BRUTON’S TYROSINE KINASE (BTK) MUTATIONS IN CHRONIC LYMPHOCYTIC LEUKEMIA (CLL): A CLINICAL VIEW.
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Keywords
CLL, BTK mutations,BTK inhibitors resistance, non-covalent BTK inhibitors.
Abstract
Bruton’s tyrosine kinase inhibitors (BTKis) have reshaped the management of chronic lymphocytic leukemia (CLL). The first-generation BTKi ibrutinib demonstrated significant efficacy, leading to the development of second-generation agents (acalabrutinib, zanubrutinib) with improved selectivity and safety. However, resistance—most often driven by BTK C481S mutations—remains a major therapeutic limitation.
Non-covalent BTKis, such as pirtobrutinib, offer effective options for patients relapsing after covalent BTKi therapy. However, the emergence of novel resistance mutations continues to limit durable responses. As insights into the molecular basis of BTK resistance evolve, routine mutation testing is poised to become integral to personalized treatment in CLL. Future clinical trials are expected to adopt mutation-driven stratification to guide therapeutic sequencing. Ultimately, overcoming BTKi resistance will require innovative strategies, including BTK degraders, bispecific antibodies, and T cell–engaging immunotherapies.
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References
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2. Burger JA, Tedeschi A, Barr PM, et al. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015;373(25):2425-2437.
3. Woyach JA, Ruppert AS, Heerema NA, et al. Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL. N Engl J Med. 2018;379(26):2517-2528.
4. Shanafelt TD, Wang XV, Kay NE, et al. Ibrutinib-rituximab or chemoimmunotherapy for chronic lymphocytic leukemia. N Engl J Med. 2019;381(5):432-443.
5. 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-naive chronic lymphocytic leukemia. Leukemia. 2022;36(4):1171-1175.
6. 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(8):1031-1043.
7. 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(31):3441-3452.
8. Brown JR, Eichhorst B, Hillmen P, et al. Zanubrutinib or ibrutinib in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2023;388(4):319-332.
9. Eichhorst B, Ghia P, Niemann CU, et al. ESMO Clinical Practice Guideline interim update on new targeted therapies in the first line and at relapse of chronic lymphocytic leukaemia.Ann Oncol. Ann Of Oncol. 2024 Sep;35(9):762–768.
10. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Version 1.2025. Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma. —. 2024 Oct 1. Available from: https://www.nccn.org/professionals/physician_gls/pdf/cll.pdf
11. Woyach JA, Ruppert AS, Guinn D, et al. BTK(C481S)-mediated resistance to ibrutinib in chronic lymphocytic leukemia. J Clin Oncol. 2017;35(13):1437–1443.
12. Gruessner C, Wiestner A, Sun C. Resistance mechanisms and approach to chronic lymphocytic leukemia after BTK inhibitor therapy. Leuk Lymphoma. 2025 Feb 19:1-13. doi: 10.1080/10428194.2025.2466101. Online ahead of print.
13. Jones D, Woyach JA, Zhao W, Caruthers S, Tu H, Coleman J, Byrd JC, Johnson AJ, Lozanski G. PLCG2 C2 domain mutations co-occur with BTK and PLCG2 resistance mutations in chronic lymphocytic leukemia undergoing ibrutinib treatment. Leukemia. 2017; 31:1645–47.
14. Woyach JA, Ghia P, Byrd JC, et al. B-cell receptor pathway mutations are infrequent in patients with chronic lymphocytic leukemia on continuous ibrutinib therapy. Clin Cancer Res. 2023;29(16):3065-3073.
15. Skarbnik AP, Danilov AV, Hoffmann M, et al Mutations in the Bruton Tyrosine Kinase (BTK) Gene in Patients with Chronic Lymphocytic Leukemia (CLL) Receiving BTK Inhibitors (BTKis). Blood 2024, 144 (Supplement 1): 4623.
16. Bonfiglio S, Sutton LA, Ljungström V, et al. BTK and PLCG2 remain unmutated in one third of patients with CLL relapsing on ibrutinib. Blood Adv. 2023;7(12):2794-2806.
17. Woyach JA, Jones D, Jurczak W, et al Mutational profile in previously treated patients with chronic lymphocytic leukemia progression on acalabrutinib or ibrutinib. Blood 2024 Sep 5;144(10):1061-1068.
18. Brown JR, Li J, Eichhorst B, Lamanna N, et al ACQUIRED MUTATIONS IN PATIENTS WITH RELAPSED/REFRACTORY CLL WHO PROGRESSED IN THE ALPINE STUDY. Blood Adv. 2025 Jan 24:bloodadvances.2024014206. doi: 10.1182/bloodadvances.2024014206. Online ahead of print.
19. Quinquenel A, Fornecker LM, Letestu R, et al. Prevalence of BTK and PLCG2 mutations in a real-life CLL cohort still on ibrutinib after 3 years: a FILO group study. Blood. 2019;134(7):641-644.
20. Woyach J, Huang Y, Rogers K, et al. Resistance to acalabrutinib in CLL is mediated primarily by BTK mutations [abstract]. Blood. 2019;134(suppl 1):504.
21. Kanagal-Shamanna R, Jain P, Patel KP, et al Targeted multigene deep sequencing of Bruton tyrosine kinase inhibitor-resistant chronic lymphocytic leukemia with disease progression and Richter transformation. Cancer 2019 Feb 15;125(4):559-574.
22. Bodor C, Kotmayer L, Laszlo T, et al Screening and monitoring of the BTKC481S mutation in a real-world cohort of patients with relapsed/refractory chronic lymphocytic leukaemia during ibrutinib therapy. Br J Haematol. 2021 Jul;194(2):355-364.
