Cases from the Community: Investigators Discuss the Optimal Management of Chronic Lymphocytic Leukemia — Symposium Proceedings

Faculty

TARGET AUDIENCE  

This activity is intended for medical oncologists, hematologists, hematology-oncology fellows, radiation oncologists, surgeons and other allied healthcare professionals involved in the treatment of chronic lymphocytic leukemia (CLL).  

LEARNING OBJECTIVES  

• Individualize the selection of systemic therapy for patients with newly diagnosed CLL, considering new research findings, clinical presentation, biomarker profile, coexisting medical conditions and patient preferences. 
• Review the similarities and differences between covalent and noncovalent Bruton tyrosine kinase (BTK) inhibitors, and assess the implications for the efficacy and tolerability of these agents. 
• Evaluate available and emerging Phase III data demonstrating the efficacy of BTK inhibitors as first-line therapy for CLL, and use this information to counsel patients regarding front-line treatment options. 
• Understand published research findings with Bcl-2 inhibitors in combination with anti-CD20 antibodies as first-line treatment for CLL, and counsel patients regarding the risks and benefits of this novel treatment strategy. 
• Appreciate the scientific rationale for the investigation of combined BTK and Bcl-2 inhibition, and review recently presented data and the potential role of this strategy for patients with newly diagnosed CLL. 
• Discuss available clinical research findings demonstrating the efficacy and safety of noncovalent BTK inhibitors for newly diagnosed and relapsed/refractory CLL, and identify patients appropriate for these agents. 
• Evaluate the biological rationale for the investigation of CD19-directed chimeric antigen receptor T-cell therapy for CLL, and identify patients for whom treatment with this novel therapeutic strategy would be appropriate. 
• Recall available data with novel agents and combination strategies currently under investigation for CLL, and as applicable discuss clinical trial participation with eligible patients. 

ACCREDITATION STATEMENT  
Research To Practice is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.  

CREDIT DESIGNATION STATEMENT  
Research To Practice designates this enduring material for a maximum of 2.25 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.  

AMERICAN BOARD OF INTERNAL MEDICINE (ABIM) — MAINTENANCE OF CERTIFICATION (MOC)   
Successful completion of this CME activity, which includes participation in the evaluation component and a post-test, enables the participant to earn up to 2.25 Medical Knowledge MOC points in the American Board of Internal Medicine’s (ABIM) Maintenance of Certification (MOC) program. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider’s responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit.  

Please note, this program has been specifically designed for the following ABIM specialties: medical oncology and hematology.  

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HOW TO USE THIS CME ACTIVITY  
To receive credit for this activity, the participant should review the CME information, watch the video, complete the post-test with a score of 80% or better and fill out the evaluation. 

CONTENT VALIDATION AND DISCLOSURES  
Research To Practice (RTP) is committed to providing its participants with high-quality, unbiased and state-of-the-art education and adheres to the ACCME’s Standards for Integrity and Independence in Accredited Continuing Education. Any individuals in a position to control the content of an accredited continuing education activity, including faculty, planners, reviewers and others, are required to disclose all relevant financial relationships with ineligible entities (commercial interests). All relevant financial relationships have been mitigated prior to the commencement of this activity. In addition, all activity content is reviewed by RTP scientific staff and an external, independent physician reviewer for fair balance, scientific objectivity of studies referenced and patient care recommendations.   

FACULTY — The following faculty reported relevant financial relationships with ineligible entities:  

