HR, 0.27; P<.001) and IGHV-mutated CLL (HR, 0.27; P<.001).21 The biomarker subgroup analysis of the SEQUOIA study confirmed that PFS was significantly better for zanubrutinib (compared to BR) in patients with IGHV-unmutated and IGHV-mutated CLL. ${ }^{22}$ In the FLAIR study, the PFS was significantly better for ibrutinib + venetoclax (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.23

IGHV-unmutated status remains a prognostic factor for shorter PFS after time-limited treatment with BCL2 inhibitor (BCL2i)-containing regimens(venetoclax + obinutuzumab [VenO] and venetoclax + ibritinib).24-30

The extended follow-up data from the CLL14 study showed that 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).25 The 4-year follow-up data from the phase III randomized GAIA/CLL13 trial showed that VenO with or without ibritunib resulted in significant PFS benefit (compared to chemoimmunotherapy) among patients with IGHV-unmutated CLL as well as in those with IGHV-mutated CLL.27 In an exploratory subgroup analysis, unmutated IGHV was a predictor of shorter PFS across all treatment groups than was mutated IGHV.

Venetoclax + ibrutinib prolonged PFS independent of IGHV mutation status in the GLOW trial and the estimated 60-month PFS rates were 52% and 83% for IGHV-unmutated and IGHV-mutated CLL, respectively.28,29

In the AMPLIFY trial, the 36-month PFS rates were higher for VenO+acalabrutinib (84%) and venetoclax + acalabrutinib (86%) in the subgroup of patients with IGHV-mutated CLL compared to chemoimmunotherapy (80%). ${ }^{30}$ The addition of obinutuzumab resulted in higher survival benefit in the subgroup of patients with IGHV-unmutated CLL (36-month PFS rate was 83% for VenO + acalabrutinib compared to 69% for venetoclax + acalabrutinib).

Cytogenetic Abnormalities

Cytogenetic abnormalities detected by fluorescence in situ hybridization(FISH) are present in >80% of patients with CLL.31

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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.31

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.32,33

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.13,31,34 TP53 mutations (independent of 17p chromosome status) are predictors of shorter PFS and OS with fludarabine- or bendamustine-containing chemoimmunotherapy regimens.35-38

TP53 aberrations also remain an independent predictor of inferior PFS and OS for time-limited treatment with venetoclax-containing regimens.24.39 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.24,39 Continuous treatment with a cBTKi also results in shorter PFS and OS in patients with del(17p) or TP53-mutated CLL.18,19,21-23 However, the survival outcomes for CLL in patients with TP53 aberrations treated with either a BTKi-based regimen or a venetoclax-containing regimen are much better than the survival outcomes in patients treated with chemoimmunotherapy.

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). However, low variant allele frequencies(VAF;<10%) of TP53 mutations may have prognosis similar to TP53 wild type.40,41 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).36,42

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 >5,000 patients with available cytogenetic data indicated that CK was associated with variable clinical behavior.43 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 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

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regimens.44-47 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 irubinitin-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. ${ }^{44}$ In an analysis of 308 patients 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. ${ }^{47}$ In patients $\geq 65$ 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-naive CLL treated with zanubirutin in the SEQUOIA study. ${ }^{22}$ 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. ${ }^{48}$ TP53 aberration [del(17p)and/or TP53 mutation] 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.49 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) among patients treated with chemoimmunotherapy, whereas only high CK(≥5 unrelated chromosomal abnormalities) was an independent adverse prognosticator for PFS in the pooled venetoclax arms.49 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 in patients treated with first-line chemoimmunotherapy.50,51 Beta-2 microglobulin was incorporated in prognostic models for the risk stratification of patients with CLL.52-55 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.56-60 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.59 In the CLL14 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.39

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

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[del(13q) only].61 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 I/GHV 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.53,62,63 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.53 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.

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.64 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, lGHV mutation status, and CD38 expression. ${ }^{65}$ 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.52 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.66 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.67 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 of patients treated with targeted therapies. ${}^{54,55}$ The first prognostic model is predictive of survival in patients treated 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. ${}^{54}$ 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

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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 (ibrinutib,idelisib, and venetoclax).55 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).

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.

Minimal Residual Disease

Response Criteria

The response criteria developed by the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) are outlined in the algorithm on CSLL-E. In the clinical practice setting, response assessment involves both physical examination and evaluation of blood parameters. The iwCLL guidelines provide further recommendations for the evaluations and response assessments appropriate for the general clinical practice setting versus for clinical trials. ${ }^{68}$

Assessment of measurable residual disease(MRD; also referred to as minimal residual disease) is a highly sensitive indicator of disease burden in patients with CLL, and MRD assessment as part of response evaluation is incorporated into some clinical trials. Consensus recommendations for the methodology for MRD determination, assay requirements and tissue selection (blood vs. bone marrow), and the use of MRD in clinical practice versus clinical trials were published.71,72

Treatment with both cBTKi (ibrutinib, acalabrutinib, zanubrutinib) and noncovalent (reversible) BTKi (ncBTKi; pirtobrutinib) and phosphatidylinositol 3-kinase inhibitors (PI3Ki; idealisib and duvelisib) cause mobilization of lymphocytes into blood early during treatment initiation, resulting in a transient lymphocytosis in most patients, which does not signify disease progression. 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.69

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 MRD at the level of 10-6(MRD6),and is the only assay currently available in the United States that is cleared by the FDA.73-76 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 MRD at the level of 10-4(MRD4) to 10-5 (MRD5) 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 of less than MRD4.77 ASO-PCR detects MRD at the level of less than MRD5; however, it is less widely used since it is expensive and more labor intensive.78

Considering these findings, the iwCLL response criteria were revised to more precisely predict the outcome of patients with CLL treated with BTKi and PI3Ki.70 The revised iwCLL response criteria allow for the response

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BTKi monotherapy does not typically result in undetectable MRD(uMRD),but the use of cBTKi in combination with anti-CD20 monoclonal antibody(mAb) results in higher rates of uMRD compared to monotherapy.19,79,80 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.81 However,PFS was significantly longer in patients with MRD levels of<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 or time-limited treatment with BCL2i-containing regimens (venetoclax-containing regimens) is an independent predictor of improved survival among patients with previously untreated as well as relapsed or refractory CLL. Several randomized clinical trials showed that time-limited treatment with BCL2i-containing regimens resulted in higher rates of uMRD4 or uMRD6 (MRD levels <10-6) in blood or bone marrow than chemoimmunotherapy. uMRD4 rates at the EOT with venetoclax-containing regimens from selected trials are summarized in Table 1.

The association between uMRD status at EOT and PFS are discussed below. However, it should be noted that none of the trials studied the use of MRD to direct treatment. MRD assessment may be useful in clinical practice to provide insight into anticipated PFS duration, but not to recommend treatment duration or treatment decisions for patients on targeted therapy at the present time.

Previously Untreated CLL/SLL

BCL2i-Containing Regimens

In the CLL14 study,uMRD4 status at the EOT correlated with improved survival in both treatment arms. ${}^{24,25}$ 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 MRD4.25 The 6-year OS rate was 87% for patients with uMRD4 and 59% for those with detectable MRD4. VenO also resulted in higher rates of uMRD at 15 months in blood (uMRD4: 81% vs. 55%;uMRD6: 64% vs.28%) compared to chemoimmunotherapy with FCR or bendamustine and rituximab (BR) in the phase III CRYSTALLO study.82

In the phase III randomized GAIA/CLL13 trial, VenO (with or without brutinib) 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.26

The results of the phase II randomized CAPTIVATE study showed that time-limited treatment with venetoclax + brutinib resulted in high rates of uMRD4 in all subgroups [del(17p) and/or mutated TP53, del(11q), and IGHV-unmutated CLL]. In the time-limited treatment cohort, uMRD4 rates were 81%(blood) and 41%(bone marrow) for patients with del(17p)and/or mutated TP53; uMRD4 rates were higher in patients with IGHV-unmutated CLL (84% in blood; 64% in bone marrow) compared to IGHV-mutated CLL (67% in blood; 53% in bone marrow).83 In the MRD cohort, patients were assigned to subsequent treatment based on the uMRD4 status at EOT. ${}^{84,85}$ Patients without confirmed uMRD4 were randomized to receive venetoclax + brutinib (n = 32) or ibrutinib (n = 31);post-randomization uMRD4 rates were higher with venetoclax + ibrutinib than with ibrutinib. ${}^{84}$ The estimated 3-year PFS rates were 97% for

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patients in both treatment arms. Patients with confirmed uMRD4(n= 86)were randomized to receive placebo or brirutinib. The estimated 4-year PFS rates were 95% for those assigned to brinuxinib 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).85 uMRD4 at the EOT correlated with high PFS rates in patients with or without bulky lymphadenopathy and the 5.5-year PFS rates were higher in patients with uMRD4 in blood at the EOT irrespective of the depth of lymph node long diameter (LDi; 77%, 75% and 72% for those with LDi≤1.5 cm, >1.5 to ≤2 cm, or >2 cm, respectively).86

In the phase III randomized GLOW study, a higher rate of uMRD4 at 3 months after EOT(EOT+3) was observed with time-limited venetoclax + brixinib across all subgroups, including del(11q) and IGHV-unmutated CLL.28.29 The estimated PFS rate for patients with uMRD4 in the bone marrow at 12 months after EOT(EOT+12) was 96% for venetoclax + brixinib compared to 83% for chlorambucil + obinutuzumab.28 The rate of uMRD5 was also higher with brixinib + venetoclax (45% in blood; 40% in bone marrow). 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 brixinib + venetoclax among patients with IGHV-mutated CLL(≥84%) independent of the MRD status at EOT+3.29

In the FLAIR study, uMRD in bone marrow at 2 years was observed in 52% of patients in the ibrutinib + rituximab arm and in 50% of patients in the FCR group.87 The corresponding uMRD rates at 5 years were 66%and 50%, respectively. The uMRD rates in blood after 5 years were also higher with venetoclax + ibrutinib (93%) compared to FCR (68%). In the interim analysis of the FLAIR study (274 patients randomized between

bricutin and venetoclax + ibrinutib), the uMRD4 rates were higher in patients with IGHV-unmutated CLL (83% in blood; 80% in bone marrow)compared to IGHV-mutated CLL (64% in blood; 56% in bone marrow)within 2 years of treatment with venetoclax + bricutinib.88

The uMRD rates (MRD4) in the blood at the EOT and at 3 months after the EOT in the AMPLIFY trial was also higher with VenO+ acalabrutinib(95% and 94%，respectively) than with chemoimmunotherapy(73% and 78%, respectively).30 The corresponding uMRD rates were 45% and 38%for venetoclax + acalabrutinib, suggesting that the addition of obinutuzumab also increases uMRD rate. However, the lower uMRD rate did not correspond to lower PFS rate with venetoclax and acalabrutinib and longer follow-up is needed to confirm these findings.

Large ongoing clinical trials will help to clarify the optimal duration of first-line treatment with combined targeted therapy and the importance of the difference in uMRD rates between IGHV-mutated and IGHV-unmutated CLL with different regimens.

Chemoimmunotherapy

In the combined analysis of two randomized phase III studies (CLL8 and CLL10), MRD status at the EOT with chemoimmunotherapy correlated with better survival in a multivariable analysis.89 Among patients who achieved complete response (CR) and PR, PFS was longer for those with uMRD4 CR and uMRD4 PR (61 months and 54 months, respectively) than those with MRD-positive CR and MRD-positive PR (35 months and 21 months, respectively).89 The persistence of post-treatment splenomegaly as a sole abnormality in patients with uMRD4 did not have a negative impact on PFS.

In a prospective study of 289 patients with previously untreated CLL,uMRD4 at the EOT with FCR correlated with longer PFS. ${ }^{90}$ The median PFS was not reached for patients with uMRD compared to 38 months for

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those with detectable MRD(P<.001). MRD level(≤1% vs.>1%) after three courses of FCR predicted greater likelihood of achieving uMRD by the EOT(64% vs.9%; P<.001). PFS was significantly longer for patients with MRD≤1% versus>1% after three courses of FCR(median 73 months vs.41 months, P<.001), but similar for<0.01% versus 0.01%-1%.

venetoclax resulted in sustained uMRD4 status and ability to discontinue treatment.95

These findings confirm that uMRD4 after EOT with regimens containing venetoclax is an independent predictor of longer PFS.

Relapsed or refractory CLL/SLL

In the MURANO study comparing VenR vs. BR, uMRD as best MRD response at any time during the study was higher with VenR (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.91,92 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% and 73%, for those with uMRD4 and low MRD-positive disease (10-4 to <10-2) or high MRD-positive disease (>10-2),respectively.92 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.92 Pre-existing TP53, NOTCH1, and B/RC3 mutations were associated with lower rates of initial attainment of uMRD4 among patients treated with VenR.93

Diagnosis

The diagnosis of CLL requires the presence of at least $5 \times 10^{9} / L$ monoclonal B-lymphocytes in the peripheral blood and the clonality of B cells should be confirmed by flow cytometry. ${ }^{68}$ The diagnosis of SLL requires the presence of lymphadenopathy and/or splenomegaly with less than $5 \times 10^{9} / L$ monoclonal B lymphocytes in the peripheral blood. ${ }^{68}$ 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.

Immunophenotype by flow cytometry (blood) is adequate for the diagnosis of CLL; bone marrow biopsy is generally not required. A diagnosis of SLL should ideally be confirmed by lymph node biopsy. Evaluation of cyclin D1 (flow cytometry or IHC) or FISH analysis for t(11;14), flow cytometry evaluation of 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. ${}^{96-99}$

The results of the phase II single-arm CLARITY study showed that treatment with ibrutinib+ venetoclax also resulted in high rates of uMRD4 in patients with relapsed or refractory CLL/SLL.94,95 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 ibrutinib+

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

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proliferative activity of the leukemic cells. CpG oligonucleotide stimulation can be utilized to enhance metaphase cytogenetics.100,101

Molecular analysis for IGHV mutation status is preferred over flow cytometry. IGHV mutation testing is recommended based on reproducibility and ready availability. IGHV mutation status is necessary when considering treatment with chemoimmunotherapy.

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.102,103 An absolute monoclonal B-lymphocyte count of <5 x 109/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.104

MBL is further categorized into low-count MBL (<0.5 x 109/L) that rarely progresses to CLL and high-count MBL (0.5-4.9x $109/L$) that can progress to CLL requiring therapy at a rate of 1% to 2% per year. ${}^{105,106}$ High-count MBL is distinguished from Rai 0 CLL based on whether the monoclonal B-cell count is above or below $5 \times 109 / L$ . ${ }^{107}$ 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. ${ }^{108}$

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.103 Observation is recommended for all individuals with MBL.

Workup

The workup for CLL/SLL is like the workup for other lymphoid neoplasms. Quantitative immunoglobulin levels may be informative in patients with recurrent infections. Measurement of beta-2 microglobulin may provide useful prognostic information.53 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.

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 $\pm$ 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. PET scan is generally not useful in CLL but can assist in directing nodal biopsy if Richter's transformation is suspected. ${}^{109,110}$

Assessment of Functional Status and Comorbidity

CLL/SLL is diagnosed mainly in older adults, with a median age of 72 years at diagnosis. The age cutoff of 65 years is used in most of the chemoimmunotherapy-based clinical trials, including the studies conducted by the German CLL Study Group(GCLLLSG).111 Comorbidities are frequently present in older patients, and the presence of multiple

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comorbidities (≥2 comorbidities) was an independent predictor of clinical outcome, independent of patients' age or disease stage. ${ }^{112}$

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 (CrCl) was used by the GCLLSG to assess the overall fitness of patients enrolled in clinical trials. ${ }^{112,113}$ In the CLL14 study, CLIRS score >6 or an estimated CrCl < 70 mL/min was used as the eligibility criteria for patients with significant comorbidities. ${ }^{114,115}$

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).116 The results of the CLL12 trial did not demonstrate survival benefit for early treatment with ibrutinib in patients

with early-stage, high-risk CLL (high risk defined according to the GCLLSG index).117

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.68 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.68 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(if not previously done) are recommended prior to initiating treatment.1GHV mutation status is important for the selection of initial treatment when considering chemoimmunotherapy and is helpful in discussing the anticipated remission duration with time-limited targeted therapy.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.

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

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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 regimens, other recommended regimens, 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, based on the results of the phase III randomized studies (AMPLIFY, CLL14,ELEVATE-TN, and SEQUOIA).19,20,30,115

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

BCL2i-Containing Regimens

Venetoclax + Acalabrutinib ± obinutuzumab

In the AMPLIFY study, time-limited treatment with venetoclax + acalrabutinib $\pm$ 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 VenO+ acalabrutinib vs. FCR/BR). ${ }^{30}$ There was also a trend towards OS benefit with venetoclax + acalabrutinib compared to chemoimmunotherapy (P<.0001). In the VenO+ acalabrutinib arm,obinutuzumab (1000 mg IV) was administered for cycle 2 (days 1, 8, and 15) and cycles 3-7 (day 1).

Venetoclax + acalabrutinib ± obinutuzumab is included as a preferred treatment option with a category 1 recommendation.

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).114,115 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. ${ }^{118}$

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. ${ }^{26}$ The 4-year follow-up data confirmed that VenO with or without ibrutinib was associated with superior PFS compared to chemoimmunotherapy (FCR or BR). ${ }^{27}$

VenO was granted broad FDA approval for the treatment of patients with CLL. The Panel members agreed that VenO is also an appropriate time-limited chemotherapy-free treatment option for younger patients without comorbidities, and the Panel consensus was to include VenO as a preferred treatment option(category 1) regardless of patient age or the presence of significant comorbidities.

Venetoclax + Ibrutinib

The results of the CAPTIVATE study showed that time-limited treatment with venetoclax + ibrutinib results in improved PFS with high rates of durable response and uMRD4 across all patient subgroups. ${ }^{83-85}$ In the time-limited treatment cohort, with a median follow-up of 28 months, the estimated 24-month PFS rate was 95% for the overall study population $[96 \%$ for patients without del(17p)/TP53 mutation; 93% and 97% for

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those with IGHV-unmutated and IGHV-hmutated CLL respectively].83 The estimated 24-month OS rates were 98% for patients in the overall study population and also for patients without del(17p). The FLAIR study demonstrated that venetoclax + ibrutinib is also superior to FCR in terms of PFS in patients without del(17p)/TP53 mutation.87,88 PFS was also significantly longer for venetoclax + ibrutinib compared to chlorambucil + obinutuzumab in the GLOW trial.28,119 The 64-month follow-up data showed that venetoclax + ibrutinib was also associated with OS benefit compared to chlorambucil + obinutuzumab.29

In the GLOW trial, venetoclax + ibrutinib was associated with significant toxicity (grade $\ge 3$ adverse events [AEs] 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. ${ }^{119}$ Cardiac or sudden deaths during treatment occurred in patients with a CIRS score of $\ge 10$ 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.

