Ask AI
Frontline CLL Tx Guide

CME

On the Frontlines of CLL/SLL: International Perspectives on First-line Treatments for CLL/SLL

Physicians: Maximum of 1.00 AMA PRA Category 1 Credit

Released: February 10, 2026

Expiration: August 09, 2026

Activity

Progress
1 2
Course Completed

References

  1. Lewis KL, Cheah CY. Non-covalent BTK inhibitor--the new BTKids on the block for B-cell malignancies. J Pers Med. 2021;11:764.
  2. Montoya S, Thompson MC. Non-covalent Bruton’s tyrosine kinase inhibitors in the treatment of chronic lymphocytic leukemia. Cancers (Basel). 2023;15:3648.
  3. Pirtobrutinib [summary of product characteristics]. Utrecht, The Netherlands: Lilly; 2025.
  4. Pirtobrutinib [prescribing information]. Indianapolis, IN: Eli Lilly; 2025.
  5. Kaptein A, de Bruin Gerjan, Emelot-van Hoek M, et al. Potency and selectivity of BTK inhibitors in clinical development for B-cell malignancies. Presented at: 60th American Society of Hematology Annual Meeting and Exposition; December 1-4, 2018. Abstract 1871.
  6. Woyach JA, Furman RR, Liu T-M, et al. Resistance mechanisms for the Bruton’s tyrosine kinase inhibitor ibrutinib. N Engl J Med. 2014;370:2286-2294.
  7. Woyach JA, Ruppert AS, Guinn D, et al. BTKC481S-mediated resistance to ibrutinib in chronic lymphocytic leukemia. J Clin Oncol. 2017;35:1437-1443.
  8. Tam C, Thompson PA. BTK inhibitors in CLL: second-generation drugs and beyond. Blood Adv. 2024;8:2300-2309.
  9. Gu D, Tang H, Wu J, et al. Targeting bruton tyrosine kinase using non-covalent inhibitors in B cell malignancies. J Hematol Oncol. 2021;14:40.
  10. Wang E, Mi Xiaoli, Thomson MC, et al. Mechanisms of resistance to noncovalent Bruton’s tyrosine kinase inhibitors. N Engl J Med. 2022;386:736-743.
  11. Mato AR, Shah NN, Jurczak W, et al. Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): a phase 1/2 study. Lancet. 2021;397:892-901.
  12. Mato AR, Flinn IW, Pagel JM, et al. Results from a first-in-human, proof-of concept phase I trial in pretreated B-cell malignancies for Loxo-305, a next-generation, highly selective, non-covalent BTK inhibitor. Presented at: 61st American Society of Hematology Annual Meeting and Exposition; December 7-10, 2019. Abstract 501.
  13. Robak T, Witkowska M, Smolewski P. The role of Bruton’s kinase inhibitors in chronic lymphocytic leukemia: current status and future directions. Cancers (Basel). 2022;14:771.
  14. Brandhuber B, Gomez E, Smith S, et al. LOXO-305, a next generation non-covalent BTK inhibitor, for overcoming acquired resistance to covalent BTK inhibitors. Presented at: 6th Annual Meeting of the Society of Hematologic Oncology; September 12-15, 2018. Abstract CLL-200.
  15. Gomez EB, Ebata K, Randeria HS, et al. Preclinical characterization of pirtobrutinib, a highly selective, noncovalent (reversible) BTK inhibitor. Blood. 2023;142:62-72.
  16. Woyach JA, Ruppert A, Heerema NA, et al. Ibrutibib regimens versus chemoimmunotherapy in older patients with untreated CLL. N Engl J Med. 2018;379:2517-2528.
  17. Woyach JA, Perez G, Ruppert AS, et al. Follow-up from the A041202 study shows continued efficacy of ibrutinib regimens for older adults with CLL. Blood. 2024;143:1616.
  18. Galitzia A, Maccaferri M, Mauro FR, et al. Chronic lymphocytic leukemia: management of adverse events in the era of targeted agents. Cancers (Basel). 2024;16:1996.
  19. Lipsky A, Lamanna N. Managing toxicities of Bruton tyrosine kinase inhibitors. Hematology Am Soc Hematol Educ Program. 2020;2020:336-345.
  20. Ruppert AS, Booth AM, Ding W, et al. Adverse event burden in older patients with CLL receiving bendamustine plus rituximab or ibrutinib regimens: Alliance A041202. Leukemia. 2021;35:2854-2861.
  21. Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzumab for treatment-naive chronic lymphocytic leukaemia (ELEVATE-TN): a randomised, controlled, phase 3 trial. Lancet. 2020;395:1278-1291.
  22. Sharman JP, Egyed M, Jurczak W, et al. Efficacy and safety in a 4-year follow-up of the ELEVATE-TN study comparing acalabrutinib with or without obinutuzumab versus obinutuzumab plus chlorambucil in treatment-naïve chronic lymphocytic leukemia. Leukemia. 2022;36:1171-1175.