Dr Allan — Advisory Committees: NeoGenomics; Consulting Agreements: AbbVie Inc, Adaptive Biotechnologies Corporation, ADC Therapeutics, AstraZeneca Pharmaceuticals LP, BeOne, Genentech, a member of the Roche Group, Janssen Biotech Inc, Lilly, Pharmacyclics LLC, an AbbVie Company; Contracted Research: Adaptive Biotechnologies Corporation, BeOne, Bristol Myers Squibb, Genentech, a member of the Roche Group; Data and Safety Monitoring Boards/Committees: Merck; Speakers Bureaus: AbbVie Inc, BeOne. Dr Fakhri — Advisory Committees: AbbVie Inc, AstraZeneca Pharmaceuticals LP, Genentech, a member of the Roche Group, Pharmacyclics LLC, an AbbVie Company; Contracted Research: AbbVie Inc, BeOne, Genmab US Inc, Loxo Oncology Inc, a wholly owned subsidiary of Eli Lilly & Company. Dr Ma — Advisory Committees: AbbVie Inc, AstraZeneca Pharmaceuticals LP, BeOne, Bristol Myers Squibb, Genentech, a member of the Roche Group, Lilly; Consulting Agreements: AbbVie Inc; Contracted Research: AbbVie Inc, AstraZeneca Pharmaceuticals LP, BeOne, Carna Biosciences, Juno Therapeutics, a Celgene Company, Loxo Oncology Inc, a wholly owned subsidiary of Eli Lilly & Company, Nurix Therapeutics Inc; Speakers Bureaus: AstraZeneca Pharmaceuticals LP, BeOne, Lilly. Dr Shadman — Advisory Committees and Consulting Agreements: AbbVie Inc, ADC Therapeutics, Ascentage Pharma, AstraZeneca Pharmaceuticals LP, BeOne, Bristol Myers Squibb, Fate Therapeutics, Genentech, a member of the Roche Group, Genmab US Inc, Incyte Corporation, Janssen Biotech Inc, Kite, A Gilead Company, Lilly, Merck, MorphoSys, Nurix Therapeutics Inc, Pfizer Inc, Pierre Fabre; Contracted Research: AstraZeneca Pharmaceuticals LP, BeOne, Genentech, a member of the Roche Group, Genmab US Inc, Incyte Corporation, Janssen Biotech Inc, Merck, MorphoSys, Nurix Therapeutics Inc, Sana Biotechnology; Stock Options — Private Companies: Koi Biotherapeutics Inc; Nonrelevant Financial Relationships: Bristol Myers Squibb (spouse employment). 

MODERATOR — Dr Abramson — Consulting Agreements: AbbVie Inc, ADC Therapeutics, AstraZeneca Pharmaceuticals LP, BeOne, Bristol Myers Squibb, Celgene Corporation, Foresight Diagnostics, a wholly-owned subsidiary of Natera Inc, Genentech, a member of the Roche Group, Gilead Sciences Inc, Interius BioTherapeutics, Miltenyi Biotec, Novartis, Roche Laboratories Inc, Seagen Inc; Contracted Research: Bristol Myers Squibb, Celgene Corporation, Cellectis, Genentech, a member of the Roche Group, Merck, Mustang Bio, Regeneron Pharmaceuticals Inc, Seagen Inc, Takeda Pharmaceuticals USA Inc. 

EDITOR — Dr Love is president and CEO of Research To Practice. Research To Practice receives funds in the form of educational grants to develop CME activities from the following companies: Aadi Bioscience, AbbVie Inc, ADC Therapeutics, Agendia Inc, Alexion Pharmaceuticals, Amgen Inc, Array BioPharma Inc, a subsidiary of Pfizer Inc, Arvinas, Astellas, AstraZeneca Pharmaceuticals LP, Aveo Pharmaceuticals, Bayer HealthCare Pharmaceuticals, BeOne, Biotheranostics Inc, A Hologic Company, Black Diamond Therapeutics Inc, Blueprint Medicines, Boehringer Ingelheim Pharmaceuticals Inc, Bristol Myers Squibb, Catalyst Pharmaceuticals Inc, Celcuity, Clovis Oncology, Coherus BioSciences, Corcept Therapeutics Inc, CTI BioPharma, a Sobi Company, Daiichi Sankyo Inc, Eisai Inc, Elevation Oncology Inc, Exact Sciences Corporation, Exelixis Inc, Genentech, a member of the Roche Group, Genmab US Inc, Geron Corporation, Gilead Sciences Inc, GSK, Helsinn Therapeutics (US) Inc, ImmunoGen Inc, Incyte Corporation, Ipsen Biopharmaceuticals Inc, Jazz Pharmaceuticals Inc, Johnson & Johnson, Karyopharm Therapeutics, Kite, A Gilead Company, Kura Oncology, Legend Biotech, Lilly, MEI Pharma Inc, Merck, Mersana Therapeutics Inc, Mirati Therapeutics Inc, Mural Oncology Inc, Natera Inc, Novartis, Novartis Pharmaceuticals Corporation on behalf of Advanced Accelerator Applications, Novocure Inc, Nuvalent, Nuvation Bio Inc, Pfizer Inc, Pharmacyclics LLC, an AbbVie Company, Puma Biotechnology Inc, Regeneron Pharmaceuticals Inc, Revolution Medicines Inc, Rigel Pharmaceuticals Inc, R-Pharm US, Sanofi, Seagen Inc, Servier Pharmaceuticals LLC, SpringWorks Therapeutics Inc, Stemline Therapeutics Inc, Sumitomo Pharma America, Summit Therapeutics, Syndax Pharmaceuticals, Taiho Oncology Inc, Takeda Pharmaceuticals USA Inc, TerSera Therapeutics LLC, Tesaro, A GSK Company, and Verastem Inc. 