Venetoclax + ibrutinib is not approved for the treatment of CLL/SLL in the United States. Based on the safety profile (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 other approved targeted therapies for first-line therapy (other than ibrutinib), the Panel consensus was to include venetoclax + ibrutinib as a category 2A recommendation under other recommended regimens.

cBTKi-Based Regimens

Acalabrutinib ± Obinutuzumab

In the phase III ELEVATE-TN trial, acalabrutinib $\pm$ obinutuzumab resulted in superior PFS compared to chlorambucil + obinutuzumab in patients with

previously untreated CLL.19 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 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. 120

Acalabrutinib was granted broad FDA approval for the treatment of patients with untreated and relapsed or refractory CLL based on the results of the ELEVATE-TN and ELEVATE-RR trials. ${ }^{19,121}$ Acalabrutinib $\pm$obinutuzumab is included as a preferred treatment option with a category 1 recommendation.

Zanubrutinib

Zanubrutinib is a highly selective/specific bTKi 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,0.42;P<.0001).20 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 $(P<.01).^{22}$

Based on the results of the SEQUOIA study, zanubrutinib is included as a preferred treatment option with a category 1 recommendation.

Ibrutinib

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 $\geq 65$ years

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without del(17p).122 With 57% of patients switching to ibrutinib after disease progression on chlorambicul, 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

The Alliance North American Intergroup Study (A041202) showed primary benefit for ibrutinib and ibrutinib + rituximab in patients with IGHV-unmutated CLL(61% of patients had unmutated IGHV) rather than IGHV-mutated CLL.38 The presence of CK did not have an impact on PFS among patients treated with ibrutinib. The estimated 2-year PFS rates were 91% and 87%, respectively, for ibrutinib and ibrutinib +rituximab among patients with CK.79

Irbutinib 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).18,122 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.21,23 The results of two other randomized phase III trials 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.38,79,80,123

Irbutinib is included as an option under other recommended regimens with a category 1 recommendation regardless of patient age and the presence of comorbidities. The Panel consensus to list irbutinib under other recommended regimens is based on the toxicity profile. Randomized clinical trials demonstrated a more favorable toxicity profile for acalabrutinib and zanubrutinib(compared to irbutinib). ${}^{121,124}$

Ibrutinib + Obinutuzumab or Rituximab

Ibrutinib + Obinutuzumab or Rituximab 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.80

The results from randomized studies have confirmed that ibrutinib+ rituximab is more effective than cheimmonotherapy for previously untreated CLL without del(17p) or TP53 mutation in patients≥65 years or younger patients with comorbidities.21,23,38,79,80,123 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.38 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.123

In all of the above-mentioned randomized clinical trials that evaluated ibrutinib+ rituximab or obutinutuzumab, ibrutinib was given continuously until disease progression or intolerance and obutinuzumab 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 obutinuzumab) during the first 6 months of treatment.

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

Ibrutinib + rituximab and ibrutinib + obinutuzumab are included as options(useful under 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 the preferred first-line treatment option for the vast majority of patients. However, the majority of Panel members acknowledge that chemoimmunotherapy(discussed below) may be an acceptable treatment option in selected circumstances:fit patients with IGHV-mutated CLL, in instances when rapid disease debulking is needed, or in a small fraction of patients in whom BTKi and venetocl-containing regimens are contraindicated.

The FCR regimen results in high response rates and improved PFS and OS particularly in fit patients with previously untreated IGHV-mutated CLL.11,13,21,125 FCR could be considered as a first-line therapy option for IGHV-mutated CLL in patients <65 years without significant comorbidities since the FCR regimen results in high response rates and improved PFS and OS in this specific subgroup of patients, with a plateau on the PFS curve beyond 10 years. ${ }^{11,13,125}$

In the CLL10 study, although the PFS benefit of FCR was significant in physically fit patients <65 years, there was no significant difference in PFS between BR and FCR as first-line therapy for CLL without del(17p) in patients >65 years. ${}^{125}$ The incidence of severe neutropenia and infections was significantly more frequent in the FCR arm, especially among patients>65 years, and the incidences of secondary acute myeloid leukemia(AML) or myelodysplastic syndrome (MDS) were also significantly higher

in the FCR arm.125 Bendamustine + anti-CD20 mAb (rituximab or obinutuzumab) may be a reasonable alternative for patients ≥65 years or younger patients with significant comorbidities.125-127

Given the favorable tolerability profile, obinutuzumab monotherapy or in combination with chlorambucil might be an acceptable treatment option for a small fraction of patients for whom more intensive regimens are not appropriate.128-130 Obinutuzumab± chlorambucil is included with a category 2A recommendation for patients≥65 years or younger patients with significant comorbidities (CrCl < 70 mL/min).

High-dose methylprednisolone (HDMP) + rituximab was associated with a lower risk of myelosuppression and lower incidences of infectious complications (attributed to treatment of previously untreated CLL in patients with good PS, use of anti-infective prophylaxis, and the administration of intravenous immunoglobulin [IVIG] to patients with infections and hypogammaglobulinemia). ${ }^{131,132}$ HDMP + rituximab or obinutuzumab is included with a category 2B recommendation for patients $\geq 65$ years or younger patients with significant comorbidities and a category 3 recommendation for patients <65 years without significant comorbidities.

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. Patients with del(17p) CLL were not eligible for enrollment in the RESONATE-2 study, the E1912 study, the GLOW study, the FLAIR study, the GAIA/CLL13 study, or the AMPLIFY study.18,21,23,26,30,119 Enrollment in an appropriate clinical trial is recommended for patients with untreated del(17p) CLL/SLL.

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Data for del(17p) or TP53-mutated CLL available from subgroup analyses of clinical studies that included this patient population are discussed below.

Given currently available data (as discussed above), BCL2i containing regimens (VenO and venetoclax + acalabrutinib $\pm$ obinutuzumab) are included as preferred treatment options for first-line therapy with a category 2A recommendation.

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].115

In the CAPTIVATE study (n= 159; 27 patients had del(17p) and/or TP53 mutation), the estimated 24-month PFS and OS rates for venetoclax + ibrutinib were 84% and 96% for those with del(17p)/TP53 mutation,respectively.83

Patients with del(17p) or TP53 mutation were not enrolled in the AMPLIFY study because the control arm included investigator's choice of chemoimmunotherapy.30 In an earlier phase II study, the combination of VenO+ acalabrutinib resulted in an ORR of 98%(71% CR) in patients with TP53 aberrations(n= 45).133 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 venetoclax + acalabrutinib $\pm$ obinutuzumab is an appropriate treatment option for patients with del(17p)or TP53 mutation. The panel acknowledged that there are no data for acalabrutinib + venetoclax in patients with del(17p) CLL. However, the panel consensus for the inclusion of acalabrutinib + venetoclax as a preferred treatment option for this patient population is based on the efficacy of acalabrutinib (monotherapy) and venetoclax (in combination with obinutuzumab) in patients with del(17p) CLL as shown in other randomized clinical trials (ELEVATE-TN and CLL14 studies respectively).19,115,120

Venetoclax + ibrutinib is included as an option (category 2B) under other recommended regimens.

BTKi-Based Regimens

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

In a phase II trial that included 34 treatment-naive patients 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. 134

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. ${ }^{135}$ With a median follow-up of 50 months, the estimated 4-year PFS and OS rates were 79% and 88%, respectively. The ORRR 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). ${ }^{36}$

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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 chemimmunotherapy, respectively.120

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.20 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 compared to BR. 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%).136

cBTKi-based regimens (acalabrutinib $\pm$ obutinuzumab, zanubrutinib) are included as preferred treatment options for first-line therapy.lbrutinib is included as an option under other recommended regimens. The Panel consensus to list ibrutinib under other recommended regimens is based on the toxicity profile.

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 obinutuzumab131,132 or obinutuzumab128 can be considered in selected circumstances when rapid disease debulking is needed or in a small fraction of patients in whom cBTKi and venetoclax-containing regimens are contraindicated.

Second-Line and Subsequent Therapy

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

In patients with relapsed or refractory disease requiring treatment, the selection of second-line therapy should be based on the type of first-line therapy, duration of remission, and acquired resistance to treatment.Recommendations for the selection of second-line therapy based on outcomes after first-line therapy are outlined on CSLL-4A, CSLL-4B, 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.92,137 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).92

Venetoclax monotherapy is effective for relapsed or refractory CLL after prior treatment with ibrutin or idelalisib,138-142 although the results of a

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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).143 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 idelisib) and also in patients who had received only one BTKi or PI3Ki (compared to those who had received >1 BTKi or PI3Ki).144,145

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(idelisib).146 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.

The results of retrospective analyses suggest that retreatment with the venetoclax-containing regimen(Ven2) is effective for patients with CLL/SLL previously treated with a venetoclax-containing regimen(Ven1).147,148 An international retrospective study showed that this approach is effective in any line of therapy.147 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.148 Retreatment with VenR was also effective for disease

progression while off treatment after achieving response to time-limited treatment with VenR.149

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]. VenO has not been evaluated in prospective clinical trials for patients with relapsed or refractory CLL/SLL. In a real-world study of 40 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 ORR of 90%(63% CR) and the 2-year PFS rate was 81%.150 The CLL11 and GAIA/CLL13 studies also showed that obinutuzumab when used in combination with chlorambucil or venetoclax, respectively, 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.26,130

The panel acknowledged that data supporting the use of BCL2i-containing regimen for relapsed or refractory CLL/SLL is available only for venetoclax with or without rituximab. However, 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,150,26,130 the panel consensus supported the inclusion of VenO as a preferred treatment option for second-line therapy. Retreatment with venetoclax± anti-CD20 mAb(VenO is preferred) is also included as an option for disease relapse after a period of remission following treatment with a time-limited venetoclax-containing regimen, irrespective of del(17p)/TP53 mutation status.

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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 uMRD4.94 This study included patients with relapsed or refractory CLL/SLL after prior chemoimmunotherapy or idealisib and patients treated with 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. ${ }^{94}$

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 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).154

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.153 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.

BTKi-Based Regimens

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).121,151-153 The PFS benefit compared to chemoimmunotherapy was seen across all patient subgroups including those with del(17p) or TP53 mutation.

cBTKis (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.155,156

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.151 The phase III ELEVATE-RR trial demonstrated that acalabrutinib is non-inferior to brinuxinib 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.121

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.152 In an exploratory analysis that combined data from patients with del(17p) and TP53 mutation, the median PFS was 41

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

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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.155 The estimated median PFS was 17 months and 19 months, respectively, for patients with del(17p) or TP53 mutation and those with I/GHV-unmutated CLL. The ORR (including PR-L)was higher irrespective of the status of prior therapy with BCL2is (83% for BCL2i-naive and 80% for BCL2i exposed); however, PFS was longer in the BCL2i-naive group than in the BCL2i-exposed group (23 months and 16 months, respectively).156 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 idealisib +rituximab [IdR], n = 82) in patients with CLL/SLL 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).157 At a median follow-up of 12 months, pirtobrutinib resulted in significant improvement in PFS (HR, 0.55;P = 0007) across all subgroups of patients including those with CLL previously treated with venetoclax-containing regimens (HR, 0.54) and those with TP53 mutation and/or del(17p) (HR, 0.52).

Based on the results of BRUIN CLL-321 study, the Panel consensus was to include pirtobrutinib as a preferred treatment option [irrespective of del(17p)/TP53 mutation] for patients with intolerance to prior cBTKi or for those with disease that is resistant to cBTKi. ${}^{157}$ Pirtobrutinib is also included as preferred option [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. ${}^{155,156}$

PI3K Inhibitor-Based Regimens

Idelisabil and duvelisib also demonstrated efficacy (in terms of median PFS) in randomized phase III studies for patients with relapsed or refractory CLL/SLL.158-163

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).159 IdR significantly prolonged survival in patients with del(17p) or TP53 mutation compared with those treated with rituximab + placebo and there was no difference in survival benefit compared to those without del(17p).159 The median OS was 29 months for patients treated with IdR compared to 15 months for those treated 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).157.13 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.160 The indication for idelisib 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 idelisib, the Panel consensus was to continue listing idelisib monotherapy as an option for relapsed or refractory SLL, given demonstrated efficacy. ${ }^{160}$

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Duvelisib also significantly extended median PFS (17 months vs. 9 months) compared to ofatumumab in the subgroup of patients with del(17p).161 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.163

Duvelisib and idealisib± 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)].

Chimeric Antigen Receptor (CAR) T-Cell Therapy

Lisocabtagene maraleucel was approved for relapsed or refractory CLL/SLL after at least two prior lines of therapy, including a BTKi and a BCL2i(venetoclax), based on the results of the TRANSCEND CLL 004 study. ${ }^{164,165}$

This study evaluated the safety and efficacy of lisocabtagene maraleculed in patients with relapsed or refractory CLL/SLL after≥2 prior lines of therapy (N= 137; 117 patients received infusion with lisocabtagene maralecul and all had received prior BTKi). 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 on BTKi) reported an ORR of 43% (18% CR) as assessed by an independent review committee.164 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).164 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.164.165 The median PFS was longer in patients who had uMRD(26 months vs. 3 months for those with detectable MRD).164 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.165 The median DOR was 30 months for all patients with responding disease and it was not reached for patients achieving a CR.

Lisocabtagene maraleucel is a one-time infusion that does not require continuous treatment. It 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].

Other Systemic Therapy Regimens

Chemoimmunotherapy regimens including FCR and BR demonstrated activity in patients with relapsed or refractory disease.166-168

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.169,170

Lenalidomide $\pm$ rituximab also demonstrated activity in patients with relapsed or refractory disease. ${ }^{171-173}$ 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.

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Alemutuzumab + rituximab results in a higher ORR than that observed with alemutuzumab monotherapy.174,175 Myelosuppression and infections were the most common grade 3-4 toxicities. However, it should be noted that bulky lymphadenopathy does not typically respond well to alemtuzumab monotherapy in patients with refractory CLL.176 Obinutuzumab(as monotherapy) also demonstrated activity in patients with relapsed or refractory CLL/SLL.129

mutations.56,177-183 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.184,185 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 as an effective treatment option for relapsed or refractory CLL, allogeneic HCT is not considered as a reasonable treatment option for relapsed or refractory CLL after initial purine analogue-based therapy.186

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

FCR, lenalidomide $\pm$ rituximab, obinutuzumab, bendamustine + rituximab(category 2B for patients 265 years or patients <65 years with significant comorbidities), and HDMP + anti-CD20 mAb (category 2B) are included as options for relapsed or refractory disease after prior therapy with BTKi-based regimens and venetoclax-containing regimens. However,these regimens are not recommended for patients who received these as first-line therapy.

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. 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.187,188

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

Alemutuzumab $\pm$ rituximab, HDMP +anti-CD20 mAb, and lenalidomide $\pm$ rituximab are included as options for relapsed or refractory disease after prior therapy with BTKi-based regimens and venetoclax-containing regimens. These recommendations 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.

Special Considerations for the Use of Small-Molecule Inhibitors

Management of Resistance to Small-Molecule Inhibitors

Covalent BTK Inhibitors

Acquired resistance to cBTKis is predominantly mediated by BTK and PLCG2 mutations.47,189,190

BTK and/or PLCG2 mutations were detected at an estimated median of 9 months before progression in patients 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.47,189 In the randomized ELEVATE-RR trial, acquired BTK mutations were detected at the time of disease progression in 66% of

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

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patients treated with acalabrutinib and in 37\% of patients treated with 15.6\% for acalabrutinib and britinib, respectively). PLCG2 mutations were detected in 6\% of patients treated with acalabrutinib and 20\% of patients treated with ibrutinib, with a median VAF of 2\% and 10\% for acalabrutinib and ibrutinib, respectively. The reported 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.47,189,190 Long-term follow-up is needed to confirm if BTK C481 mutations will emerge in patients treated with zanubrutinib. Alternative cBTKi(acalabrutinib or zanubrutinib) is not a reasonable treatment option for patients with a mutation in either BTK or PLCG2.

Venetoclax is effective for relapsed or refractory CLL after prior treatment with ibrutinib or idealisib.138-141,143-145 Pirtobrutinib is an effective option for the management of resistance to cBTKi, including in patients with BTK C481 mutations.155,156 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.191 The use of pitrotubin for relapsed or refractory CLL following BCL2i-containing regimens without prior exposure to cBTKi has not been evaluated.

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.

BCL2 Inhibitors

Acquisition of BCL2 mutations (G101V and D103Y) was implicated in resistance to venetoclax.192,193 BCL2 G101V mutation (low VAF) was identified in patients with progressive CLL during venetoclax therapy up to 25 months before clinical progression.192 BCL2 mutations are uncommonly associated with clinical resistance to venetoclax; therefore,other resistance mechanisms must be important.

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 appear to result in durable remissions.147,194-196

Management of Adverse Events

BTK Inhibitors

Diarrhea, fatigue, arthralgia, infections, cytopenias, bleeding, and cardiovascular toxicities(including atrial fibrillation, ventricular arrhythmias,and hypertension) are AEs associated with BTKis.

AEs 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 AEs was lower with acalabrutinib(15%vs. 21% for ibrutinib).121,197 The incidences of AEs of special interest were also lower with acalabrutinib compared to ibrutinib: atrial fibrillation(9% vs.16%), hypertension(9% vs.23%),and bleeding (38% vs. 51%).121,197 The incidences of atrial fibrillation and hypertension were also lower for acalabrutinib when used in combination with venetoclax± obinutuzumab

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in the AMPLIFY trial.30 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. ${ }^{121}$ 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.153 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.155-157 Longer-term follow-up data are needed to assess the incidence of these AEs.

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

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

A baseline assessment of cardiac function should be done prior to initiation of cBTKi. 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 [PPls],H2-receptor antagonists). Acalabrutinib tablets are the primary formulation and distribution of acalabrutinib capsules was discontinued.

Switching to alternate cBTKi therapy can be considered in the setting of non-adherence or intolerance to therapy in the absence of disease progression, especially in patients with atrial fibrillation or hypertension that is not medically controllable. Acalbrutinib and zanubrutinib were shown to be effective for the management of disease in patients with brutinib intolerance. ${}^{124,198,199}$ Pirtobrutinib is also an acceptable option for the management of intolerance to cBTKi. ${}^{155,156}$ Data from real-world studies suggest that dose modification of ibrutinib may resolve intolerance without compromising efficacy. ${}^{200-202}$ 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.

BCL2 Inhibitor

TLS was an important side effect of venetoclax in early clinical trials.Initation 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.203 Initiation and

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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.138,204,205 Recommendations for TLS prophylaxis based on tumor burden are outlined in the algorithm on CSLL-F.