  23. 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. Presented at: 65th American Society of Hematology Annual Meeting and Exposition; December 9-12, 2023. Abstract 636.
  24. Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib-obinutuzumab improves survival vs chemoimmunotherapy in treatment-naive CLL in the 6-year follow-up of ELEVATE-TN. Blood. 2025;146:1276–85.
  25. Tam CS, Munir T, Robak T, et al. Sustained efficacy of zanubrutinib vs bendamustine + rituximab in treatment-naive chronic lymphocytic leukemia/small lymphocytic lymphoma and continued favorable survival in non-randomized patients with del(17p): 6-year follow-up in the phase 3 SEQUIOA study. Presented at: 67th Annual Meeting of the American Society of Hematology; December 6-9, 2025. Abstract 2129.
  26. Tam CS, Brown JR, Kahl BS, et al. Zanubrutinib versus bendamustine and rituximab in untreated chronic lymphocytic leukaemia and small lymphocytic lymphoma (SEQUOIA): a randomised, controlled, phase 3 trial. Lancet Oncol. 2022;23:1031-1043.
  27. Al-Sawaf O, Zhang C, Jin HY, et al. Transcriptomic profiles and 5-year results from the randomized CLL14 study of venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab in chronic lymphocytic leukemia. Nat Commun. 2023;14:2147.
  28. 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.
  29. Jurczak W, Kwiatek M, Czyz J, et al. BRUIN CLL-313: Randomized phase III trial of pirtobrutinib versus bendamustine plus rituximab in untreated patients with chronic lymphocytic leukemia/small lymphocytic lymphoma. J Clin Oncol. 2025;0:JCO-25-02380.
  30. Jurczak W, Kwiatek M, Czyz J, et al. Pirtobrutinib vs bendamustine plus rituximab (BendaR) in patients with CLL/SLL: First results from a randomized phase III study examining a non-covalent BTK inhibitor in untreated patients. Presented at: 67th Annual Meeting of the American Society of Hematology; December 6-9, 2025. Abstract LBA3.
  31. Woyach JA, Qiu L, Grosicki S, et al. Pirtobrutinib versus ibrutinib in treatment-naïve and relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma. J Clin Oncol. 2025;0:JCO-25-02477.
  32. Woyach JA, Qiu L, Grosicki S, et al. Pirtobrutinib vs ibrutinib in treatment-naïve and relapsed/refractory CLL/SLL: Results from the first randomized phase III study comparing a non-covalent and covalent BTK inhibitor. Presented at: 67th Annual Meeting of the American Society of Hematology; December 6-9, 2025. Abstract 683.
  33. Wierda WG, Barr PM, Siddiqi T, et al. Fixed-duration (FD) ibrutinib (I) + venetoclax (V) for first-line (1L) treatment (tx) of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL): three-year follow-up from the FD cohort of the phase 2 CAPTIVATE study. J Clin Oncol. 2022;40(16 suppl):7519.
  34. Wierda W, Barr P, Allan J, et al. Final analysis of fixed-duration ibrutinib + venetoclax for chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) in the phase 2 CAPTIVATE study. Presented at: European Hematology Association Congress; June 12-15, 2025. Abstract S156.
  35. Munir T, Cairns DA, Bloor A, et al; National Cancer Research Institute Chronic Lymphocytic Leukemia Subgroup. Chronic lymphocytic leukemia therapy guided by measurable residual disease. N Engl J Med. 2024;390:326-337
  36. Munir T, Girvan S, Cairns DA, et al. Measurable residual disease–guided therapy for chronic lymphocytic leukemia. NEJM. 2025;393:1177–90.
  37. Ibrutinib [summary of product characteristics]. Beerse, Belgium: Janssen-Cilag International; 2024.
  38. Munir T, Moreno C, Owen C, et al. First prospective data on minimal residual disease (MRD) outcomes after fixed-duration ibrutinib plus venetoclax (Ibr+Ven) versus chlorambucil plus obinutuzumab (Clb+O) for first-line treatment of CLL in elderly or unfit patients: the GLOW study. Presented at: 63rd American Society of Hematology Annual Meeting and Exposition; December 11-14, 2021. Abstract 70.
  39. 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.
  40. Niemann CU, Munir T, Moreno C, et al. Fixed-duration ibrutinib-venetoclax versus chlorambucil-obinutuzumab in previously untreated chronic lymphocytic leukaemia (GLOW): 4-year follow-up from a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2023;24:1423-1433.