RESEARCH TO PRACTICE CME PLANNING COMMITTEE MEMBERS, STAFF AND REVIEWERS — Planners, scientific staff and independent reviewers for Research To Practice have no relevant financial relationships to disclose.  

This educational activity contains discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. Research To Practice does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors.  

This activity is supported by educational grants from AstraZeneca Pharmaceuticals LP and Lilly.  

Release date: July 2026  
Expiration date: July 2027   

After completing the post-test, learners may download and review the answers here in order to identify further areas of study.  

Dr Fakhri 

Brown JR et al. Acquired mutations in patients (Pts) with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) that progressed in the ALPINE study. ASH 2023;Abstract 1890.

Burger JA et al. Final analysis of the RESONATE-2 study: Up to 10 years of follow-up of first-line ibrutinib treatment for CLL/SLL. Blood 2025;146(18):2168-76. Abstract

Byrd JC et al. Acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia: Results of the first randomized phase III trial. J Clin Oncol 2021;39(31):3441-52. Abstract

Constantine T et al. Sustained efficacy of zanubrutinib (zanu) vs bendamustine + rituximab (BR) in treatment (tx)-naive chronic lymphocytic leukemia/small lymphocytic lymphoma (TN SLL/CLL) and continued favorable survival in non-randomized patients (pts) with del(17p): 6-year follow-up in the phase 3 SEQUOIA study. ASH 2025;Abstract 2129.

Jurczak W et al. Pirtobrutinib vs bendamustine plus rituximab (BR) in patients with CLL/SLL: First results from a randomized phase III study Examining a non-covalent BTK inhibitor in untreated patients. ASH 2025;Abstract LBA-3.

Seymour JF et al. Detailed safety profile of acalabrutinib vs ibrutinib in previously treated chronic lymphocytic leukemia in the ELEVATE-RR trial. Blood 2023;142(8):687-99. Abstract 

Sharman JP et al. Acalabrutinib-obinutuzumab improves survival vs chemoimmunotherapy in treatment-naive CLL in the 6-year follow-up of ELEVATE-TN. Blood 2025;146(11):1276-85. Abstract

Woyach JA et al. Pirtobrutinib versus ibrutinib in treatment-naïve and relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma. J Clin Oncol 2026;44(6):476-85. Abstract

Woyach JA et al. BRUIN CLL-314: A phase III open-label, randomized study of pirtobrutinib (LOXO-305) versus ibrutinib in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma. Blood 2022;140:12427-8. Abstract

Dr Allan

Al-Sawaf O et al. Fixed-duration versus continuous treatment for chronic lymphocytic leukemia. N Engl J Med 2026;394(11):1084-96. Abstract

Al-Sawaf O et al. Venetoclax-obinutuzumab for previously untreated chronic lymphocytic leukemia: 6-year results of the randomized phase 3 CLL14 study. Blood 2024 Oct 31;144(18):1924-35. Abstract

Brown JR et al. Fixed-duration acalabrutinib combinations in untreated chronic lymphocytic leukemia. N Engl J Med 2025;392(8):748-62. Abstract

Brown JR et al. Fixed-duration acalabrutinib plus venetoclax with or without obinutuzumab versus chemoimmunotherapy for first-line treatment of chronic lymphocytic leukemia: Interim analysis of the multicenter, open-label, randomized, phase 3 AMPLIFY trial. ASH 2024;Abstract 1009.