Several trials including AMPLIFY suggest that debulking with a BTKi is effective in reducing the risk of TLS prior to venetoclax. ${ }^{206}$ 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%). ${ }^{30}$ 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.207

Other AEs associated with BCL2i-containing regimens are summarized in Table 5. In the AMPLIFY trial, Veno+ acalabrutinib was associated with higher rates of infections compared to other two treatment arms. ${}^{30}$ 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.

PI3K Inhibitors

Hepatotoxicity (transaminase elevations),severe diarrhea or colitis,pneumonitis, opportunistic infections, and febrile neutropenia were observed in patients treated with idealisib or duvelisib.

Hepatotoxicity is a major concern in younger patients treated with idealisib as first-line therapy.208 Close monitoring of transaminase levels is essential and concurrent administration of idealisib or duvelisib with other hepatotoxic drugs should be avoided.

The addition of anti-CD20 mAb or chemoimmunotherapy to idelisib increases the risk of febrile neutropenia.209 Anti-infective prophylaxis for herpes simplex virus(HSV) and Pneumocystis jirovecii pneumonia(PJP),and monitoring for cytomegalovirus(CMV) reactivation are recommended for patients receiving idelalisib or duvelisib.

CAR T-Cell Therapy

In the primary safety analysis of the TRANSCEND CLL 004 study,cytokine release syndrome (CRS) and neurologic events were the AEs of special interest (AESI) reported in 85% (grade 3, 9%) and 45% (grade 3,18%) of patients, respectively.164 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. 165

CRS and neurologic toxicity should be managed based on the toxicity grade as outlined in the Management of CAR T-Cell-Related Toxicities inmunotherapy-Related Toxicities.

Histologic Transformation

Histologic transformation of CLL 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.210-214 Clinical outcomes in patients with Richter transformation to DLBCL are exceedingly poor with a pattern of no response to minimal

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responses to chemoimmunotherapy and a median survival of 5 to 12 months from diagnosis, although the median survival was significantly better for patients who did not receive prior treatment for CLL (46 vs.8 months; P $<$ .001). $^{215-218}$

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. ${ }^{219}$ The exact mechanism of Richter transformation is not well understood; however, it has been associated with molecular characteristics of the patients' CLL and prior CLL-directed therapies. The following molecular characteristics have been associated with the risk of developing Richter's transformation and may be linked to the pathogenesis of the disease:220-228

● IGHV-unmutated status;

● Stereotyped BCR subset 8 combined with IGHV4-39 usage;

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

● Genetic abnormalities such as NOTCH1 mutation, C-MYC activation, or inactivation of TP53 or CDKN2A/B.

The incidence of Richter transformation increases with the number of prior chemoimmunotherapy regimens, and the rate is higher in patients treated with a combination of purine nucleoside analogues and alkylating agents.227 Richter transformation has also been reported following treatment with ibrutinib and venetoclax.229-232 Unlike progressive CLL,Richter transformation developing after treatment with ibrutinib lacked resistance to BTK and PLCG2 mutations.230 Progression on treatment,elevated LDH, and lymphadenopathy without lymphocytosis were independent prognostic variables for Richter transformation at progression in patients who received treatment with ibrutinib for CLL.232 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 relapsed or refractory CLL.231 Further studies are needed to determine the exact risk profile and mechanism of Richter transformation.

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. ${ }^{213,214,233,234}$ Optimal management for these cases has not been established.

Diagnosis and Workup

The diagnosis of histologic transformation should be confirmed by excisional lymph node biopsy (if lymph node is accessible). Core needle biopsy is acceptable when excisional or incisional lymph node biopsy is not feasible. CD19, CD20, CD22, PAX5, MUM1, and LEF1 are the most commonly expressed immunohistochemical markers, whereas CD5 and CD23 are variable. 219,235

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.

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.110,236-238 A maximum standardized uptake value(SUVmax)≥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.232,239 In the

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aforementioned retrospective analysis of patients who developed Richter transformation after ibrutinib therapy, the median SUVmax was 15 for patients who developed Richter transformation compared with an SUVmax of 8 for those who did not develop Richter transformation. ${ }^{232}$ However, other studies have reported that SUVmax $\geq 10$ alone lacks both sensitivity and specificity to distinguish Richter transformation from CLL in patients who develop Richter transformation while on bricutinib. ${ }^{240,241}$ In both these studies, biopsy-proven Richter transformation was diagnosed in patients who had an SUVmax between 5 and 10, suggesting that PET alone is insufficient and lymph node biopsy is required for the definitive diagnosis of Richter transformation. 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. ${ }^{232}$

transformed tumor cells. IGHV gene sequencing or clonal IGHV rearrangements can be used to establish the clonal relationship between CLL and histologically transformed tumor cells.226,244

Richter Transformation to DLBCL

Richter transformation to clonally unrelated DLBCL should be treated as de novo DLBCL as outlined in the NCCN Guidelines for B-Cell Lymphomas.

Enrollment in a clinical trial is the preferred initial treatment option for Richter transformation to clonally related (or unknown clonal status)DLBCL. In the absence of a suitable clinical trial, chemoimmunotherapy regimens recommended for DLBCL can be used; however, these regimens typically result in poor responses.215 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 chemoimmunotherapy.215 However, the use of these prognostic variables for selection of optimal first-line therapy for Richter transformation has not yet been established.

Epstein-Barr virus (EBV) infection has been reported in 16\% of patients with Richter transformation and is associated with a poor outcome. ${ }^{242}$ 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. ${ }^{243}$ Biopsy specimen should be evaluated for EBV infection using LMP1 staining or EBV-encoded RNA in situ hybridization (EBER-ISH).

The regimens listed below are used at the NCCN Member Institutions based on published data (mostly from single-arm phase l/ll studies;Table 6).

DLBCL arising from CLL/SLL can either be clonally related to underlying CLL/SLL (78%) or clonally unrelated to underlying CLL/SLL (22%).226,244 Richter transformation to clonally unrelated DLBCL is characterized by a significantly lower prevalence of TP53 disruption and a significantly longer median survival than clonally related DLBCL (62 months vs.14 months).226 The majority of patients with Richter transformation to clonally related DLBCL carry IGHV-unmutated.244 Molecular analysis is useful to establish the clonal relationship between baseline CLL tumor cells and histologically

● R-CHOP(rituximab,cyclophosphamide, doxorubicin, vincristine,and prednisone)245

● R-EPOCH(rituximab,etoposide,prednisone, vincristine,cyclophosphamide, and doxorubicin)246

● R-hyper-CVAD (rituximab, cyclophosphamide, vincristine,liposomal daunorubicin, and dexamethasone alternating with methotrexate and cytarabine) $^{247,248}$

● OFAR (oxaliplatin, fludarabine, cytarabine, and rituximab) 249,250

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● RCHOP + venetoclax (category 2B)$^{251}$

Data from ongoing clinical trials (discussed below) suggest that immune check point inhibitors (ICls) and BTKis have activity in patients with Richter transformation (treatment naive or previously treated).

In a phase II study that included 9 patients with Richter transformation,pembrolizumab monotherapy resulted in an ORR of 44% with a median PFS and OS of 5 months and 11 months, respectively.252 In a subsequent phase II trial that included 23 patients with Richter transformation,pembrolizumab resulted in a lower ORR(13%), with a median PFS and OS of 2 months and 4 months, respectively. The use of nivolumab or pembrolizumab as monotherapy in a non-trial population (10 patients with biopsy-proven Richter transformation to DLBCL treated with prior BTKi)was also associated with poor efficacy with a short time to disease progression.253

In a phase l/II trial of 25 patients with Richter transformation (treatment naive or previously treated), acalabrutinib (cBTKi) resulted in an ORR of 40% and the median PFS was 3 months.254 In the BRUIN phase l/II study that included 82 patients with heavily pretreated Richter transformation(including prior therapy with chemommunotherapy 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.255

ICIs in combination with BTKis have also been evaluated in phase II studies. Nivolumab+ ibrutinib resulted in an ORR of 42%. The median DOR and median OS were 15 months and 13 months, respectively.256

Tislelizumab+ zanubrutinib was also effective resulting in an ORR of 58%and the median DOR was not reached. ${ }^{257}$ The median PFS and OS were

10 months and not reached, respectively, and the estimated 12-month OS rate was 75%.

CAR T-cell therapy also has demonstrated efficacy in patients with Richter transformation. ${ }^{258,259}$ 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.259 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 $\geq$3 CRS and immune effector cell-associated neurotoxicity syndrome(ICANS).

Allogeneic HCT can be considered for patients with disease responding to initial chemoimmunotherapy.215,260-264 In a non-randomized comparative analysis, the estimated cumulative 3-year survival rate was significantly higher(75%) for patients who underwent allogeneic HCT after achieving a CR or PR to initial therapy compared with those with disease responding to initial therapy but 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).215 Treatment-sensitive disease and≤3 previous lines of therapy were associated with superior PFS and OS outcomes following allogeneic HCT with reduced-intensity conditioning.263

Autologous HCT may also be appropriate for patients with disease responding to initial therapy but who are not candidates for allogeneic HCT due to age, comorbidities, or lack of a suitable donor. 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.260 In a multivariate analysis,

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chemotherapy-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. The corresponding 3-year PFS and OS rates were 48% and 57%, respectively,for patients who underwent autologous HCT. Deeper remissions at the time of transplant was associated with better survival outcomes after allogeneic HCT.262

There are no effective treatment options for patients with Richter transformation refractory to chemoimmunotherapy. Clinical trial is the preferred treatment option for patients with Richter transformation refractory to chemoimmunotherapy. In the absence of a suitable clinical trial, CAR T-cell therapy with liscobatagene maraleucel or treatment recommendations as outlined for relapsed or refractory DLBCL in the NCCN Guidelines for B-Cell Lymphomas are acceptable options for this group of patients.

The Panel acknowledged that there are limited published data supporting the use of ICls and BTKi in patients with Richter transformation refractory to chemoimmunotherapy and that additional data will be forthcoming. Few Panel members felt that monotherapy with ICls(nivolumab or pembrolizumab) is not an effective treatment option for patients with relapsed or refractory Richter transformation(outside of clinical trials).However, some Panel members felt that given the unmet clinical need and the lack of effective treatment options, inclusion of ICls and BTKis as treatment options is reasonable for Richter transformation refractory to chemoimmunotherapy(especially in patients who are not candidates to receive chemoimmunotherapy regimens). In addition, some Panel

members pointed out that these agents would also be appropriate as an initial treatment option for patients with del(17p) or TP53 mutation.

ICIs (nivolumab or pembrolizumab) ± ibrutinib, zanubrutinib + tisleizumab,and pirtobrutinib are included as options for Richter transformation refractory to chemoimmunotherapy in patients who are candidates for alternative chemoimmunotherapy or for those with del(17p) or TP53 mutation. Acalabrutinib is also an option with a category 2B recommendation for the same patient population.

Histologic Transformation to Hodgkin Lymphoma

Histologic transformation to HL is clinically less aggressive than Richter transformation to DLBCL but it is associated with a poorer prognosis than de novo HL.211,212,265,266 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.267-269

Richter transformation to HL should be treated as outlined in the NCCN Guidelines for Hodgkin Lymphoma.

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.270,271 Patients with heavily pretreated fludarabine-refractory CLL have high susceptibility to developing serious infections.272

IVIG is associated with a significant decrease in the occurrence of infections but with no improvement in OS outcome. ${ }^{273-277}$ Monitoring IVIG levels and monthly administration of IVIG (0.3-0.5 g/kg to maintain nadir

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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,idelisab, corticosteroids, and/or alemtuzumab during treatment and thereafter.

Hepatitis B Virus Reactivation

Hepatitis B virus (HBV) reactivation was reported in patients treated with chemotherapy $\pm$ immunotherapy agents. $278,279$ 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.280

Antiviral prophylaxis and monitoring are recommended for patients receiving anti-CD20 mAb, alemtuzumab, purine analogs, and idealisib.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.281,282 Lamivudine prophylaxis should be avoided due to the risks for the development of resistance. The

rituximab-associated HBV reactivation.281,282 Lamivudine prophylaxis 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

recommended that surveillance and antiviral prophylaxis should be continued for up to 12 months after the completion of treatment.283

HBV reactivation and invasive fungal infections were rarely reported in patients treated with ibrutinib.284,285 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, idelisib, or alemtuzumab. 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.286 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.287,288 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.289,290 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.291 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.291-294 Purine analog-based therapy was associated with AIHA. Higher incidence of AIHA was reported in patients treated with fludarabine or chlorambucil compared to those who received fludarabine-based combination regimens.291,295 AIHA should not preclude the use of regimens containing fludarabine. However, patients should be observed carefully and

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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.296 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.296

AIHA and ITP can be managed with corticosteroids in most cases. IVIG,cyclosporine,297 and splenectomy should be used in steroid-refractory cases. Rituximab was also effective for the treatment of patients with autoimmune cytopenias.298-302 Elstrombopag and rompilostim 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.303-307

PRCA is less common in patients with CLL. PRCA can be managed with corticosteroids, cyclophosphamide, cyclosporine, or anti-thymocyte globulin.290 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.290

Tumor Flare Reactions

Tumor flare reaction associated with lenalidomide is typically observed as painful enlargement of lymph nodes, and may be accompanied by lymphocytosis, spleen enlargement, low-grade fever, rash, and/or bone pain.308 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).309 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. ${ }^{310}$

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 treated with the combination regimen.

Venous Thromboembolism

Lenalidomide may also be associated with venous thromboembolism(VTE) in patients with CLL/SLL.311,312 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 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. TLS associated with venetoclax therapy should be managed as outlined in CSLL-F.

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Management of Intolerance to anti-CD20 Monoclonal Antibody Therapy

Rare complications such as mucocutaneous reactions including paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis can occur in patients treated with anti-CD20 mAb. 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. 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. ${ }^{313,314}$ However, it is unclear if such a substitution poses the same risk of recurrence.

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.315 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 adverse reactions.

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.316,317 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.318-322 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 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.

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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(if considering chemimmunotherapy), patient's age,PS,comorbid conditions, and the agent's toxicity profile. In addition, 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.

Venetoclax + acalabrutinib ± obinutuzumab, acalabrutinib ± and zanubrutinib and Veno are preferred first-line therapy options for all patients including those with high-risk CLL/SLL [del(17p)/TP53 mutation and IGHV-unmutated]. Acalabrutinib, zanubrutinib, and venetoclax ± obinutuzumab are preferred treatment options for second-line and subsequent therapy. lbrutinib is included as an option for previously untreated and relapsed or refractory CLL/SLL under other recommended regimens due to its toxicity profile compared to acalabrutinib and zanubrutinib.

Pirtobrutinib is an effective alternative for the management of intolerance or resistance to a cBTKi and it is also an option for relapsed or refractory CLL/SLL after prior treatment with BTKi-based regimens and venetoclax-containing regimens. Lisocabtagene maraleucel is an option for relapsed or refractory CLL/SLL after prior treatment with BTKi and venetoclax-containing regimens.

The benefit/risk of a continuous versus time-limited treatment approach should also be carefully evaluated. Venetoclax-containing regimens are time-limited with a treatment-free remission period, whereas BTKis are given continuously until disease progression or intolerance.

Chemoimmunotherapy can be considered in selected circumstances(eg,fit patients with /GHV-mutated CLL, in circumstances when rapid disease debulking is needed or in a small fraction of patients in whom BTKi and venetoclax-containing regimens are contraindicated).

Histologic transformation of CLL 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 of CLL/SLL management.

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Table 1: Undetectable MRD Rates for BCL2i-Containing Regimens(Update in Progress. Last updated: April 2, 2025)

|Disease Setting|Trial|Regimen|No. of Patients|Patient Characteristics|Median Follow-up|Undetectable MRD (≤104, uMRD4)|Method used for MRD detection| |---|---|---|---|---|---|---|---| |Previously Untreated CLL/SLL|CLL1424 (Phase III)|Venetoclax + obinutuzumab (Veno)|216|≥65 years (CIRS>6; CrCl<70 mL/min)|65 months|EOT+2:75%(blood) (mL/min)|ASO-PCR; MRD-flow;NGS| |Previously Untreated CLL/SLL|CLL1424 (Phase III)|Chlorambucil + obinutuzumab|216|≥65 years (CIRS>6; CrCl<70 mL/min)|65 months|EOT+2:33%(blood)|ASO-PCR; MRD-flow;NGS| |Previously Untreated CLL/SLL|CAPTIVATE83 (Phase II; Time-limited cohort)|Venetoclax + ibrutinib|159|≤70 years; ECOG PS 0-1|28 months|EOT+3:77%(blood); 60(BM)|MRD-flow (8-color flow cytometry)| |Previously Untreated CLL/SLL|CAPTIVATE84 (Phase II; MRD cohort)|Venetoclax + ibrutinib (3 cycles of lead-in ibrutinib followed by 12 cycles of ibrutinib + venetoclax)|164|≤70 years; ECOG PS 0-1 (Perandomization) ≤70 years; ECOG PS 0-1 <70 years; ECOG PS 0-1 (Randomization; 150 mRD not confirmed)|31 months|75%(blood); 68(BM)|MRD-flow (8-color flow cytometry)| |Previously Untreated CLL/SLL|CAPTIVATE84 (Phase II; MRD cohort)|Venetoclax + ibrutinib|32|≤70 years; ECOG PS 0-1 (Randomization; 150 mRD not confirmed)|31 months|69%(blood); 66(BM)|MRD-flow (8-color flow cytometry)| |Previously Untreated CLL/SLL|CAPTIVATE84 (Phase II; MRD cohort)|Ibrutinib|31|≤65 years or<65 years who also had CIRS>6 or CrCl<70 mL/min|31 months|34 months|MRD-flow (8-color flow cytometry)| |Previously Untreated CLL/SLL|GLOW (Phase III)28|Venetoclax + ibrutinib|106|≥65 years or<65 years who also had CIRS>6 or CrCl<70 mL/min|34 months||| |Previously Untreated CLL/SLL|GLOW (Phase III)28|Chlorambucil + obinutuzumab|105|EOT+3:39%(blood); 17(BM/min|||| |Previously Untreated CLL/SLL|GAIA/CLL1328 (Phase III)|Venetoclax + ibrutinib + obinutuzumab|231|≤65 years or>65 years [without del(17p) or TP53 mutation]|39 months|15 months:92%(blood); 78(BM)|MRD-flow (4-color flow cytometry)| |Previously Untreated CLL/SLL|GAIA/CLL1328 (Phase III)|Veno|229|≤65 years or>65 years [without del(17p) or TP53 mutation]|39 months|15 months:87%(blood); 73(BM)|MRD-flow (4-color flow cytometry)| |Previously Untreated CLL/SLL|GAIA/CLL1328 (Phase III)|Venetoclax + rituximab (VenR)|237|≤65 years or>65 years [without del(17p) or TP53 mutation]|39 months|15 months: 57%(blood); 43(BM)|MRD-flow (4-color flow cytometry)| |Previously Untreated CLL/SLL|GAIA/CLL1328 (Phase III)|Chemoimmunotherapy (FCR ≤65 years; BR >65 years)|229|≤65 years or>65 years [without del(17p) or TP53 mutation]|39 months|15 months: 52%(blood); 37%(BM)|MRD-flow (4-color flow cytometry)| |Previously Untreated CLL/SLL|AMPLIFY30|Venetoclax + acalabrutinib|291|Median age: 61 years [without del(17p) or TP53 mutation])|41 months|EOT:45%(blood); EOT+3:38%(blood)|NGS; MRD-flow| |Previously Untreated CLL/SLL|AMPLIFY30|VenO + acalabrutinib|286|Median age: 61 years [without del(17p) or TP53 mutation])|41 months||NGS; MRD-flow| |Previously Untreated CLL/SLL|AMPLIFY30|FCR or Bendamustine + rituximab (BR)|290|Median age: 61 years [without del(17p) or TP53 mutation])|41 months||NGS; MRD-flow| |Previously Untreated CLL/SLL|Relapsed or Refractory CLL/SLL|MURANO (Phase III)91|VenR|194|≥18 years; ECOG PS 0-1; adequate bone marrow, liver, and kidney function|36 months|62%(blood)| |BR|Relapsed or Refractory CLL/SLL|MURANO (Phase III)91|195|13%(blood)|≥18 years; ECOG PS 0-1; adequate bone marrow, liver, and kidney function|36 months|| |CLARITY94 (Phase II)|Relapsed or Refractory CLL/SLL|Ibrutinib + venetoclax|53|Median age: 64 years ECOG PS 0-2|21 months|53%(blood); 36%(BM)|MRD-flow|