  41. Morena C, Munir T, Owen C, et al. First-line fixed-duration ibrutinib plus venetoclax (Ibr+Ven) vs chlorambucil plus obinutuzumab (Clb+O): 55-month follow-up from the GLOW study. Presented at: 12th Annual Meeting of the Society of Hematologic Oncology 2024 Annual Meeting; September 4-7, 2024. Abstract CLL-487.
  42. Brown JR, Seymour JF, Jurczak W, et al. Fixed-duration acalabrutinib combinations in untreated chronic lymphocytic leukemia. N Engl J Med. 2025;392:748-762.
  43. Brown JR, Seymour JF, Jurczak W, 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. Presented at: 66th American Society of Hematology Annual Meeting and Exposition; December 7-10, 2024. Abstract 1009.
  44. Acalabrutinib [summary of product characteristics]. Södertälje, Sweden: AstraZeneca; 2025.
  45. Al-Sawaf O, Stumpf J, Zhang C, et al. Fixed-duration versus continuous targeted treatment for previously untreated chronic lymphocytic leukemia: Results from the randomized CLL17 trial. Presented at: 67th Annual Meeting of the American Society of Hematology; December 6-9, 2025. Abstract 1.
  46. Al-Sawaf O, Stumpf J, Zhang C, et al. Fixed-duration versus continuous treatment for chronic lymphocytic leukemia. NEJM. 2025;[Epub ahead of print].
  47. Ibrutinib [prescribing information]. Horsham, PA: Janssen Biotech; South San Francisco, CA: Pharmacyclics; 2025.
  48. Acalabrutinib [prescribing information]. Wilmington, DE: AstraZeneca Pharmaceuticals; 2025.
  49. National Comprehensive Cancer Network. Clinical practice guidelines in oncology: chronic lymphocytic leukemia/small lymphocytic lymphoma. v.2.2026. nccn.org. Accessed January 26, 2026.
  50. Zanubrutinib [summary of product characteristics]. Dublin, Ireland: BeiGene Ireland; 2025
  51. Zanubrutinib [prescribing information]. San Mateo, CA: BeiGene USA. 2025.
  52. Tausch E, Schneider C, Stilgenbauer S. Risk-stratification in frontline CLL therapy: standard of care. Hematology Am Soc Hematol Educ Program. 2024;2024:457-466.
  53. Barr PM, Owen C, Robak T, et al. Up to 8-year follow-up from RESONATE-2: first-line ibrutinib treatment for patients with chronic lymphocytic leukemia. Blood Adv. 2022;6:3440-3450.
  54. Moreno C, Greil R, Demirkan F, et al. First-line treatment of chronic lymphocytic leukemia with ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab: final analysis of the randomized, phase III iLLUMINATE trial. Haematologica. 2022;107:2108-2120.
  55. Shanafelt TD, Wang XV, Hanson CA, et al. Long-term outcomes for ibrutinib-rituximab and chemoimmunotherapy in CLL: updated results of the E1912 trial. Blood. 2022;140:112-120.
  56. Hillmen P, Pitchford A, Bloor A, et al. Ibrutinib and rituximab versus fludarabine, cyclophosphamide, and rituximab for patients with previously untreated chronic lymphocytic leukaemia (FLAIR): interim analysis of a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2023;24:535-552.
  57. 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.
  58. Fürstenau M, Kater AP, Robrecht S, et al. First-line venetoclax combinations versus chemoimmunotherapy in fit patients with chronic lymphocytic leukaemia (GAIA/CLL13): 4-year follow-up from a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2024;25:744-759.
  59. 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.
  60. Byrd JC, Hillmen P, Ghia P, et al. First results of a head-to-head trial of acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia. J Clin Oncol. 2021;39(15 suppl):7500.
  61. Sharman JP, Munir T, Grosicki S, et al. Phase III trial of pirtobrutinib versus idelalisib/rituximab or bendamustine/rituximab in covalent Bruton tyrosine kinase inhibitor-pretreated chronic lymphocytic leukemia/small lymphocytic lymphoma (BRUIN CLL-321). J Clin Oncol. 2025;43:2538-2549.
  62. Niemann C, Fürstenau M, Zhang C, et al. Efficacy of 2nd-line treatment in CLL after venetoclax-based 1st-line treatment: Results from the GAIA/CLL13 trial. Presented at: 67th Annual Meeting of the American Society of Hematology; December 6-9, 2025. Abstract 795.
  63. O'Brien SM, Brown JR, Byrd JC, et al. Monitoring and managing BTK inhibitor treatment-related adverse events in clinical practice. Front Oncol. 2021;11:720704.