Shadman M et al. Combination of zanubrutinib (zanu) + venetoclax (ven) for treatment-naive (TN) CLL/SLL: Results in SEQUOIA arm D. ASCO 2025;Abstract 7009.

Shadman M et al. Zanubrutinib + venetoclax for treatment-naive chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), including patients with del(17p) and/or TP53 mutation and unmutated immunoglobulin heavy-chain variable status: 3-year results from SEQUOIA arm D. ASH 2025;Abstract 5669.

Visentin A, Mauro FR. Lights and shades of front-line treatment with covalent BTK inhibitors combined with venetoclax in patients with chronic lymphocytic leukemia. Oncol Rev 2025;19:1703228. Abstract

Dr Ma

Anderson MA et al. Venetoclax initiation in chronic lymphocytic leukemia: International insights and innovative approaches for optimal patient care. Cancers (Basel) 2024;16(5):980. Abstract

Awan FT et al. International consensus statement on the management of cardiovascular risk of Bruton’s tyrosine kinase inhibitors in CLL. Blood Adv 2022;6(18):5516-25. Abstract

Barr PM et al. Up to 8-year follow-up from RESONATE-2: First-line ibrutinib treatment for patients with chronic lymphocytic leukemia. Blood Adv 2022;6(11):3440-50. Abstract

Brown JR et al. Sustained benefit of zanubrutinib vs ibrutinib in patients with R/R CLL/SLL: Final comparative analysis of ALPINE. Blood 2024;144(26):2706-17. Abstract

Byrd JC et al. Acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia: Results of the first randomized phase III trial. J Clin Oncol 2021;39(31):3441-52. Abstract

Cheson BD et al. Tumor lysis syndrome in chronic lymphocytic leukemia with novel targeted agents. Oncologist 2017;22(11):1283-91. Abstract

Davids M et al. Preliminary results of the ongoing multicenter, phase 2 study of retreatment with venetoclax plus obinutuzumab (REVENG) in patients with recurrent chronic lymphocytic leukemia (CLL). EHA 2025;Abstract PF575.

Galitzia A et al. Chronic lymphocytic leukemia: Management of adverse events in the era of targeted agents. Cancers (Basel) 2024;16(11):1996. Abstract

Ganatra S et al. Diagnosis and management of cardiovascular adverse effects of targeted oncology therapies: Bruton’s tyrosine kinase, immune checkpoint, and vascular endothelial growth factor inhibitors: 2025 ACC Concise Clinical Guidance: A report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol 2026;87(5):654-82. Abstract

Hillmen P et al. First results of a head-to-head trial of acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia. EHA 2021;Abstract S145.

Jurczak W et al. Long-term safety with ≥12 months of pirtobrutinib in relapsed/refractory (R/R) B-cell malignancies. EHA 2023;Abstract P618.

Munir T et al. Practical management of cardiovascular adverse events with BTKi treatment in patients with chronic lymphocytic leukemia: A consensus report by hematologists and cardiologists. Acta Haematol 2026;149(3):297-312. Abstract

Seymour JF et al. Venetoclax-rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med 2018;378(12):1107-20. Abstract

Tam CS. Upfront therapy: The case for continuous treatment. Hematology Am Soc Hematol Educ Program 2021;2021(1):55-8. Abstract

Thompson PA, Tam CS. Pirtobrutinib: A new hope for patients with BTK inhibitor-refractory lymphoproliferative disorders. Blood 2023;141(26):3137-42. Abstract

Dr Shadman

Al-Sawaf O et al. A phase 3, randomized, open-label, multicenter study of sonrotoclax (BGB-11417) plus anti-CD20 antibody therapies vs venetoclax plus rituximab in patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL-RR1/CELESTIAL-RRCLL). ASH 2025;Abstract 2137.

Brown JR et al. Zanubrutinib or ibrutinib in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med 2023;388(4):319-32. Abstract

Byrd JC et al. Acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia: Results of the first randomized phase III trial. J Clin Oncol 2021;39(31):3441-52. Abstract

Castonguay M et al. Venetoclax retreatment in chronic lymphocytic leukemia is biologically rational and clinically effective. Blood Adv 2026;10(10):3357-66. Abstract

Eyre T et al. Pirtobrutinib outcomes in second-line (2L) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) after first-line (1L) cBTKi therapy: A pooled analysis from the BRUIN LOXO-BTK-18001 and BRUIN CLL-321 studies. ASH 2025;Abstract 5670.