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Table 2: Phase III Randomized Studies of Small-Molecule Inhibitor Therapy for Treatment-Naive CLL/SLL

(Update in Progress. Last updated: April 2, 2025)

|Trial|Regimen|No. of Patients|Patient Characteristics|Median Follow-up|ORR|PFS|OS| |---|---|---|---|---|---|---|---| |ELEVATE-TN19,120|Acalabrutinib|179 [del(17p) and/or mutated TP53, n = 23]|≥65 years or <65 years with comorbidities (CRIS > 6; CrCl < 70 mL/min); ECOG PS of s2 and adequate hemologic, hepatic, and renal function|75 months|90%(11% CR)|Median: Not reached (72-month:62%)|Median: Not reached (72-month: 76%)| |ELEVATE-TN19,120|Acalabrutinib + obinutuzumab|179 [del(17p) and/or mutated TP53, n = 25]|≥65 years or <65 years with comorbidities (CRIS > 6; CrCl < 70 mL/min); ECOG PS of s2 and adequate hemologic, hepatic, and renal function|75 months|96%(31% CR)|Median: Not reached (72-month: 78%)|Median: Not reached (72-month: 84%)| |ELEVATE-TN19,120|Chlorambucil + obinutuzumab|177 [del(17p) and/or mutated TP53, n = 25]|≥65 years or <65 years with comorbidities (CRIS > 6; CrCl < 70 mL/min); ECOG PS of s2 and adequate hemologic, hepatic, and renal function|75 months|83%|Median: 28 months (72-month: 17%)|Median: Not reached (72-month: 75%)| |RESONATE-218|lbrutinib|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)38|lbrutinib + rituximab|182|≥65 years ≥65 years [without del(17p)]|55 months|93% (7% CR)|4-year: 76%|4-year: 85%| |Alliance North American Intergroup (A041202)38|lbrutinib + rituximab|182|≥65 years ≥65 years [without del(17p)]|55 months|94% (12% CR)|4-year: 76%|4-year: 86%| |Alliance North American Intergroup (A041202)38|Bendamustine + rituximab(BR)|183|≥65 years ≥65 years [without del(17p)]|55 months|81% (26% CR)|4-year: 47%|4-year: 84%| |E1912 study21|lbrutinib + rituximab|354|≤70 years|70 months|96% (17% CR)|5-year: 78%|5-year: 95%| |E1912 study21|FCR|175|≤70 years|70 months|81% (30% CR)|5-year: 51%|5-year: 89%| |SEQUOI A [without del(17p)] ${}^{20}$|Zanubrutinib|241 (mutated TP53, n = 15)|≥65 years of age OR unsuitable for treatment with FCR (CIRS > 6; CrCl <70 mL/min or a history of severe/multiple infections within 2 years); median age 70 years|27 months|95% (7% CR)|Median: Not reached (24-month: 86%; P < .0001)|Median: Not reached (24-month: 94%)| |SEQUOI A [without del(17p)] ${}^{20}$|BR|238 (mutated TP53, n = 13)|≥65 years of age OR unsuitable for treatment with FCR (CIRS > 6; CrCl <70 mL/min or a history of severe/multiple infections within 2 years); median age 70 years|27 months|85% (15% CR)|Median: Not reached (24-month: 70%)|Median: Not reached (24-month: 95%)| |SEQUOI A [with del(17p)] ${}^{20}$|Zanubrutinib (Non-randomized cohort)|111|≥65 years of age OR unsuitable for treatment with FCR (CIRS > 6; CrCl <70 mL/min or a history of severe/multiple infections within 2 years); median age 70 years|27 months|31 months|90% (3% CR)|Median: Not reached (24-month: 89%)|

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Table 2(continued): Phase III Randomized Studies of Small-Molecule Inhibitor Therapy for Treatment-Naive CLL/SLL(Update in Progress. Last updated: April 2, 2025)

|Trial|Regimen|No. of Patients|Patient Characteristics|Median Follow-up|ORR|PFS|OS| |---|---|---|---|---|---|---|---| |AMPLIFY30|Venetoclax + acalabrutinib|291|Median age: 61 years [without del(17p) or TP53 mutation])|41 months|93%|36-month: 77%|36-month: 94%| |AMPLIFY30|VenO+ acalrabutinib|286|Median age: 61 years [without del(17p) or TP53 mutation])|41 months|93%|36-month: 83%|36-month: 88%| |AMPLIFY30|FCR or Bendamustine + rituximab (BR)|290|Median age: 61 years [without del(17p) or TP53 mutation])|41 months|75%|36-month: 67%|36-month: 86%| |CLL1424,25|Venetoclax + obinutuzumab (VenO)|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)|6-year:53% (P<.0001)|6-year:79%| |CLL1424,25|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)|6-year:22%|6-year: 69%| |CLL1424,25|GLOW (Phase III)28,29|Venetoclax + ibrutinib|≥65 years with comorbidities (CIRS >6 ; CrCl <70 mL/min)|76 months|106 (mutated TP53, n=7)|≥65 years or <65 years who also had CIRS >6 or CrCl <70 mL/min|64 months| |GAIA/CLL1328,27|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/CLL1328,27|Veno|229|≤65 years or >65 years [without del(17p) or TP53 mutation]|51 months|96% (57% CR)|4-year: 82%|4-year:95%| |GAIA/CLL1328,27|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%| |Chemoimmunotherapy (FCR ≤65 years; BR >65 years)|229|81%|≤65 years or >65 years [without del(17p) or TP53 mutation]|51 months|4-year: 62%|4-year: 94%|| |FLAIR87,88|Venetoclax + ibrutinib|260|≤65 years or >65 years [without del(17p) or TP53 mutation]|51 months|Median age 62 years (>65 years, 31%) [without del(17p)]|44 months|87%| |FLAIR87,88|FCR|263|76%|3-year: 77% 4-year: 65%|Median age 62 years (>65 years, 31%) [without del(17p)]|44 months|3-year: 93% 4-year: 87%|

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Table 3. Phase III Randomized Studies of Small-Molecule Inhibitor Therapy for Relapsed or refractory CLL/SLL(Update in Progress. Last updated: April 2, 2025)

|Trial|Regimen|No. of Patients|Patient Characteristics|Median Follow-up|ORR|PFS|OS| |---|---|---|---|---|---|---|---| |ASCEND151|Acarabutinib|155 [del(17p),n=28; mutated TP53, n=39]|Median age 67-68 years with ECOG PS≤2 and adequate hematologic, hepatic, and renal function|47 months|83%|Median: Not reached 42-month:62% (HR,0.28;P<.0001)|Median: Not reached 42-month:78%| |ASCEND151|Idelalisib+ rituximab (IdR) or Bendamustine+ rituximab(BR)|155 [IdR, n=119; BR,n=36]; [del(17p),n=21; mutated TP53, n=34]|Median age 67-68 years with ECOG PS≤2 and adequate hematologic, hepatic, and renal function|47 months|84%|Median: 17 months 42-month: 23%|Median: Not reached 42-month: 65%| |ASCEND151|ELEVATE-RR121|Acaalbrutinib|Median age 67-68 years with ECOG PS≤2 and adequate hematologic, hepatic, and renal function|47 months|268|≥18 years;ECOG PS ≤2 and the presence of del(17p) and/or del(11q)|41 months| |Ibrutinib|ELEVATE-RR121|265|77% (4% CR)|||≥18 years;ECOG PS ≤2 and the presence of del(17p) and/or del(11q)|41 months| |RESONATE152|Ibrutinib|195 [del(17p),n=63; mutated TP53,n=79]|Median age 67 years|74 months|91% (11% CR)|Median: 44 months 60-month: 40%|Median: 68 months| |RESONATE152|Ofatumumab|196 [del(17p),n= 64; mutated TP53, n=68]|Median age 67 years|74 months|-|Median: 8 months 60-month: 3%|Median: 65 months| |ALPINE153|Zanubrutinib|327 [del(17p) and/or mutated TP53, n= 41]|Median age 67 years; ECOG PS ≤ 1; relapsed or refractory disease after ≥1 prior systemic therapy|42.5 months|86% (12% CR)|36-month: 65% (HR,0.67;P=.002)|36-month: 83%| |ALPINE153|Ibrutinib|325 [del(17p) and/or mutated TP53, n=38]|Median age 67 years; ECOG PS ≤ 1; relapsed or refractory disease after ≥1 prior systemic therapy|42.5 months|75% (8% CR)|36-month: 54%|36-month: 80%| |MURANO91,92|Venetoclax + rituximab (VenR)|194 [del(17p),n=46; mutated TP53,n=48]|≥18 years;ECOG PS ; ECOG PS 0-1; relapsed or refractory disease 1; relapsed or refractory disease after ≥1 prior systemic therapy (8% CR)|59 months|92% (8% CR)|Median: 54 months (HR,0.19;P<.0001)|5-year: 82% (HR,0.40;P<.0001)| |MURANO91,92|BR|195 [del(17p),n=46; mutated TP53,n=51]|≥18 years;ECOG PS ; ECOG PS 0-1; relapsed or refractory disease 1; relapsed or refractory disease after ≥1 prior systemic therapy (8% CR)|59 months|72% (4% CR)|Median: 17 months|5-year: 62%|

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Table 4. Adverse Events of BTKis (Update in Progress. Last updated: April 2, 2025)

|Adverse Events|Treatment-Naive CLL|Treatment-Naive CLL|Treatment-Naive CLL|Treatment-Naive CLL|Relapsed or refractory CLL|||| |---|---|---|---|---|---|---|---|---| |Adverse Events|ELEVATE-TN19|RESONATE-218|SEQUOIA20|ELEVATE-RR121|ELEVATE-RR121|ALPINE153|ALPINE153|BRUIN155,157| |Adverse Events|Acalabrutinib|lbrutinib|Zanubrutinib|Acalabrutinib|lbrutinib|Zanubrutinib|lbrutinib|Pirtobrutinib| |Most common adverse events(AEs; all grades)|Acalabrutinib|||||||| |Diarrhea|40%|50%|14%|35%|46%|19%|26%|16%*| |Headache|38%|-|11%|35%|20%|NR|NR|17%| |Cough|22%|36%|11%|29%|21%|NR|NR|24%| |Fatigue|22%|36%|11%|20%|17%|11%|15%|32%| |Arthralgia|20%|26%|14%|16%|23%|17%|19%|-| |Anemia|-|26%|4%|22%|19%|17%|19%|21%*| |Neutropenia|12%|13%(Grade ≥3)|16%|21%|25%|32%|30%|16%*| |Adverse events of special interest (AESI)||||||||| |Atrial fibrillation/Flutter||||||||| |Any grade|Any grade|6%|16%|3%|9%|16%|7%|17%| |Grade ≥3|Grade ≥3|1%|5%|<1%|5%|3%|3%|5%| |Bleeding|Bleeding|Bleeding|Bleeding|Bleeding|Bleeding|Bleeding|Bleeding|Bleeding| |Any grade|Any grade|42%|NR|45%|38%|51%|20%|22%| |Grade ≥3|Grade ≥3|3%|NR|4%|-|-|-|1%| |Major bleeding|Major bleeding|||||||| |Any grade|Any grade|4%|11%|5%|-|-|-|21%| |Grade≥3|Grade≥3|3%|7%|4%|-|-|-|1%| |Hypertension|Hypertension|||||||| |Any grade|Any grade|7%|23%|14%|9%|23%|27%|25%| |Grade ≥3|Grade ≥3|3%|8%|6%|4%|9%|17%*|16%*| |Infections|Infections|Infections|Infections|Infections|Infections|Infections||| |Any grade|74%|26%|62%|-|-|29%*|20%*|71%| |Grade ≥3|16%|-|16%|-|-|2%|1%|4%|

*Data from BRUIN CLL-321 study

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Table 5. Adverse Events of BCL2 Inhibitor-Containing Regimens (Update in Progress. Last updated: April 2, 2025)

|Adverse Events (All Grades)|Treatment-Naive CLL|Treatment-Naive CLL|Treatment-Naive CLL|Treatment-Naive CLL|Relapsed or refractory CLL|| |---|---|---|---|---|---|---| |Adverse Events (All Grades)|CLL1411|GAIA/CLL1328|AMPLIFY30|AMPLIFY30|MURANO137|M13-982146| |Adverse Events (All Grades)|VenO|VenO|avalabrutinib|Venotoclax+ acalabrutinib|VenR|Venetoclax| |Thrombocytopenia|24%|18%|5%|9%|13%|23%| |Anemia|17%|8%|5%|7%|16%|27%| |Infusion-related reaction|45%|51%|20%|0%|8%|NR| |Diarrhea|28%|33%|36%|33%|40%|44%| |Nausea|19%|NR|22%|15%|22%|38%| |Constipation|13%|NR|8%|7%|14%|13%| |Pyrexia|23%|24%|16%|6%|15%|19%| |Fatigue|15%|NR|14%|15%|18%|27%| |Cough|16%|NR|-|-|18%|19%| |Headache|11%|NR|28%|35%|11%|18%|

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Table 6: Chemoimmunotherapy for Richter Transformation (Update in Progress. Last updated: April 2, 2025)

|Regimen|No. of Patients|Median Follow-up|ORR|Median PFS|OS| |---|---|---|---|---|---| |RCHOP245|15|69 months|67%(7% CR)|10 months|Median: 21 months| |REPOCH246|46|39 months|39%|4 months|Median: 6 months| |R-hyper-CVAD248|30|8 months|43%(27% CR)|一|1-year:28%| |OFAR249|20|9 months|50%|一|6-month: 53%| |Modified OFAR250|35|26 months|39%(7% CR)|一|Median: 7 months 2-year: 20%| |Venetoclax + RCHOP251|26|6 months|68%(48% CR)|7 months|Median: 20 months|

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43. Baliakas P, Jeromin S, Iskas M, et al. Cytogenetic complexity in chronic lymphocytic leukemia: definitions, associations, and clinical impact. Blood 2019;133:1205-1216. Available at:https://www.ncbi.nlm.nih.gov/pubmed/30602617.

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44. Thompson PA, O'Brien SM, Wierda WG, et al. Complex karyotype is a stronger predictor than del(17p) for an inferior outcome in relapsed or refractory chronic lymphocytic leukemia patients treated with brinuxitin-based regimens. Cancer 2015;121:3612-3621. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26193999.

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54. Ahn IE, Tian X, Ipe D, et al. Prediction of outcome in patients with chronic lymphocytic leukemia treated with ibritun: Development and validation of a four-factor prognostic model. J Clin Oncol 2021;39:576-585. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33026937.

47. Woyach JA, Ruppert AS, Guinn D, et al. BTK(C481S)-Mediated Resistance to Brutinib in Chronic Lymphocytic Leukemia. J Clin Oncol 2017;35:1437-1443. Available at:https://www.ncbi.nlm.nih.gov/pubmed/28418267.

55. Soumerai JD, Ni A, Darif M, et al. Prognostic risk score for patients with relapsed or refractory chronic lymphocytic leukaemia treated with targeted therapies or chemoimmunotherapy: a retrospective, pooled cohort study with external validations. Lancet Haematol 2019;6:e366-e374. Available at:https://www.ncbi.nlm.nih.gov/pubmed/31109827.

48. Azevedo RS, Mikhaleva M, Mashima K, et al. Complex karyotype, but not isolated TP53 mutation, predicts overall survival in chronic lymphocytic leukemia patients in the era of targeted therapy [abstract]. Blood 2024;144:Abstract 583. Available at: https://doi.org/10.1182/blood-2024-206576.

56. Dreger P, Schnaiter A, Zenz T, et al. TP53, SF3B1, and NOTCH1 mutations and outcome of allotransplantation for chronic lymphocytic leukemia: six-year follow-up of the GCLLLSG CLL3X trial. Blood 2013;121:3284-3288. Available at:https://www.ncbi.nlm.nih.gov/pubmed/23435461.

49. Furstenau M, Thus YJ, Robrecht S, et al. High karyotypic complexity is an independent prognostic factor in patients with CLL treated with venetoclax combinations. Blood 2023;142:446-459. Available at:https://www.ncbi.nlm.nih.gov/pubmed/37172204.

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57. Schnaiter A, Paschka P, Rossi M, et al. NOTCH1, SF3B1, and TP53 mutations in fludarabine-refractory CLL patients treated with alemtuzumab: results from the CLL2H trial of the GCLLSG. Blood

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58. Messina M, Del Giudice I, Khiabanian H, et al. Genetic lesions associated with chronic lymphocytic leukemia chemo-fractoriness. Blood 2014;123:2378-2388. Available at:https://www.ncbi.nlm.nih.gov/pubmed/24550227.

59. Nadeu F, Delgado J, RoyO C, et al. Clinical impact of clonal and subclonal TP53, SF3B1, BIRC3, NOTCH1, and ATM mutations in chronic lymphocytic leukemia. Blood 2016;127:2122-2130. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26837699.

60. Blakemore SJ, Clifford R, Parker H, et al. Clinical significance of TP53, BIRC3, ATM and MAPK-ERK genes in chronic lymphocytic leukaemia:data from the randomised UK LRF CLL4 trial. Leukemia 2020;34:1760-1774. Available at:https://www.ncbi.nlm.nih.gov/pubmed/32015491.

