Ask AI
CLL BTK Inhibitor Tx and AE Guide

CME

Global Perspectives and Clinical Resources to Guide Treatment Decisions and Management of Adverse Events With BTK Inhibitor Therapy in CLL 

Physicians: Maximum of 1.00 AMA PRA Category 1 Credit

Released: March 13, 2025

Expiration: September 12, 2025

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 [prescribing information]. Indianapolis, IN: Eli Lilly; 2023.
  4. 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.
  5. 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.
  6. Woyach JA, Ruppert AS, Guinn D, et al. BTKC481S-mediated resistance to ibrutinib in chronic lymphocytic leukemia. J Clin Oncol. 2017;35:1437-1443.
  7. Tam C, Thompson PA. BTK inhibitors in CLL: second-generation drugs and beyond. Blood Adv. 2024;8:2300-2309.
  8. 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.
  9. 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.
  10. 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.
  11. 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.
  12. 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.
  13. 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.
  14. Gomez EB, Ebata K, Randeria HS, et al. Preclinical characterization of pirtobrutinib, a highly selective, noncovalent (reversible) BTK inhibitor. Blood. 2023;142:62-72.
  15. 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.
  16. 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.
  17. 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.
  18. Lipsky A, Lamanna N. Managing toxicities of Bruton tyrosine kinase inhibitors. Hematology Am Soc Hematol Educ Program. 2020;2020:336-345.
  19. 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.
  20. 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.
  21. 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.
  22. 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.
  23. Shadman M, Munir T, Robak T, et al. Zanubrutinib versus bendamustine and rituximab in patients with treatment-naïve chronic lymphocytic leukemia/small lymphocytic lymphoma: median 5-year follow-up of SEQUOIA. J Clin Oncol. 2025;43:780-787.
  24. 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.
  25. 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.
  26. 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.
  27. 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.
  28. 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.
  29. 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.
  30. 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.
  31. 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.
  32. 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.
  33. 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.
  34. 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.
  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, Brown JR, O’Brien S, et al. Final analysis from RESONATE: up to six years of follow-up on ibrutinib in patients with previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma. Am J Hematol. 2019;94:1353-1363.
  37. Kater A, Harrup R, Kipps TJ, et al. 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). Presented at: 28th Annual Congress of the European Hematology Association; June 8-11, 2023. Abstract S201.
  38. 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.
  39. 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.
  40. Seymour JF, Kipps TJ, Eichhorst BF, et al. Enduring undetectable MRD and updated outcomes in relapsed/refractory CLL after fixed-duration venetoclax-rituximab. Blood. 2022;140:839-850.
  41. 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.
  42. 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.
  43. Venetoclax [prescribing information]. San Francisco, CA: Genentech; 2024.
  44. Venetoclax [producto information]. Ludwigshafen, Germany: AbbVie Deutschland; 2025.
  45. Sharman JP, Munir T, Grosicki S, et al. BRUIN CLL-321: randomized phase III trial of pirtobrutinib versus idelalisib plus rituximab (IdelaR) or bendamustine plus rituximab (BR) in BTK inhibitor pretreated chronic lymphocytic leukemia/small lymphocytic lymphoma. Presented at: 66th American Society of Hematology Annual Meeting and Exposition; December 7-10, 2024. Abstract 886.
  46. Follows G, Burke JM, Grosicki S, et al. BRUIN CLL-321: A phase 3 open-label, randomized study of pirtobrutinib versus investigator’s choice of idelalisib plus rituximab or bendamustine plus rituximab in BTK inhibitor pretreated chronic lymphocytic leukemia/small lymphocytic lymphoma. J Clin Oncol. 2023;41(16 suppl):TPS7582.
  47. 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.
  48. Wierda WG, Jacobs R, Barr PM, et al. Outcomes in high-risk subgroups after fixed-duration ibrutinib + venetoclax for chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL): up to 5.5 years of follow-up in the phase 2 CAPTIVATE study. J Clin Oncol. 2024;42(16 suppl):7009.
  49. Hillmen P, Pitchford A, Bloor A, et al. The combination of ibrutinib plus venetoclax results in a high rate of MRD negativity in previously untreated CLL: the results of the planned interim analysis of the phase III NCRI FLAIR trial. Presented at: 27th Annual Congress of the European Hematology Association; June 9-12, 2022. Abstract S145.
  50. Ibrutinib [summary of product characteristics]. Beerse, Belgium: Janssen-Cilag International; 2024.
  51. 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.
  52. 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.
  53. 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.
  54. 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.
  55. Ibrutinib [prescribing information]. Horsham, PA: Janssen Biotech; South San Francisco, CA: Pharmacyclics; 2024.
  56. Acalabrutinib [summary of product characteristics]. Södertälje, Sweden: AstraZeneca; 2024.
  57. Acalabrutinib [prescribing information]. Wilmington, DE: AstraZeneca Pharmaceuticals; 2025
  58. Zanubrutinib [summary of product characteristics]. Dublin, Ireland: BeiGene Ireland; 2024
  59. Zanubrutinib [prescribing information]. San Mateo, CA: BeiGene USA. 2025.
  60. National Comprehensive Cancer Network. Clinical practice guidelines in oncology: chronic lymphocytic leukemia/small lymphocytic lymphoma. v.2.2025. nccn.org. Accessed February 26, 2025.
  61. 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.