Ghosh N et al. Treatment effectiveness of venetoclax-based therapy after Bruton tyrosine kinase inhibitors in chronic lymphocytic leukemia: An international real-world study. Am J Hematol 2025;100(3):511-5.
Abstract 

Kater AP et al. The MURANO study: Final analysis and retreatment/crossover substudy results of VenR for patients with relapsed/refractory CLL. Blood 2025;145(23):2733-45. Abstract 

Lavie D et al. BELLWAVE-010: An open-label, phase 3 study of nemtabrutinib plus venetoclax in relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma. International Workshop on CLL 2025;Abstract 1510.

Shadman M, Davids DS. How I treat patients with CLL after prior treatment with a covalent BTK inhibitor and a BCL-2 inhibitor. Blood 2025;146(17):2029-36. Abstract

Sharman JP et al. Phase III trial of pirtobrutinib versus idelalisib/rituximab or bendamustine/rituximab in covalent Bruton tyrosine kinase inhibitor–pretreated chronic lymphocytic leukemia/small lymphocytic lymphoma (BRUIN CLL-321). J Clin Oncol 2025;43(22):2538-49. Abstract

Wierda W et al. Pirtobrutinib in post-cbtki CLL/SLL: Final update from the Phase 1/2 BRUIN study with more than 5 years follow-up. ASH 2025;Abstract 2115.

Woyach JA 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. ASH 2023;Abstract 325.

Dr Abramson

Ahn I et al. Updated efficacy and safety results of the Bruton tyrosine kinase (BTK) degrader BGB-16673 in patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) from the ongoing phase 1 CaDAnCe-101 study. ASH 2025;Abstract 85.

Danilov A et al. Epcoritamab monotherapy in patients (Pts) with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL): Results from CLL expansion and optimization cohorts of Epcore CLL-1. ASH 2024;Absract 883.

Hoffmann M et al. MRD-guided therapy of sonrotoclax (BGB-11417) + obinutuzumab (O) in patients with treatment-naive CLL: Initial results from an ongoing phase 1/1b study, BGB-11417-101. ASH 2025;Abstract 793.

Kater AP et al. Epcoritamab monotherapy for Richter transformation (EPCORE CLL-1): Findings from a single-arm, multicentre, open-label, phase 1b/2 trial. Lancet Haematol 2026;13(1):e8-21. Abstract

Omer Z et al. Bexobrutideg (NX-5948), a novel Bruton’s tyrosine kinase (BTK) degrader, demonstrates rapid and durable clinical responses in relapsed/refractory chronic lymphocytic leukemia (CLL): New and updated findings from an ongoing phase 1a/b trial. ASH 2025;Abstract 86.

Sidiqqi T et al. Lisocabtagene maraleucel (liso-cel) in patients (pts) with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL): Updated follow-up of Transcend CLL 004. ASH 2024;Abstract 4633.

Soumerai J et al. Zanubrutinib + obinutuzumab + sonrotoclax in patients with treatment-naive chronic lymphocytic leukemia/small lymphocytic lymphoma (TN CLL/SLL): Initial results from an ongoing phase 1/1b study, BGB-11417-101. ASH 2025;Abstract 3890.

Tam C et al. Frontline treatment of sonrotoclax (BGB-11417) and zanubrutinib for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) demonstrates high undetectable minimal residual disease (uMRD) rates with favorable tolerability: Updated data from BGB-11417-101, an ongoing phase 1/1b study. ASH 2025;Abstract 3891.

Wierda WG et al. Lisocabtagene maraleucel (liso-cel) combined with ibrutinib (ibr) for patients (pts) with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL): Primary results from the open-label, phase 1/2 Transcend CLL 004 Study. ASH 2024;Abstract 887.

Winter AM et al. Real-world outcomes of lisocabtagene maraleucel (liso-cel) in patients (pt) with Richter transformation (RT) from the Center for International Blood and Marrow Transplant Research (CIBMTR). ASCO 2024;Abstract 7010.