61. Rossi D, Rasi S, Spina V, et al. Integrated mutational and cytogenetic analysis identifies new prognostic subgroups in chronic lymphocytic leukemia. Blood 2013;121:1403-1412. Available at:https://www.ncbi.nlm.nih.gov/pubmed/23243274.

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63. Molica S, Mauro FR, Callea V, et al. The utility of a prognostic index for predicting time to first treatment in early chronic lymphocytic leukemia:the GIMEMA experience. Haematologica 2010;95:464-469. Available at:https://www.ncbi.nlm.nih.gov/pubmed/19903673.

64. Wierda WG, O'Brien S, Wang X, et al. Multivariable model for time to first treatment in patients with chronic lymphocytic leukemia. J Clin Oncol 2011;29:4088-4095. Available at:https://www.ncbi.nlm.nih.gov/pubmed/21969505.

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65. Visentin A, Facco M, Frezzato F, et al. Integrated CLL scoring system,a new and simple index to predict time to treatment and overall survival in patients with chronic lymphocytic leukemia. Clin Lymphoma Myeloma Leuk 2015;15:612-620 e611-615. Available at:https://www.ncbi.nlm.nih.gov/pubmed/320233718.

66. Gentile M, Shanafelt TD, Mauro FR, et al. Predictive value of the CLL-IPI in CLL patients receiving chemo-immunotherapy as first-line treatment.Eur J Haematol 2018. Available at:https://www.ncbi.nlm.nih.gov/pubmed/30039576.

67. Condoluci A, Terzi di Bergamo L, Langerbeins P, et al. International prognostic score for asymptomatic early-stage chronic lymphocytic leukemia. Blood 2020;135:1859-1869. Available at:

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68. Hallek M, Cheson BD, Catovsky D, et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood 2018;131:2745-2760. Available at:https://www.ncbi.nlm.nih.gov/pubmed/29540348.

69. Woyach JA, Smucker K, Smith LL, et al. Prolonged lymphocytosis during ibritun therapy is associated with distinct molecular characteristics and does not indicate a suboptimal response to therapy. Blood 2014;123:1810-1817. Available at:https://www.ncbi.nlm.nih.gov/pubmed/24415539.

70. Cheson BD, Byrd JC, Rai KR, et al. Novel targeted agents and the need to refine clinical end points in chronic lymphocytic leukemia. J Clin Oncol 2012;30:2820-2822. Available at:https://www.ncbi.nlm.nih.gov/pubmed/22778323.

71. Rawstron AC, Kreuzer KA, Soosapilla A, et al. Reproducible diagnosis of chronic lymphocytic leukemia by flow cytometry: An European Research Initiative on CLL(ERIC) & European Society for Clinical Cell Analysis (ESCCA) Harmonisation project. Cytometry B Clin Cytom 2018;94:121-128. Available at:

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72. Wierda WG, Rawstron A, Cymbalista F, et al. Measurable residual disease in chronic lymphocytic leukemia: expert review and consensus recommendations. Leukemia 2021;35:3059-3072. Available at:https://www.ncbi.nlm.nih.gov/pubmed/34168283.

79. Woyach JA, Ruppert AS, Heerema NA, et al. Ibrutinib Regimens versus Chemoimmunotherapy in Older Patients with Untreated CLL. N Engl J Med 2018;379:2517-2528. Available at:https://www.ncbi.nlm.nih.gov/pubmed/30501481.

73. Logan AC, Gao H, Wang C, et al. High-throughput VDJ sequencing for quantification of minimal residual disease in chronic lymphocytic leukemia and immune reconstitution assessment. Proc Natl Acad Sci U S A 2011;108:21194-21199. Available at:https://www.ncbi.nlm.nih.gov/pubmed/22160699.

80. Moreno C, Greil R, Demirkan F, et al. First-line treatment of chronic lymphocytic leukemia with ibrinitin b plus obutinutizumab versus chlorambucil plus obinutuzumab: final analysis of the randomized, phase III iLLUMINATE trial. Haematologica 2022;107:2108-2120. Available at:https://www.ncbi.nlm.nih.gov/pubmed/35021599.

74. Rawstron AC, Fazi C, Agathangelidis A, et al. A complementary role of multiparameter flow cytometry and high-throughput sequencing for minimal residual disease detection in chronic lymphocytic leukemia: an European Research Initiative on CLL study. Leukemia 2016;30:929-936.Available at:https://www.ncbi.nlm.nih.gov/pubmed/26639181.

81. Wang XV, Hanson CA, Tschumper RC, et al. Measurable residual disease does not preclude prolonged progression-free survival in CLL treated with ibrutinib. Blood 2021;138:2810-2827. Available at:https://www.ncbi.nlm.nih.gov/pubmed/34407545.

75. 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.

82. Sharman JP, Laurenti L, Ferrant E, et al. CRISTALLO: Results from a phase III trial of venetoclax-obinutuzumab versus fludarabine,cyclophosphamide and rituximab or bendamustine-rituximab in patients with untreated chronic lymphocytic leukemia without del(17p) or TP53 mutations[abstract]. Blood 2024;144:Abstract 3237. Available at:https://doi.org/10.1182/blood-2024-200632.

76. Thompson PA, Srivastava J, Peterson C, et al. Minimal residual disease undetectable by next-generation sequencing predicts improved outcome in CLL or after chemoimmunotherapy. Blood 2019;134:1951-1959.Available at:https://www.ncbi.nlm.nih.gov/pubmed/31537528.

83. Tam CS, Allan JN, Siddiqi T, et al. Fixed-duration ibrutinib plus venetoclax for first-line treatment of CLL: primary analysis of the CAPTIVATE FD cohort. Blood 2022;139:3278-3289. Available at:https://www.ncbi.nlm.nih.gov/pubmed/35196370.

77. Rawstron AC, Bottcher S, Letestu R, et al. Improving efficiency and sensitivity: European Research Initiative in CLL(ERIC) update on the international harmonised approach for flow cytometric residual disease monitoring in CLL. Leukemia 2013;27:142-149. Available at:https://www.ncbi.nlm.nih.gov/pubmed/23041722.

84. 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. J Clin Oncol 2021;39:3853-3865. Available at:https://www.ncbi.nlm.nih.gov/pubmed/34618601.

78. Raponi S, Della Starza I, De Propris MS, et al. Minimal residual disease monitoring in chronic lymphocytic leukaemia patients. A comparative analysis of flow cytometry and ASO IgH RQ-PCR. Br J Haematol 2014;166:360-368. Available at:https://www.ncbi.nlm.nih.gov/pubmed/24735016.

85. Allan JN, Siddiqi T, Kilpps TJ, et al. Treatment outcomes after undetectable MRD with first-line ibrutinib(IBR) plus venetoclax(VEN):fixed duration treatment(placebo) versus continued ibr with up to 5 years median follow-up in the CAPTIVATE study[abstract]. Blood 2022;140:224-227. Available at:https://doi.org/10.1182/blood-2022-160338.

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86. Wierda WG, Jacobs R, Barr PM, et al. Consistently high 5.5-year progression-free survival (PFS) rates in patients with and without bulky baseline lymphadenopathy v2 cm are associated with high undetectable minimal residual disease (uMRD4) rates after first-line treatment with fixed-duration britinub + venetoclax for chronic lymphocytic leukemia(CLL)/small lymphocytic lymphoma (SLL) in the phase 2 CAPTIVATE study [abstract]. Blood 2024;144:Abstract 1869. Available at:https://doi.org/10.1182/blood-2024-200936.

87. Munir T, Cairns DA, Bloor A, et al. Chronic Lymphocytic Leukemia Therapy Guided by Measurable Residual Disease. N Engl J Med 2024;390:326-337. Available at:

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88. Hillmen P, Cairns DA, Bloor AOC, et al. Ibrutinib plus venetoclax with MRD-directed duration of treatment is superior to FCR and is a new standard of care for previously untreated CLL: report of the phase III UK NCRI FLAIR study (abstract). Blood 2023;142:Abstract 631. Available at:https://doi.org/10.1182/blood-2023-178298.

89. Kovacs G, Robrecht S, Fink AM, et al. Minimal residual disease assessment improves prediction of outcome in patients with chronic lymphocytic leukemia(CLL) who achieve partial response:

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90. Thompson PA, Peterson CB, Strati P, et al. Serial minimal residual disease (MRD) monitoring during first-line FCR treatment for CLL may direct individualized therapeutic strategies. Leukemia 2018;32:2388-2398.Available at: https://www.ncbi.nlm.nih.gov/pubmed/29769624.

91. 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.

92. Seymour JF, Kipps TJ, Eichhorst BF, et al. Enduring undetectable MRD and updated outcomes in relapsed/refractory CLL after fixed-duration venetocl-rituximab. Blood 2022;140:839-850. Available at:https://www.ncbi.nlm.nih.gov/pubmed/35605176.

93. Kater AP, Wu JQ, Kipps T, et al. Venetoclax 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. Available at:https://www.ncbi.nlm.nih.gov/pubmed/32986498.

94. Hillmen P, Rawstron AC, Brock K, et al. Ibrutinib plus venetoclax in relapsed/refractory chronic lymphocytic leukemia: The CLARITY study.J Clin Oncol 2019;37:2722-2729. Available at:https://www.ncbi.nlm.nih.gov/pubmed/31295041.

95. Munir T, Cherrill L-R, Webster N, et al. MRD4 Eradication at 6 Months and Early Clearance of MRD with Combination of Ibrutinib Plus Venetoclax Results in Sustained Clinical and MRD Responses:Exploratory Analysis of the Blood Cancer UK TAP Clarity Study. Blood 2022;140:222-223. Available at: https://doi.org/10.1182/blood-2022-166700.

96. Gutierrez A, Jr., Tschumper RC, Wu X, et al. LEF-1 is a prosurvival factor in chronic lymphocytic leukemia and is expressed in the preleukemic state of monoclonal B-cell lymphocytosis. Blood 2010;116:2975-2983. Available at:

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97. Palumbo GA, Parrinello N, Fargione G, et al. CD200 expression may help in differential diagnosis between mantle cell lymphoma and B-cell chronic lymphocytic leukemia. Leuk Res 2009;33:1212-1216. Available at:https://www.ncbi.nlm.nih.gov/pubmed/19230971.

98. Sandes AF, de Lourdes Chauffaille M, Oliveira CR, et al. CD200 has an important role in the differential diagnosis of mature B-cell neoplasms by multiparameter flow cytometry. Cytometry B Clin Cytom 2014;86:98-105. Available at: https://www.ncbi.nlm.nih.gov/pubmed/24243815.

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99. Menter T, Dirnhofer S, Tzankov A. LEF1: a highly specific marker for the diagnosis of chronic lymphocytic B cell leukaemia/small lymphocytic B cell lymphoma. J Clin Pathol 2015;68:473-478. Available at:https://www.ncbi.nlm.nih.gov/pubmed/25713417.

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100. Dicker F,Schnittger S,Haferlach T,et al.Immunostimulatory oligonucleotide-induced metaphase cytogenetics detect chromosomal aberrations in 80% of CLL patients: A study of 132 CLL cases with correlation to FISH,IgVH status, and CD38 expression. Blood 2006;108:3152-3160. Available at:https://www.ncbi.nlm.nih.gov/pubmed/16840733.

107. Shanafelt TD, Kay NE, Rabe KG, et al. Brief report: natural history of individuals with clinically recognized monoclonal B-cell lymphocytosis compared with patients with Rai 0 chronic lymphocytic leukemia. J Clin Oncol 2009;27:3959-3963. Available at:https://www.ncbi.nlm.nih.gov/pubmed/19620484.

108. Gibson SE, Swerdlow SH, Ferry JA, et al. Reassessment of small lymphocytic lymphoma in the era of monoclonal B-cell lymphocytosis.Haematologica 2011;96:1144-1152. Available at:https://www.ncbi.nlm.nih.gov/pubmed/21546505.

101. Heerema NA, Byrd JC, Dal Cin PS, et al. Stimulation of chronic lymphocytic leukemia cells with CpG oligodeoxynucleotide gives consistent karvotypic results among laboratories: a CLL Research Consortium(CRC) study. Cancer Genet Cytogenet 2010:203:134-140.Available at:https://www.ncbi.nlm.nih.gov/pubmed/21156225.

109. Conte MJ, Bowen DA, Wiseman GA, et al. Use of positron emission tomography-computed tomography in the management of patients with chronic lymphocytic leukemia/small lymphocytic lymphoma. Leuk Lymphoma 2014;55:2079-2084. Available at:https://www.ncbi.nlm.nih.gov/pubmed/24286263.

102. Rawstron AC, Bennett FL, O'Connor SJ, et al. Monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia. N Engl J Med 2008;359:575-583. Available at:https://www.ncbi.nlm.nih.gov/pubmed/18687638.

110.Falchi L, Keating MJ, Marom EM, et al. Correlation between FDG/PET, histology, characteristics, and survival in 332 patients with chronic lymphoid leukemia, Blood 2014;123:2783-2790. Available at:https://www.ncbi.nlm.nih.gov/pubmed/24615780.

111. Woyach JA, Ruppert AS, Rai K, et al. Impact of age on outcomes after initial therapy with chemotherapy and different chemoimmunotherapy regimens in patients with chronic lymphocytic leukemia: results of sequential cancer and leukemia group B studies. J Clin Oncol 2013;31:440-447. Available at:https://www.ncbi.nlm.nih.gov/pubmed/23233702.

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103. Rossi D, Sozzi E, Puma A, et al. The prognosis of clinical monoclonal B cell lymphocytosis differs from prognosis of Rai 0 chronic lymphocytic

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112. Goede V, Cramer P, Busch R, et al. Interactions between comorbidity and treatment of chronic lymphocytic leukemia: results of German Chronic Lymphocytic Leukemia Study Group trials. Haematologica 2014;99:1095-1100. Available at:https://www.ncbi.nlm.nih.gov/pubmed/24584349.

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113. Salvi F, Miller MD, Grilli A, et al. A manual of guidelines to score the modified cumulative illness rating scale and its validation in acute hospitalized elderly patients. J Am Geriatr Soc 2008;56:1926-1931.Available at:https://www.ncbi.nlm.nih.gov/pubmed/18811613.

120. Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib± obinutuzumab vs obinutuzumab+ chlorambucil in treatment-naive chronic lymphocytic leukemia: 6-year follow-up of Elevate-TN[abstract]. Blood 2023;142:ABstract 636. Available at:https://doi.org/10.1182/blood-2023-174750.

114. Fischer K, Al-Sawaf O, Bahlo J, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med 2019;380:2225-2236. Available at:https://www.ncbi.nlm.nih.gov/pubmed/31166681.

121.Byrd JC, Hillmen P, Ghia P, et al. Acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia: Results of the first randomized phase III trial. J Clin Oncol 2021;39:3441-3452. Available at:https://www.ncbi.nlm.nih.gov/pubmed/34310172.

115. Al-Sawaf O, Zhang C, Tandon M, et al. Venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab for previously untreated chronic lymphocytic leukaemia(CLL14): follow-up results from a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol 2020;21:1188-1200. Available at:

122. Burger JA, Barr PM, Robak T, et al. Long-term efficacy and safety of first-line brutinib treatment for patients with CLL/SLL: 5 years of follow-up from the phase 3 RESONATE-2 study. Leukemia 2020;34:787-798.Available at: https://www.ncbi.nlm.nih.gov/pubmed/31628428.

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116. Herling CD, Cymbalista F, Gross-Ophoff-Muller C, et al. Early treatment with FCR versus watch and wait in patients with stage Binet A high-risk chronic lymphocytic leukemia(CLL): a randomized phase 3 trial.Leukemia 2020;34:2038-2050. Available at:https://www.ncbi.nlm.nih.gov/pubmed/32071431.

123. Burger JA, Sivina M, Jain N, et al. Randomized trial of bricutinib vs bricutinib plus rituximab in patients with chronic lymphocytic leukemia.Blood 2019;133:1011-1019. Available at:https://www.ncbi.nlm.nih.gov/pubmed/30530801.

124. Brown JR, Eichhorst B, Hillmen P, et al. Zanubrutinib or Ibrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia. N Engl J Med 2023;388:319-332. Available at:https://www.ncbi.nlm.nih.gov/pubmed/36511784.

117. Riecke A, Tausch E, Yosifov DY, et al. Genetic markers and brikutinib vs placebo treatment in early stage chronic lymphocytic leukemia-results from the GCLLSG CLL12 trial. Blood 2023;142:199-199. Available at:https://doi.org/10.1182/blood-2023-180558.

125. Kutsch N, Bahlo J, Robrecht S,et al. Long term follow-up data and health-related quality of life in frontline therapy of fit patients treated with FCR versus BR (CLL10 trial of the GCLLSG). Hemosphere 2020;4:e336.Available at:https://www.ncbi.nlm.nih.gov/pubmed/32072150.

118. Al-Sawaf O, Zhang C, Lu T, et al. Minimal residual disease dynamics after venetoclax-obinutuzumab treatment: Extended off-treatment follow-up from the randomized CLL14 study. J Clin Oncol 2021;39:4049-4060.Available at:https://www.ncbi.nlm.nih.gov/pubmed/34709929.

126. Michallet AS, Aktan M, Hiddemann W, et al. Rituximab plus bendamustine or chlorambucil for chronic lymphocytic leukemia: primary analysis of the randomized, open-label MABLE study. Haematologica 2018;103:698-706. Available at:https://www.ncbi.nlm.nih.gov/pubmed/29419437.

119. Kater AP, Owen C, Moreno C, et al. Fixed-Duration Ibrutinib-Venetoclax in Patients with Chronic Lymphocytic Leukemia and Comorbidities. NEJM Evid 2022;1:EVIDoa2200006. Available at: https://www.ncbi.nlm.nih.gov/pubmed/38319255.

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127. Sharman JP, Burke JM, Yimer HA, et al. Phase 2, multicenter GBB study of obinutuzumab plus bendamustine in previously untreated patients

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128.Byrd JC, Flynn JM, Kipps TJ,et al. Randomized phase 2 study of obinutuzumab monotherapy in symptomatic, previously untreated chronic lymphocytic leukemia. Blood 2016;127:79-86. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26472752.

129. Stilgenbauer S, Bosch, Flanhan O, et al. Safety and efficacy of obinutuzumab alone or with chemotherapy in previously untreated or relapsed/refractory chronic lymphocytic leukaemia patients: Final analysis of the Phase IIIb GREEN study. Br J Haematol 2021;193:325-338.Available at: https://www.ncbi.nlm.nih.gov/pubmed/33605445.

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131. 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. Available at:https://www.ncbi.nlm.nih.gov/pubmed/19693094.

132. Castro JE,Amaya-Chanaga Cl, Velez Lujan J,et al.Obinutuzumab(Gazyva) and high-dose methylprednisolone(HDMP) combination for patients with chronic lymphocytic leukemia(CLL)- a phase lb/ll study[abstract]. Blood 2017;130:Abstract 1730. Available at:https://www.sciencedirect.com/science/article/pii/S0006497119822462.

133. 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.Available at:https://www.ncbi.nlm.nih.gov/pubmed/39645236.

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134. Ahn IE, Tian X, Wiestner A. lbrutinib for chronic lymphocytic leukemia with TP53 alterations. N Engl J Med 2020;383:498-500. Available at:https://www.nejm.org/doi/full/10.1056/NEJMc2005943.

135. Allan JN, Shanafelt T, Wiestner A, et al. Long-term efficacy of first-line ibrutinib treatment for chronic lymphocytic leukaemia in patients with TP53 aberrations: a pooled analysis from four clinical trials. Br J Haematol 2022;196:947-953. Available at:https://www.ncbi.nlm.nih.gov/pubmed/34865212.

136.Tam CS,Robak T, Ghia P,et al. Zanubrutin monotherapy for patients with treatment naive chronic lymphocytic leukemia and 17p deletion. Haematologica 2020;106:2354-2363. Available at:https://www.ncbi.nlm.nih.gov/pubmed/33054121.

137. Seymour JF, Kipps TJ, Eichhorst B, et al. Venetoclax-rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med 2018;378:1107-1120. Available at:https://www.ncbi.nlm.nih.gov/pubmed/39605445.

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138. Jones JA, Mato AR, Wierda WG, et al. Venetoclax for chronic lymphocytic leukaemia progressing after irbrutinib: an interim analysis of a multicentre, open-label, phase 2 trial. Lancet Oncol 2018;19:65-75.Available at: https://www.ncbi.nlm.nih.gov/pubmed/29246803.

139. Coutre S,Choi M,Furman RR,et al.Venetoclax for patients with chronic lymphocytic leukemia who progressed during or after idealisibl therapy. Blood 2018;131:1704-1711. Available at:https://www.ncbi.nlm.nih.gov/pubmed/29305552.

140.Eyre TA, Kirkwood AA, Gohill S, et al. Efficacy of venetoclax monotherapy in patients with relapsed chronic lymphocytic leukaemia in the post-BCR inhibitor setting: a UK wide analysis. Br J Haematol 2019;185:656-669. Available at:https://www.ncbi.nlm.nih.gov/pubmed/30768675.

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141. Innocenti I, Morelli F, Autore F, et al. Venetoclax in CLL patients who progress after B-cell Receptor inhibitor treatment: a retrospective multi-centre Italian experience. Br J Haematol 2019;187:e8-e11. Available at:https://www.ncbi.nlm.nih.gov/pubmed/31364153.

142. Kater AP, Arslan O, Demirkan F, et al. Activity of venetoclax in patients with relapsed or refractory chronic lymphocytic leukaemia:

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143. Roberts AW, Ma S, Kipps TJ, et al. Efficacy of venetoclax in relapsed chronic lymphocytic leukemia is influenced by disease and response variables. Blood 2019;134:111-122. Available at:https://www.ncbi.nlm.nih.gov/pubmed/31023700.

144. Mato AR, Hill BT, Lamanna N,et al. Optimal sequencing of brutinib,idelisib, and venetocl in chronic lymphocytic leukemia: results from a multicenter study of 683 patients. Ann Oncol 2017;28:1050-1056.Available at:https://www.ncbi.nlm.nih.gov/pubmed/28453705.

145. Wierda WG, Byrd JC, Davids MS, et al. Venetoclax for chronic lymphocytic leukaemia patients who progress after more than one B-cell receptor pathway inhibitor. Br J Haematol 2019;185:961-966. Available at:https://www.ncbi.nlm.nih.gov/pubmed/30478940.

146. 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. Available at:https://www.ncbi.nlm.nih.gov/pubmed/38290108.

147. 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. Available at:https://www.ncbi.nlm.nih.gov/pubmed/35736670.

148. Kater A, Harrup R, Kipps TJ, et al. S201: Final 7-Year Follow up and Retreatment Substudy Analysis of Murano: Venetoclax-Rituximab(VenR)-Treated Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia(R/R CLL). HemaSphere 2023;7. Available at:

149. Brander D, Roberts A, Kipps T, et al. Retreatment with venetoclax and rituximab combination following disease progression while off therapy in patients with chronic lymphocytic leukemia[abstract]. EHA;2024:Abstract P682. Available at:

150. Lei MM, Sorial MN, Lou U, et al. Real-world evidence of obinutuzumab and venetoclax in previously treated patients with chronic lymphocytic leukemia or small lymphocytic lymphoma. Leuk Lymphoma 2024:1-7. Available at: https://www.ncbi.nlm.nih.gov/pubmed/38293753.

151. Ghia P, Pluta A, Wach M, et al. Acalabrutinib versus investigator's choice in relapsed/refractory chronic lymphocytic leukemia: Final ASCEND trial results. Hemasphere 2022;6:e801. Available at:https://www.ncbi.nlm.nih.gov/pubmed/36398134.

152. Munir T, Brown JR, O'Brien S, et al. Final analysis from RESONATE:Up to six years of follow-up on bricutinib in patients with previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma. Am J Hematol 2019;94:1353-1363. Available at:https://www.ncbi.nlm.nih.gov/pubmed/31512258.

153. Brown JR, Eichhorst B, Lamanna N, et al. Sustained benefit of zanubrutinib vs ibrutinib in patients with R/R CLL/SLL: final comparative analysis of ALPINE. Blood 2024;144:2706-2717. Available at:https://www.ncbi.nlm.nih.gov/pubmed/39316666.

154. O'Brien S, Jones JA, Coutre SE, et al. Ibrutinib for patients with relapsed or refractory chronic lymphocytic leukaemia with 17 pdeletion(RESONATE-17): a phase 2, open-label, multicentre study. Lancet Oncol 2016;17:1409-1418. Available at:https://www.ncbi.nlm.nih.gov/pubmed/27637985.

155. Mato AR, Woyach JA, Brown JR, et al. Pirtobrutinib after a covalent BTK inhibitor in chronic lymphocytic leukemia. N Engl J Med 2023;389:33-44. Available at: https://www.ncbi.nlm.nih.gov/pubmed/37407001.

156. Woyach JA, Brown JR, Ghia P, et al. Pirtobrutinib in post-cBTKi CLL/SLL:~30 months follow-up and subgroup analysis with/without prior BCL2i from the Phase 1/2 BRUIN study [abstract]. Blood 2023;142:Abstract 325. Available at: https://doi.org/10.1182/blood-2023-185852.

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157. Sharman JP, Munir T, Grosicki S, et al. BRUIN CLL-321:Randomized phase III trial of pirtorobutrinib versus idealisib plus rituximab(IdelaR) or bendamustine plus rituximab(BR) in

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158. Brown JR, Byrd JC, Coutre SE, et al. Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110delta, for relapsed/refractory chronic lymphocytic leukemia. Blood 2014;123:3390-3397. Available at:https://www.ncbi.nlm.nih.gov/pubmed/24615777.

159. 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 idealisib in patients with relapsed chronic lymphocytic leukemia. J Clin Oncol 2019;37:1391-1402. Available at:https://www.ncbi.nlm.nih.gov/pubmed/30995176.

160. Gopal AK, Kahl BS, de Vos S, et al. PI3Kdelta inhibition by idealisib in patients with relapsed indent lymphoma. N Engl J Med 2014;370:1008-1018. Available at:https://www.ncbi.nlm.nih.gov/pubmed/24450858.

161. Flinn IW, Hillmen P, Montillo M,et al.The phase 3 DUO trial:duvelisib vs ofatumumab in relapsed and refractory CLL/SLL. Blood 2018;132:2446-2455. Available at:https://www.ncbi.nlm.nih.gov/pubmed/30287523.

162. Flinn IW, Miller CB, Ardeshna KM, et al. DYNAMO: A phase II study of duvelisib (IPI-145) in patients with refractory indolent non-Hodgkin lymphoma. J Clin Oncol 2019;37:912-922. Available at:https://www.ncbi.nlm.nih.gov/pubmed/30742566.

163. Davids MS, Kuss BJ, Hillmen P, et al. Efficacy and safety of duvelisib following disease progression on ofatumumab in patients with relapsed/refractory CLL or SLL in the DUO Crossover Extension Study.Clin Cancer Res 2020;26:2096-2103. Available at:https://www.ncbi.nlm.nih.gov/pubmed/31964785.

164. Siddiqi T, Maloney DG, Kenderian SS,et al. Lisocabtabgene 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. Available at:https://www.ncbi.nlm.nih.gov/pubmed/37295445.

165. Siddiqi T, Maloney DG, Kenderian SS, et al. Lisocabtabegane Maraleucel(liso-cel) in R/R CLL/SLL: 24-Month Median Follow-up of TRANSCEND CLL 004. Blood 2023;142:330-330. Available at:https://doi.org/10.1182/blood-2023-179529.

166.Robak T, Dmoszynska A, Solal-Celigny P, et al. Rituximab plus fludarabine and cyclophosphamide prolongs progression-free survival compared with fludarabine and cyclophosphamide alone in previously treated chronic lymphocytic leukemia. J Clin Oncol 2010;28:1756-1765.Available at: https://www.ncbi.nlm.nih.gov/pubmed/20194844.

167.Badoux XC,Keating MJ, Wang X,et al. Fludarabine,cyclophosphamide, and rituximab chememoimmunotherapy is highly effective treatment for relapsed patients with CLL. Blood 2011;117:3016-3024.Available at:https://www.ncbi.nlm.nih.gov/pubmed/21245487.

168. 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 Leukemia Study Group.J Clin Oncol 2011;29:3559-3566. Available at:https://www.ncbi.nlm.nih.gov/pubmed/21844497.

169. Castro JE, Sandoval-Sus JD, Bole J, et al. Rituximab in combination with high-dose methylprednisolone for the treatment of fludarabine refractory high-risk chronic lymphocytic leukemia. Leukemia 2008;22:2048-2053. Available at:https://www.ncbi.nlm.nih.gov/pubmed/18754025.

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170. Dungarwalla M, Evans SO, Riley U, et al. High dose methylprednisolone and rituximab is an effective therapy in advanced refractory chronic lymphocytic leukemia resistant to fludarabine therapy.Haematologica 2008;93:475-476. Available at:http://www.ncbi.nlm.nih.gov/pubmed/18310545.

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171.Badoux XC,Keating MJ, Wen S,et al. Phase II study of lenalidomide and rituximab as salvage therapy for patients with relapsed or refractory chronic lymphocytic leukemia.J Clin Oncol 2013;31:584-591. Available at:https://www.ncbi.nlm.nih.gov/pubmed/23270003.

178. Schetelig J, van Biezen A, Brand R, et al. Allogeneic hematopoietic stem-cell transplantation for chronic lymphocytic leukemia with 17p deletion: a retrospective European Group for Blood and Marrow Transplantation analysis. J Clin Oncol 2008;26:5094-5100. Available at:https://www.ncbi.nlm.nih.gov/pubmed/18711173.

172. Buhler A, Wendtner CM, Kipps TJ,et al. Lenalidomide treatment and prognostic markers in relapsed or refractory chronic lymphocytic leukemia:data from the prospective, multicenter phase-II CLL-009 trial. Blood Cancer J 2016;6:e404. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26967821.

179. Sorror ML, Storer BE, Sandmaier BM, et al. Five-year follow-up of patients with advanced chronic lymphocytic leukemia treated with allogeneic hematopoietic cell transplantation after nonmyeloablative conditioning. J Clin Oncol 2008;26:4912-4920. Available at:https://www.ncbi.nlm.nih.gov/pubmed/18794548.

173. Chavez JC, Piris-Villaespesa M, Dalia S, et al. Results of a phase II study of lenalidomide and rituximab for refractory/relapsed chronic lymphocytic leukemia. Leuk Res 2016;47:78-83. Available at:https://www.ncbi.nlm.nih.gov/pubmed/2278583.

180. Khouri IF, Bassett R, Poindexter N, et al. Nonmyeloablative allogeneic stem cell transplantation in relapsed/refractory chronic lymphocytic leukemia: long-term follow-up, prognostic factors, and effect of human leukocyte histocompatibility antigen subtype on outcome.Cancer 2011;117:4679-4688. Available at:https://www.ncbi.nlm.nih.gov/pubmed/21455998.

174. Faderl S, Ferrajoli A, Wierda W, et al. Alemutzumab 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. Available at:https://www.ncbi.nlm.nih.gov/pubmed/20225334.

181. Brown JR, Kim HT, Armand P, et al. Long-term follow-up of reduced-intensity allogeneic stem cell transplantation for chronic lymphocytic leukemia: prognostic model to predict outcome. Leukemia 2013;27:362-369. Available at: https://www.ncbi.nlm.nih.gov/pubmed/22955330.

175. 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. Available at:http://www.ncbi.nlm.nih.gov/pubmed/14726385.

182. Herth I, Dietrich S, Benner A, et al. The impact of allogeneic stem cell transplantation on the natural course of poor-risk chronic lymphocytic leukemia as defined by the EBMT consensus criteria: a retrospective donor versus no donor comparison. Ann Oncol 2014;25:200-206.

176. Fiegl M, Stauder R, Steurer M, et al. Alemtuzumab in chronic lymphocytic leukemia: final results of a large observational multicenter study in mostly pretreated patients. Ann Hematol 2014;93:267-277.Available at:https://www.ncbi.nlm.nih.gov/pubmed/24292560.

183. Poon ML,Fox PS,Samuels BI,et al.Allogeneic stem cell transplant in patients with chronic lymphocytic leukemia with 17p deletion: consult-transplant versus consult- no-transplant analysis. Leuk Lymphoma 2015;56:711-715. Available at:https://www.ncbi.nlm.nih.gov/pubmed/24913509.

177. Moreno C, Villamor N, Colomer D,et al. Allogeneic stem-cell transplantation may overcome the adverse prognosis of unmutated VH gene in patients with chronic lymphocytic leukemia. J Clin Oncol 2005;23:3433-3438. Available at:

184. Jaglowski SM, Ruppert AS, Heerema NA, et al. Complex karyotype predicts for inferior outcomes following reduced-intensity conditioning allogeneic transplant for chronic lymphocytic leukaemia. Br J Haematol

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185. Kim HT, Ahn KW, Hu ZH, et al. Prognostic score and cytogenetic risk classification for chronic lymphocytic leukemia patients: Center for International Blood and Marrow Transplant Research Report. Clin Cancer Res 2019;25:5143-5155. Available at:https://www.ncbi.nlm.nih.gov/pubmed/31253630.

186. Kharfan-Dabaja MA, Kumar A, Hamadani M, et al. Clinical practice recommendations for use of allogeneic hematopoietic cell transplantation in chronic lymphocytic leukemia on behalf of the Guidelines Committee of the American Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant 2016;22:2117-2125. Available at:https://www.ncbi.nlm.nih.gov/pubmed/27660167.

187. Srorro ML, Maris MB, Storb R, et al. Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood 2005;106:2912-2919. Available at:https://www.ncbi.nlm.nih.gov/pubmed/15994282.

188. ElSawy M, Storer BE, Pulsipher MA, et al. Multi-centre validation of the prognostic value of the haematopoietic cell transplantation- specific comorbidity index among recipient of allogeneic haematopoietic cell transplantation. Br J Haematol 2015;170:574-583. Available at:https://www.ncbi.nlm.nih.gov/pubmed/25945807.

189. Ahn IE, Underbayev C, Albitar A, et al. Clonal evolution leading to ibrutinib resistance in chronic lymphocytic leukemia. Blood 2017;129:1469-1479. Available at:https://www.ncbi.nlm.nih.gov/pubmed/28049639.

190. Woyach JA, Jones D, Jurczak W, et al. Mutational profile in previously treated patients with chronic lymphocytic leukemia progression on acalabrutinib or brirutinib. Blood 2024;144:1061-1068.Available at:https://www.ncbi.nlm.nih.gov/pubmed/38754046.

191. Brown JR, Desikan SP, Nguyen B, et al. Genomic evolution and resistance during pitrobutrinith by covalent BTK-inhibitor(cBTKi)

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192. Blombery P, Anderson MA, Gong JN, et al. Acquisition of the recurrent Gly101Val mutation in BCL2 confers resistance to venetoclax in patients with progressive chronic lymphocytic leukemia. Cancer Discov 2019;9:342-353. Available at:https://www.ncbi.nlm.nih.gov/pubmed/30514704.

193. Tausch E,Close W,Dolnik A,et al.Venetoclax resistance and acquired BCL2 mutations in chronic lymphocytic leukemia. Haematologica 2019;104:e434-e437. Available at:https://www.ncbi.nlm.nih.gov/pubmed/31004028.

194. Brown JR, Davids MS, Chang JE, et al. Outcomes of ibrutinib (lbr)therapy in lbr-naive patients (pts) with chronic lymphocytic leukemia(CLL)progressing after venetoclax (Ven) [abstract]. Blood 2019;134:Abstract 4320. Available at: https://doi.org/10.1182/blood-2019-123665.

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

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196. Mato AR, Roeker LE, Jacobs R, et al. Assessment of the efficacy of therapies following venetoclax discontinuation in CLL reveals BTK inhibition as an effective strategy. Clin Cancer Res 2020;26:3589-3596.Available at:https://www.ncbi.nlm.nih.gov/pubmed/32198151.

197. Seymour JF, Byrd JC, Ghia P, et al. Detailed safety profile of acalabrutinib vs ibrutinib in previously treated chronic lymphocytic leukemia in the ELEVATE-RR trial. Blood 2023;142:687-699. Available at:https://www.ncbi.nlm.nih.gov/pubmed/37390310.

198. 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. Available at:https://www.ncbi.nlm.nih.gov/pubmed/31088809.

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200. Parikh SA, Achenbach SJ, Call TG, et al. The impact of dose modification and temporary interruption of ibrutinib on outcomes of chronic lymphocytic leukemia patients in routine clinical practice. Cancer Med 2020;9:3390-3399. Available at:https://www.ncbi.nlm.nih.gov/pubmed/32187452.

201. Stephens DM, Brown JR, Ma S, et al. Ibrutinib dose modifications for management of cardiac adverse events in patients with B-cell malignancies: Pooled analysis of 10 clinical trials. Journal of Clinical Oncology 2023:41:7538-7538. Available at:https://ascopubs.org/doi/abs/10.1200/JCO.2023.41.16 suppl.7538.

202. Shadman M, Salkar M, Srivastava B, et al. Real-world outcomes following brutinib dose reduction in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma. Leuk Lymphoma 2025;66:44-53. Available at: https://www.ncbi.nlm.nih.gov/pubmed/39352001.

203. Roberts AW, Davids MS, Pagel JM, et al. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med 2016;374:311-322. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26639348.

204. Davids M, Jones J, Eradat H, et al. Modified Venetoclax Dose Ramp-Up in Select High-Risk Patients with Chronic Lymphocytic Leukemia(CLL)with Progression after B-Cell Receptor Pathway Inhibitors (BCRi). Clinical Lymphoma Myeloma and Leukemia 2017;17:S302. Available at:http://dx.doi.org/10.1016/j.clml.2017.07.097.

205. Koenig KL, Huang Y, Dotson EK, et al. Safety of venetoclax rapid dose escalation in CLL patients previously treated with B-cell receptor signaling antagonists. Blood Adv 2020;4:4860-4863. Available at:https://www.ncbi.nlm.nih.gov/pubmed/33031541.

206. Sharman JP, Biondo JML, Boyer M, et al. A review of the incidence of tumor lysis syndrome in patients with chronic lymphocytic leukemia treated with venetoclax and debulking strategies. EJHaem 2022;3:492-506. Available at: https://www.ncbi.nlm.nih.gov/pubmed/35846043.

207. Sportoletti P, Laurenti L, Ferrant E, et al. Reduction of tumor lysis syndrome risk after debulking with obutinutuzumab in patients treated with venetoclax-obinutuzumab in the randomized phase 3 CRISTALLO Trial[abstract]. Blood 2024;144:Abstract 1873. Available at:https://doi.org/10.1182/blood-2024-198372.

208. Lampson BL, Kasar SN, Matos TR, et al. Idealisib given front-line for treatment of chronic lymphocytic leukemia causes frequent immune-mediated hepatotoxicity. Blood 2016;128:195-203. Available at:https://www.ncbi.nlm.nih.gov/pubmed/27247136.

209. Zelenetz AD, Barrientos JC, Brown JR, et al. Idelisal 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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211.Tsimberidou AM, O'Brien S, Kantarjian HM, et al. Hodgkin transformation of chronic lymphocytic leukemia: the M. D. Anderson Cancer Center experience. Cancer 2006;107:1294-1302.Available at:https://www.ncbi.nlm.nih.gov/pubmed/16902984.

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214. Campo E, Jaffe ES, Cook JR, et al. The International Consensus Classification of Mature Lymphoid Neoplasms: a report from the Clinical Advisory Committee. Blood 2022;140:1229-1253. Available at:https://www.ncbi.nlm.nih.gov/pubmed/35653592.

215. Tsimberidou AM, O'Brien, S Khouri I, et al. Clinical outcomes and prognostic factors in patients with Richter's syndrome treated with chemotherapy or chemomimmotherapy with or without stem-cell transplantation. J Clin Oncol 2006;24:2343-2351. Available at:https://www.ncbi.nlm.nih.gov/pubmed/16710033.

216. Wang Y, Tschautscher MA, Rabe KG, et al. Clinical characteristics and outcomes of Richter transformation: experience of 204 patients from a single center. Haematologica 2020;105:765-773. Available at:https://www.ncbi.nlm.nih.gov/pubmed/31197071.

217. Al-Sawaf O, Robrecht S, Bahlo J,et al. Richter transformation in chronic lymphocytic leukemia(CLL)-a pooled analysis of German CLL 176. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32203141.

218. Elnair R, Ellithi M, Kallam A, et al. Outcomes of Richter's transformation of chronic lymphocytic leukemia/small lymphocytic lymphoma(CLL/SLL): an analysis of the SEER database. Ann Hematol 2021;100:2513-2519. Available at:https://www.ncbi.nlm.nih.gov/pubmed/34279675.

219. El Hussein S, Medeiros LJ, Lyapichev KA,et al. Immunophenotypic and genomic landscape of Richter transformation diffuse large B-cell lymphoma. Pathology 2023;55:514-524. Available at:

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220. Rossi D, Spina V, Cerri M, et al. Stereotyped B-cell receptor is an independent risk factor of chronic lymphocytic leukemia transformation to Richter syndrome. Clin Cancer Res 2009;15:4415-4422. Available at:https://www.ncbi.nlm.nih.gov/pubmed/19509140.

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222. Rossi D, Rasi S, Spina V, et al. Different impact of NOTCH1 and SF3B1 mutations on the risk of chronic lymphocytic leukemia transformation to Richter syndrome. Br J Haematol 2012;158:426-429.Available at:https://www.ncbi.nlm.nih.gov/pubmed/22571487.

223. Villamor N,Conde L, Martinez-Trillos A,et al.NOTCH1 mutations identify a genetic subgroup of chronic lymphocytic leukemia patients with high risk of transformation and poor outcome. Leukemia 2013;27:1100-1106.Available at:https://www.ncbi.nlm.nih.gov/pubmed/23295735.

224. Chigrinova E, Rinaldi A, Kwee I, et al. Two main genetic pathways lead to the transformation of chronic lymphocytic leukemia to Richter syndrome. Blood 2013;122:2673-2682. Available at:https://www.ncbi.nlm.nih.gov/pubmed/24004666.

225.Fabbri G, Khiabanian H, Holmes AB, et al. Genetic lesions associated with chronic lymphocytic leukemia transformation to Richter syndrome.J Exp Med 2013;210:2273-2288. Available at:https://www.ncbi.nlm.nih.gov/pubmed/224127483.

226. Rossi D, Spina V, Deambrogi C, et al. The genetics of Richter syndrome reveals disease heterogeneity and predicts survival after transformation. Blood 2011;117:3391-3401. Available at:https://www.ncbi.nlm.nih.gov/pubmed/21266718.

227. Parikh SA, Rabe KG, Call TG, et al. Diffuse large B-cell lymphoma(Richter syndrome) in patients with chronic lymphocytic leukaemia(CLL):a cohort study of newly diagnosed patients. Br J Haematol 2013;162:774-782. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23841899.

228. Visentin A, Bonaldi L, Rigolin GM, et al. The complex karyotype landscape in chronic lymphocytic leukemia allows the refinement of the risk of Richter syndrome transformation. Haematologica 2022;107:868-876. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34092056.

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229. Kadri S, Lee J, Fitzpatrick C, et al. Clonal evolution underlying leukemia progression and Richter transformation in patients with brirutinib-relapsed CLL. Blood Adv 2017;1:715-727. Available at:https://www.ncbi.nlm.nih.gov/pubmed/29296715.

230. Innocenti I, Rossi D, Trape G, et al. Clinical, pathological, and biological characterization of Richter syndrome developing after ibrinitb in treatment for relapsed chronic lymphocytic leukemia. Hematol Oncol 2018.Available at: https://www.ncbi.nlm.nih.gov/pubmed/29484684.

231. Anderson MA, Tam C, LewT, et al. Clinicopathological features and outcomes of progression of CLL on the BCL2 inhibitor venetoclax. Blood 2017;129:3362-3370. Available at:

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232. Kittai AS, Huang Y, Beckwith KA, et al. Patient characteristics that predict Richter's transformation in patients with chronic lymphocytic leukemia treated with ibrutinib. Am J Hematol 2023;98:56-65. Available at:https://www.ncbi.nlm.nih.gov/pubmed/36216791.

233. Gine E, Martinez A, Villamor N, et al. Expanded and highly active proliferation centers identify a histological subtype of chronic lymphocytic leukemia("accelerated" chronic lymphocytic leukemia) with aggressive clinical behavior. Haematologica 2010;95:1526-1533. Available at:https://www.ncbi.nlm.nih.gov/pubmed/20421272.

234. Ciccone M, Agostinelli C, Rigolin GM, et al. Proliferation centers in chronic lymphocytic leukemia: correlation with cytogenetic and clinicobiological features in consecutive patients analyzed on tissue microarrays. Leukemia 2012;26:499-508. Available at:https://www.ncbi.nlm.nih.gov/pubmed/21941366.

235. Agbay RL, Jain N, Loghavi S, et al. Histologic transformation of chronic lymphocytic leukemia/small lymphocytic lymphoma. Am J Hematol 2016;91:1036-1043. Available at:

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236. Bruzzi JF, Macapinlac H, Tsimberidou AM, et al. Detection of Richter's transformation of chronic lymphocytic leukemia by PET/CT. J

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237. 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.

238. 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.

239. Michallet AS, Sesques P, Rabe KG, et al. An 18F-FDG-PET maximum standardized uptake value> 10 represents a novel valid marker for discerning Richter's Syndrome. Leuk Lymphoma 2016;57:1474-1477.Available at:https://www.ncbi.nlm.nih.gov/pubmed/26402256.

240. Mato AR, Wierda WG, Davis MS, et al. Utility of positron emission tomography-computed tomography in patients with chronic lymphocytic leukemia following B-cell receptor pathway inhibitor therapy.

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243. Xiao W, Chen WW, Sorbara L, et al. Hodgkin lymphoma variant of Richter transformation: morphology, Epstein-Barr virus status, clonality,and survival analysis-with comparison to Hodgkin-like lesion. Hum Pathol

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244. 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.

245. 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.

246. Rogers KA, Huang Y, Ruppert AS, et al. A single-institution retrospective cohort study of first-line R-EPOCH chemimmunotherapy for Richter syndrome demonstrating complex chronic lymphocytic leukemiakemia karyotype as an adverse prognostic factor. Br J Haematol 2018;180:259-266. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29193006.

247. Dabaja BS, O'Brien SM, Kantarjian HM, et al. Fractionated cyclophosphamide, vincristine, liposomal daunorubicin (daunoXome), and examethasone(hyperCVXD) regimen in Richter's syndrome. Leuk Lymphoma 2001;42:329-337. Available at:https://www.ncbi.nlm.nih.gov/pubmed/11699397.

248.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 plus rituximab and GM-CSF in patients with Richter syndrome or fludarabine-refractory chronic lymphocytic leukemia. Cancer 2003;97:1711-1720. Available at:https://www.ncbi.nlm.nih.gov/pubmed/12655528.

249. Tsimberidou AM, Wierda WG, Plunkett W, et al. Phase I-Il study of oxaliplatin, fludarabine, cytarabine, and rituximab combination therapy in patients with Richter's syndrome or fludarabine-refractory chronic

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250. 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. Available at:https://www.ncbi.nlm.nih.gov/pubmed/23810245.

251. 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. Hematological Oncology 2023;41:466-468. Available at:

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252. 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:

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253. 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. Available at:https://www.ncbi.nlm.nih.gov/pubmed/30028000.

254.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. Available at:https://www.ncbi.nlm.nih.gov/pubmed/34735860.

255. 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:

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256. Jain N, Senapati, 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. Available at:https://www.ncbi.nlm.nih.gov/pubmed/36287248.

263. 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.

257. Al-Sawaf O, Ligtvoet R, Robrecht S, et al. Tislelizumab plus zanubrutinib for Richter transformation: the phase 2 RT1 trial. Nat Med 2024;30:240-248. Available at:https://www.ncbi.nlm.nih.gov/pubmed/38071379.

264. 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.

258. 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.Available at:https://ascopubs.org/doi/abs/10.1200/JCO.24.00033.

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259. Winter AM, Bharadwaj S, Herrera AF, et al. Real-world outcomes of lioscabatagene maraleucil(liso-cel) in patients(pt) with Richter transformation(RT) from the Center for International Blood and Marrow Transplant Research (CIBMTR). Journal of Clinical Oncology 2024;42:7010-7010. Available at:https://ascopus.org/doi/abs/10.1200/JCO.2024.42.16 suppl.7010.

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267. 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.

260. Cwynarski K, van Biezen A, de Wedele L, et al. Autologous and allogeneic stem-cell transplantation for transformed chronic lymphocytic leukemia(Richter's syndrome): A retrospective analysis from the chronic lymphocytic leukemia subcommittee of the chronic leukemia working party and lymphoma working party of the European Group for Blood and Marrow Transplantation. J Clin Oncol 2012;30:2211-2217. Available at:https://www.ncbi.nlm.nih.gov/pubmed/22547610.

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270. Tsai HT, Caporaso NE, Kyle RA, et al. Evidence of serum immunoglobulin abnormalities up to 9.8 years before diagnosis of chronic

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285. Ghez D, Calleja A, Protin C, et al. Early-onset invasive aspergillosis and other fungal infections in patients treated with brirutinib. Blood 2018;131:1955-1959. Available at:https://www.ncbi.nlm.nih.gov/pubmed/29437588.

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300. 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.

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表 1
Method of Detection	Prognostic Variable	Clinical Associationa
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	IGHVC' mutated:>2% 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 mutationd 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 mutationd 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)

表 2
Method of Detection	Prognostic Variable	Clinical Association${}^{a}$
CpG-stimulated metaphase karyotype	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 models30,31 ●Elevated levels9 are associated with overall response, treatment free intervals, and OS in patients treated with frontlinetherapy32 ●Reduction in levels associated with prolonged PFS in patients treated with ibrutinib33,34

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 WT ●May 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 WT ●Shorter OS in historical cohorts ●Correlated 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 cBTKi ●BTK L528 or T474 mutations have been detected in patients with disease progressing on cBTKi and noncovalent (reversible) BTKi (ncBTKi)
CARD1147	●Identified in patients with disease progressing on BTK inhibitors
PLCG227,44-47	●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 109/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
Staged	Involvement	Extranodal (E) Status
Limited
Stage I	One node or a group of adjacent nodes	Single extranodal lesions without nodal involvement
Stage II	Two or more nodal groups on the same side of the diaphragm	Stage I or ll by nodal extent with limited contiguous extranodal involvement
Stage II bulkye	Il as above with "bulky" disease	Not applicable
Advanced
Stage III	Nodes on both sides of the diaphragm	Not applicable
Nodes above the diaphragm spleen involvement
Stage IV	Additional non-contiguous extralymphatic involvement	Not applicable

表 8
Trial	First-line Therapy	Regimen
FLAIR	CLL/SLL without del(17p) or TP53 mutation	●Venetoclax/lbrutinib $(category$ 1; other recommended)
SEQUOIA (Arm D)I	CLL/SLL without del(17p) or TP53 mutation	●Venetoclax/Zanubrutinib $(category$ 2A; useful in certain circumstances)
SEQUOIA (Arm D)I	CLL/SLL with del(17p) or TP53 mutation	● Venetoclax/Zanubrutinib $(category$ 2A; preferred)
Phase II study ${ }^{m}$	CLL/SLL with del(17p) or TP53 mutation	● Venetoclax/Acalabrutinib + Obinutuzumab ${ }^{b}$ (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）+ Rituximab ●HyperCVAD（Cyclophosphamide/Vincristine/Doxorubicin/Dexamethasone）+ Rituximab alternating with Cytarabine/High-Dose Methotrexate ●OFA (Oxaliplatin/Fludarabine/Cytarabine) + Rituximab
●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）

表 10
NON-CIT BASED REGIMENS $^{d}$
ICI-based regimens$	BTKi (monotherapy)	Bispecific Antibody Therapy	CAR T-cell Therapy (CD19-directed; after at least 1 prior systemic therapy regimen) ${}^{1}$
● Venetoclax${}^{}$ Atezolizumab ${}^{}$ Acolarbrutin${}^{**}$ (category 2B)	- Pirtobrutinib ${}^{**}$ ● Acalbrutinib ${}^{+}$ (category 2B)	● Epcoritamab-bysp ● Glofitamab-gxbm	● Axicabtagene ciloleucel ● Lisocabtagene maraleucel ● Tisagenlecleucel
●Nivolumb${}^{t}$ + Islebrurinib ${}^{+}$

表 11
AIHA	autoimmune hemolytic anemia
ALC	absolute lymphocyte count
ANC	absolute neutrophil count
ASO-PCR	allele-specific oligonucleotide polymerase chain reaction
BCL2i	BCL2-inhibitor
BTKi	BTK inhibitor
C/A/P	chest/abdomen/pelvis
CAR	chimeric antigen receptor
CBC	complete blood count
cBTKi	covalent BTK inhibitor
CHL	classic Hodgkin lymphoma
CIT	chemoimmunotherapy
CK	complex karyotype
CMV	cytotegalovirus
CrCI	creatinine clearance
CRS	cytokine release syndrome
DAA	direct-acting antiviral
DLBCL	diffuse large B-cell lymphoma

表 12
HBcAb	hepatitis B core antibody
HBsAg	hepatitis B surface antigen
HBV	hepatitis B virus
HCT	hematopoietic cell transplant
HCV	hepatitis C virus
HLA	human leukocyte antigen
HR	hazard ratio	qPCR
HR	immunohistochemistry
ISRT	involved-site radiation therapy
ITP	immune thrombocytopenic purpura	RT-PCR
IVF	in vitro fertilization
IVIG	intravenous immunoglobulin
SCIG	SCIG	subcutaneous immunoglobulin
JSPE	SIFE	serum immunofixation electrophoresis
LVEF	left ventricular ejection fraction	SPEP
SUV	SUV	standardized uptake value

表 13
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 14
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 15
Overview
Guidelines Update Methodology		MS-2
Literature Search Criteria		●MS-2
Sensitive /Inclusive Language Usage		MS-2
Staging.		MS-3
Prognostic Factors	Discussion	MS-3
Response Criteria		MS-8
Minimal Residual Disease		MS-8
Workup		MS-11
First-Line Therapy		MS-12
Second-Line and Subsequent Therapy		MS-13
Special Considerations for the Use of Small-Molecule Inhibitors		MS-24
Histologic Transformation		MS-27
Supportive Care		MS-31
Summary.		MS-35
References		MS-43

表 16
Disease Setting	Trial	Regimen	No. of Patients	Patient Characteristics	Median Follow-up	Undetectable MRD (≤104, uMRD4)	Method used for MRD detection
Previously Untreated CLL/SLL	CLL1424 (Phase III)	Venetoclax + obinutuzumab (Veno)	216	≥65 years (CIRS>6; CrCl<70 mL/min)	65 months	EOT+2:75%(blood) (mL/min)	ASO-PCR; MRD-flow;NGS
Previously Untreated CLL/SLL	CLL1424 (Phase III)	Chlorambucil + obinutuzumab	216	≥65 years (CIRS>6; CrCl<70 mL/min)	65 months	EOT+2:33%(blood)	ASO-PCR; MRD-flow;NGS
Previously Untreated CLL/SLL	CAPTIVATE83 (Phase II; Time-limited cohort)	Venetoclax + ibrutinib	159	≤70 years; ECOG PS 0-1	28 months	EOT+3:77%(blood); 60(BM)	MRD-flow (8-color flow cytometry)
Previously Untreated CLL/SLL	CAPTIVATE84 (Phase II; MRD cohort)	Venetoclax + ibrutinib (3 cycles of lead-in ibrutinib followed by 12 cycles of ibrutinib + venetoclax)	164	≤70 years; ECOG PS 0-1 (Perandomization) ≤70 years; ECOG PS 0-1 <70 years; ECOG PS 0-1 (Randomization; 150 mRD not confirmed)	31 months	75%(blood); 68(BM)	MRD-flow (8-color flow cytometry)
Previously Untreated CLL/SLL	CAPTIVATE84 (Phase II; MRD cohort)	Venetoclax + ibrutinib	32	≤70 years; ECOG PS 0-1 (Randomization; 150 mRD not confirmed)	31 months	69%(blood); 66(BM)	MRD-flow (8-color flow cytometry)
Previously Untreated CLL/SLL	CAPTIVATE84 (Phase II; MRD cohort)	Ibrutinib	31	≤65 years or<65 years who also had CIRS>6 or CrCl<70 mL/min	31 months	34 months	MRD-flow (8-color flow cytometry)
Previously Untreated CLL/SLL	GLOW (Phase III)28	Venetoclax + ibrutinib	106	≥65 years or<65 years who also had CIRS>6 or CrCl<70 mL/min	34 months
Previously Untreated CLL/SLL	GLOW (Phase III)28	Chlorambucil + obinutuzumab	105	EOT+3:39%(blood); 17(BM/min
Previously Untreated CLL/SLL	GAIA/CLL1328 (Phase III)	Venetoclax + ibrutinib + obinutuzumab	231	≤65 years or>65 years [without del(17p) or TP53 mutation]	39 months	15 months:92%(blood); 78(BM)	MRD-flow (4-color flow cytometry)
Previously Untreated CLL/SLL	GAIA/CLL1328 (Phase III)	Veno	229	≤65 years or>65 years [without del(17p) or TP53 mutation]	39 months	15 months:87%(blood); 73(BM)	MRD-flow (4-color flow cytometry)
Previously Untreated CLL/SLL	GAIA/CLL1328 (Phase III)	Venetoclax + rituximab (VenR)	237	≤65 years or>65 years [without del(17p) or TP53 mutation]	39 months	15 months: 57%(blood); 43(BM)	MRD-flow (4-color flow cytometry)
Previously Untreated CLL/SLL	GAIA/CLL1328 (Phase III)	Chemoimmunotherapy (FCR ≤65 years; BR >65 years)	229	≤65 years or>65 years [without del(17p) or TP53 mutation]	39 months	15 months: 52%(blood); 37%(BM)	MRD-flow (4-color flow cytometry)
Previously Untreated CLL/SLL	AMPLIFY30	Venetoclax + acalabrutinib	291	Median age: 61 years [without del(17p) or TP53 mutation])	41 months	EOT:45%(blood); EOT+3:38%(blood)	NGS; MRD-flow
Previously Untreated CLL/SLL	AMPLIFY30	VenO + acalabrutinib	286	Median age: 61 years [without del(17p) or TP53 mutation])	41 months		NGS; MRD-flow
Previously Untreated CLL/SLL	AMPLIFY30	FCR or Bendamustine + rituximab (BR)	290	Median age: 61 years [without del(17p) or TP53 mutation])	41 months		NGS; MRD-flow
Previously Untreated CLL/SLL	Relapsed or Refractory CLL/SLL	MURANO (Phase III)91	VenR	194	≥18 years; ECOG PS 0-1; adequate bone marrow, liver, and kidney function	36 months	62%(blood)
BR	Relapsed or Refractory CLL/SLL	MURANO (Phase III)91	195	13%(blood)	≥18 years; ECOG PS 0-1; adequate bone marrow, liver, and kidney function	36 months
CLARITY94 (Phase II)	Relapsed or Refractory CLL/SLL	Ibrutinib + venetoclax	53	Median age: 64 years ECOG PS 0-2	21 months	53%(blood); 36%(BM)	MRD-flow

表 17
Trial	Regimen	No. of Patients	Patient Characteristics	Median Follow-up	ORR	PFS	OS
ELEVATE-TN19,120	Acalabrutinib	179 [del(17p) and/or mutated TP53, n = 23]	≥65 years or <65 years with comorbidities (CRIS > 6; CrCl < 70 mL/min); ECOG PS of s2 and adequate hemologic, hepatic, and renal function	75 months	90%(11% CR)	Median: Not reached (72-month:62%)	Median: Not reached (72-month: 76%)
ELEVATE-TN19,120	Acalabrutinib + obinutuzumab	179 [del(17p) and/or mutated TP53, n = 25]	≥65 years or <65 years with comorbidities (CRIS > 6; CrCl < 70 mL/min); ECOG PS of s2 and adequate hemologic, hepatic, and renal function	75 months	96%(31% CR)	Median: Not reached (72-month: 78%)	Median: Not reached (72-month: 84%)
ELEVATE-TN19,120	Chlorambucil + obinutuzumab	177 [del(17p) and/or mutated TP53, n = 25]	≥65 years or <65 years with comorbidities (CRIS > 6; CrCl < 70 mL/min); ECOG PS of s2 and adequate hemologic, hepatic, and renal function	75 months	83%	Median: 28 months (72-month: 17%)	Median: Not reached (72-month: 75%)
RESONATE-218	lbrutinib	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)38	lbrutinib + rituximab	182	≥65 years ≥65 years [without del(17p)]	55 months	93% (7% CR)	4-year: 76%	4-year: 85%
Alliance North American Intergroup (A041202)38	lbrutinib + rituximab	182	≥65 years ≥65 years [without del(17p)]	55 months	94% (12% CR)	4-year: 76%	4-year: 86%
Alliance North American Intergroup (A041202)38	Bendamustine + rituximab(BR)	183	≥65 years ≥65 years [without del(17p)]	55 months	81% (26% CR)	4-year: 47%	4-year: 84%
E1912 study21	lbrutinib + rituximab	354	≤70 years	70 months	96% (17% CR)	5-year: 78%	5-year: 95%
E1912 study21	FCR	175	≤70 years	70 months	81% (30% CR)	5-year: 51%	5-year: 89%
SEQUOI A [without del(17p)] ${}^{20}$	Zanubrutinib	241 (mutated TP53, n = 15)	≥65 years of age OR unsuitable for treatment with FCR (CIRS > 6; CrCl <70 mL/min or a history of severe/multiple infections within 2 years); median age 70 years	27 months	95% (7% CR)	Median: Not reached (24-month: 86%; P < .0001)	Median: Not reached (24-month: 94%)
SEQUOI A [without del(17p)] ${}^{20}$	BR	238 (mutated TP53, n = 13)	≥65 years of age OR unsuitable for treatment with FCR (CIRS > 6; CrCl <70 mL/min or a history of severe/multiple infections within 2 years); median age 70 years	27 months	85% (15% CR)	Median: Not reached (24-month: 70%)	Median: Not reached (24-month: 95%)
SEQUOI A [with del(17p)] ${}^{20}$	Zanubrutinib (Non-randomized cohort)	111	≥65 years of age OR unsuitable for treatment with FCR (CIRS > 6; CrCl <70 mL/min or a history of severe/multiple infections within 2 years); median age 70 years	27 months	31 months	90% (3% CR)	Median: Not reached (24-month: 89%)
AMPLIFY30	Venetoclax + acalabrutinib	291	Median age: 61 years [without del(17p) or TP53 mutation])	41 months	93%	36-month: 77%	36-month: 94%
AMPLIFY30	VenO+ acalrabutinib	286	Median age: 61 years [without del(17p) or TP53 mutation])	41 months	93%	36-month: 83%	36-month: 88%
AMPLIFY30	FCR or Bendamustine + rituximab (BR)	290	Median age: 61 years [without del(17p) or TP53 mutation])	41 months	75%	36-month: 67%	36-month: 86%
CLL1424,25	Venetoclax + obinutuzumab (VenO)	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)	6-year:53% (P<.0001)	6-year:79%
CLL1424,25	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)	6-year:22%	6-year: 69%
CLL1424,25	GLOW (Phase III)28,29	Venetoclax + ibrutinib	≥65 years with comorbidities (CIRS >6 ; CrCl <70 mL/min)	76 months	106 (mutated TP53, n=7)	≥65 years or <65 years who also had CIRS >6 or CrCl <70 mL/min	64 months
GAIA/CLL1328,27	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/CLL1328,27	Veno	229	≤65 years or >65 years [without del(17p) or TP53 mutation]	51 months	96% (57% CR)	4-year: 82%	4-year:95%
GAIA/CLL1328,27	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%
Chemoimmunotherapy (FCR ≤65 years; BR >65 years)	229	81%	≤65 years or >65 years [without del(17p) or TP53 mutation]	51 months	4-year: 62%	4-year: 94%
FLAIR87,88	Venetoclax + ibrutinib	260	≤65 years or >65 years [without del(17p) or TP53 mutation]	51 months	Median age 62 years (>65 years, 31%) [without del(17p)]	44 months	87%
FLAIR87,88	FCR	263	76%	3-year: 77% 4-year: 65%	Median age 62 years (>65 years, 31%) [without del(17p)]	44 months	3-year: 93% 4-year: 87%
ASCEND151	Acarabutinib	155 [del(17p),n=28; mutated TP53, n=39]	Median age 67-68 years with ECOG PS≤2 and adequate hematologic, hepatic, and renal function	47 months	83%	Median: Not reached 42-month:62% (HR,0.28;P<.0001)	Median: Not reached 42-month:78%
ASCEND151	Idelalisib+ rituximab (IdR) or Bendamustine+ rituximab(BR)	155 [IdR, n=119; BR,n=36]; [del(17p),n=21; mutated TP53, n=34]	Median age 67-68 years with ECOG PS≤2 and adequate hematologic, hepatic, and renal function	47 months	84%	Median: 17 months 42-month: 23%	Median: Not reached 42-month: 65%
ASCEND151	ELEVATE-RR121	Acaalbrutinib	Median age 67-68 years with ECOG PS≤2 and adequate hematologic, hepatic, and renal function	47 months	268	≥18 years;ECOG PS ≤2 and the presence of del(17p) and/or del(11q)	41 months
Ibrutinib	ELEVATE-RR121	265	77% (4% CR)			≥18 years;ECOG PS ≤2 and the presence of del(17p) and/or del(11q)	41 months
RESONATE152	Ibrutinib	195 [del(17p),n=63; mutated TP53,n=79]	Median age 67 years	74 months	91% (11% CR)	Median: 44 months 60-month: 40%	Median: 68 months
RESONATE152	Ofatumumab	196 [del(17p),n= 64; mutated TP53, n=68]	Median age 67 years	74 months	-	Median: 8 months 60-month: 3%	Median: 65 months
ALPINE153	Zanubrutinib	327 [del(17p) and/or mutated TP53, n= 41]	Median age 67 years; ECOG PS ≤ 1; relapsed or refractory disease after ≥1 prior systemic therapy	42.5 months	86% (12% CR)	36-month: 65% (HR,0.67;P=.002)	36-month: 83%
ALPINE153	Ibrutinib	325 [del(17p) and/or mutated TP53, n=38]	Median age 67 years; ECOG PS ≤ 1; relapsed or refractory disease after ≥1 prior systemic therapy	42.5 months	75% (8% CR)	36-month: 54%	36-month: 80%
MURANO91,92	Venetoclax + rituximab (VenR)	194 [del(17p),n=46; mutated TP53,n=48]	≥18 years;ECOG PS ; ECOG PS 0-1; relapsed or refractory disease 1; relapsed or refractory disease after ≥1 prior systemic therapy (8% CR)	59 months	92% (8% CR)	Median: 54 months (HR,0.19;P<.0001)	5-year: 82% (HR,0.40;P<.0001)
MURANO91,92	BR	195 [del(17p),n=46; mutated TP53,n=51]	≥18 years;ECOG PS ; ECOG PS 0-1; relapsed or refractory disease 1; relapsed or refractory disease after ≥1 prior systemic therapy (8% CR)	59 months	72% (4% CR)	Median: 17 months	5-year: 62%

表 20
Adverse Events	Treatment-Naive CLL	Treatment-Naive CLL	Treatment-Naive CLL	Treatment-Naive CLL	Relapsed or refractory CLL
Adverse Events	ELEVATE-TN19	RESONATE-218	SEQUOIA20	ELEVATE-RR121	ELEVATE-RR121	ALPINE153	ALPINE153	BRUIN155,157
Adverse Events	Acalabrutinib	lbrutinib	Zanubrutinib	Acalabrutinib	lbrutinib	Zanubrutinib	lbrutinib	Pirtobrutinib
Most common adverse events(AEs; all grades)	Acalabrutinib
Diarrhea	40%	50%	14%	35%	46%	19%	26%	16%*
Headache	38%	-	11%	35%	20%	NR	NR	17%
Cough	22%	36%	11%	29%	21%	NR	NR	24%
Fatigue	22%	36%	11%	20%	17%	11%	15%	32%
Arthralgia	20%	26%	14%	16%	23%	17%	19%	-
Anemia	-	26%	4%	22%	19%	17%	19%	21%*
Neutropenia	12%	13%(Grade ≥3)	16%	21%	25%	32%	30%	16%*
Adverse events of special interest (AESI)
Atrial fibrillation/Flutter
Any grade	Any grade	6%	16%	3%	9%	16%	7%	17%
Grade ≥3	Grade ≥3	1%	5%	<1%	5%	3%	3%	5%
Bleeding	Bleeding	Bleeding	Bleeding	Bleeding	Bleeding	Bleeding	Bleeding	Bleeding
Any grade	Any grade	42%	NR	45%	38%	51%	20%	22%
Grade ≥3	Grade ≥3	3%	NR	4%	-	-	-	1%
Major bleeding	Major bleeding
Any grade	Any grade	4%	11%	5%	-	-	-	21%
Grade≥3	Grade≥3	3%	7%	4%	-	-	-	1%
Hypertension	Hypertension
Any grade	Any grade	7%	23%	14%	9%	23%	27%	25%
Grade ≥3	Grade ≥3	3%	8%	6%	4%	9%	17%*	16%*
Infections	Infections	Infections	Infections	Infections	Infections	Infections
Any grade	74%	26%	62%	-	-	29%*	20%*	71%
Grade ≥3	16%	-	16%	-	-	2%	1%	4%

表 21
Adverse Events (All Grades)	Treatment-Naive CLL	Treatment-Naive CLL	Treatment-Naive CLL	Treatment-Naive CLL	Relapsed or refractory CLL
Adverse Events (All Grades)	CLL1411	GAIA/CLL1328	AMPLIFY30	AMPLIFY30	MURANO137	M13-982146
Adverse Events (All Grades)	VenO	VenO	avalabrutinib	Venotoclax+ acalabrutinib	VenR	Venetoclax
Thrombocytopenia	24%	18%	5%	9%	13%	23%
Anemia	17%	8%	5%	7%	16%	27%
Infusion-related reaction	45%	51%	20%	0%	8%	NR
Diarrhea	28%	33%	36%	33%	40%	44%
Nausea	19%	NR	22%	15%	22%	38%
Constipation	13%	NR	8%	7%	14%	13%
Pyrexia	23%	24%	16%	6%	15%	19%
Fatigue	15%	NR	14%	15%	18%	27%
Cough	16%	NR	-	-	18%	19%
Headache	11%	NR	28%	35%	11%	18%

表 22
Regimen	No. of Patients	Median Follow-up	ORR	Median PFS	OS
RCHOP245	15	69 months	67%(7% CR)	10 months	Median: 21 months
REPOCH246	46	39 months	39%	4 months	Median: 6 months
R-hyper-CVAD248	30	8 months	43%(27% CR)	一	1-year:28%
OFAR249	20	9 months	50%	一	6-month: 53%
Modified OFAR250	35	26 months	39%(7% CR)	一	Median: 7 months 2-year: 20%
Venetoclax + RCHOP251	26	6 months	68%(48% CR)	7 months	Median: 20 months

图示：#######SLL (Lugano Stages II-IV)^k ######Lengano Stages II-IV)^k #######IF I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I

图示：FIRST-LINE THERAPYr,s THIRD-LINE THERAPYr,s,v,z,aa Suggested Regimens (CSLL-D 2 of 6) Time-limited treatment BCL2i intolerancev BCLTi Response after completion of treatment cBTKi or cregimens cBTKi Suggested Regimens (CSLL-D 1 of 6) Relapsed or Refractory disease after prior therapy with cBTKi-or nbcTki-based BCL2i-containing regimens CBSLL-5A or nbcTki Calventv CBTKi BCL2 inhibitor (BCL2i) + anti-CD20 mAb See Suggested Regimens (CSLL-D 1 of 6) BCL2 inhibitor (BCL2i) + anti-CD20 mAb See Suggested Regimens (CSLL-D 1 of 6) Response after completion of treatment BCKTi NoRevalent cBTKi CBTKi BCL2i intolerance Observe until relapse with indication for treatment cBTKi THERAPYr,s,v,z,aa Suggested Regimens (CSLL-D 2 of 6) Time-limited treatment Relapsed or Refractory disease after prior therapy with cBTKi-or nbcTki and BCL2i-containing regimens are options for relapse after a period of remission or progression on treatment. See CSLL-D 2 of 6 for suggested regimens CSLL-5A THERAPYr,s,v,z,aa S S S Conderent.1.2026,10/10/25 © 2025 National Comprehensive Cancer Network (NCCN).All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.

图示：FIRST-LINE THERAPYr,s RESPONSE TO STHERAPYr,s,v,z,aa,bb THERAPYr,s,v,z,aa,bb Suggested Regimens (CSLL-D 2 of 6)

图示：Continuous treatment Covalt BTK inhibitor\(cBTKi-based regimens) anti-CD20 mAb See Suggested Regimens Response Introduction LololeranceV BCL2i-containing or BCL2i-containing regimens ncBTKi Progression while on treatment ${w},{x},{y}$ BCL2i-containing regimens or ncBTKi ncBTKi

图示：CLINICAL PRESENTATION TREATMENT RESP Complete response Observation Clonally unrelated Clinical trial or or CIT regimens (HT-A) Partial response or Refractory disease or progression while on treatment TREATMENTJ Complete response Observation Clinical trial or CIT regimens (HT-A) Partial response or Refractory disease or progression while on treatment Not 4

图示：CLINICAL PRESENTATION TREATMENT RESPSESSMENT Case Recognition or or on CIT regimens (other or on CIT regimens (HT-A) or CIT regimens (HT-A) Complete response Partial response Reforcement on CIT R�1 TCL-It therapy (HT-A) (if eligible, after at least 1 prior systemic therapy regimen) or Non-CIT regimens (other than CAR T-cell therapy)→If CR, consider allogeneic HCT n (not previously used)→(HT-A) Infrared therapy (HT-A) or Progression while on treatment RFactory disease or treatment with non-CIT regimens (other other modimens therapy) AC DIT response 6333 ADDITIONAL THERAPYj Observation or or on CIT regimens (not previously used)→(HT-A) If CR, consider allogeneic HCTn (not previously used)→(HT-A) ·Continue the same non-CIT regimen until or progression or switch to an alternate non-CIT regimen (HT-A) 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)

引用 / 出处

（2026.V1）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.