23. Sarma A, Evans C, Dalal S, et al Molecular Analysis at Relapse of Patients Treated on the Ibrutinib and Rituximab Arm of the National Multi-Centre Phase III FLAIR Study in Previously Untreated CLL Patients. [abstract] Blood 2023, 142: (Supplement 1); 4636
24. Molica S, Allsup D, Giannarelli D. Prevalence of BTK and PLCG2 Mutations in CLL Patients With Disease Progression on BTK Inhibitor Therapy: A Meta-Analysis. Am J Hematol. 2025 Feb;100(2):334-337.
25. Montoya S, Bourcier J, Noviski M, et al. Kinase-impaired BTK mutations are susceptible to clinical-stage BTK and IKZF1/3 degrader NX-2127. Science. 2024;383(6682):eadi5798.
26. Mato AR, Shah NN, Jurczak W, et al Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): a phase 1/2 study. Lancet 2021 Mar 6;397(10277):892-901.
27. Shadman M, Manzoor BS, Sail K, et Treatment Discontinuation Patterns for Patients With Chronic Lymphocytic Leukemia in Real-World Settings: Results From a Multi-Center International Study. Shadman M, Manzoor BS, Sail K, et Treatment Discontinuation Patterns for Patients With Chronic Lymphocytic Leukemia in Real-World Settings: Results From a Multi-Center International Study.
28. Itsara A, Sun C, Bryer E, et al. Long-term outcomes in chronic lymphocytic leukemia treated with ibrutinib: 10-year follow-up of a phase 2 study. Presented at the 65th American Society of Hematology (ASH) Annual Meeting & Exposition, December 9-12, 2023; San Diego, CA: Abstract 201.
29. Kater AP, Harrup RA, Kipps TJ, et al The MURANO study: final analysis and retreatment/crossover substudy results of VenR for patients with relapsed/refractory CLL. Blood. 2025 Feb 26:blood.2024025525.
30. Kater AP, Arslan Ö, Demirkan F, et al. Activity of venetoclax in patients with relapsed or refractory chronic lymphocytic leukaemia: analysis of the VENICE-1 multicentre, open-label, single-arm, phase 3b trial. Lancet Oncol. 2024 Apr;25(4):463-473.
31. Jones JA, Mato AR, Wierda WG, et al. Venetoclax for chronic lymphocytic leukaemia progressing after ibrutinib: an interim analysis of a multicentre, open-label, phase 2 trial. Lancet Oncol. 2018;19(1):65-75.
32. Ghosh N, Eyre TA, Brown JR, Lamanna 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 Mar;100(3):511-515.
33. Hampel PJ, Rabe KG, Guieze R, et al Outcomes with Venetoclax-Based Treatment in Patients with Covalent Bruton Tyrosine Kinase Inhibitor (cBTKi)-Treated, Chemotherapy-Naïve Chronic Lymphocytic Leukemia (CLL): An International Retrospective Study. Blood (2024) 144 (Supplement 1): 1856.
34. Mato AR, Woyach JA, Brown JR, et al Pirtobrutinib after a Covalent BTK Inhibitor in Chronic Lymphocytic Leukemia. N Engl J Med 2023 Jul 6;389(1):33-44.
35. Al-Sawaf O, Jen MH, Hess LM, et al Pirtobrutinib versus venetoclax in covalent Bruton tyrosine kinase inhibitor-pretreated chronic lymphocytic leukemia: a matching-adjusted indirect comparison. Haematologica 2024 Jun 1;109(6):1866-1873.
36. Wang E, Mi X, Thompson MC, et al. Mechanisms of resistance to noncovalent Bruton’s tyrosine kinase inhibitors. N Engl J Med. 2022;386(8):735–743.
37. Naeem A, Utro F, Wang Q, et al. Pirtobrutinib targets BTK C481S in ibrutinib-resistant CLL but second-site BTK mutations lead to resistance. Blood Adv. 2023;7(9):1929–1943.
38. Dhami K, Chakraborty A, Gururaja TL, et al. Kinase-deficient BTK mutants confer ibrutinib resistance through activation of the kinase HCK. Sci Signal. 2022;15(736):eabg5216.
39. Handunnetti S, Tang C, Nguyen T, et al. BTK Leu528Trp - a potential secondary resistance mechanism specific for patients with chronic lymphocytic leukemia treated with the next generation BTK inhibitor zanubrutinib [abstract]. Blood. 2019;134(suppl 1):170
40. Blombery P, Thompson ER, Lew TE, et al. Enrichment of BTK Leu528Trp mutations in patients with CLL on zanubrutinib: potential for pirtobrutinib cross-resistance. Blood Adv. 2022;6(20):5589-5592.
41. Woyach J, Huang Y, Rogers K, et al. Resistance to acalabrutinib in CLL is mediated primarily by BTK mutations [abstract]. Blood. 2019;134(suppl 1):504.
42. Tam CS, Balendran S, Blombery P. Novel mechanisms of resistance in CLL: variant BTK mutations in second-generation and noncovalent BTK inhibitors. Blood. 2025 Mar 6;145(10):1005-1009
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Jun 29, 2025
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Molica, S. (2025) “BRUTON’S TYROSINE KINASE (BTK) MUTATIONS IN CHRONIC LYMPHOCYTIC LEUKEMIA (CLL): A CLINICAL VIEW”., Mediterranean Journal of Hematology and Infectious Diseases, 17(1), p. e2025053. doi: 10.4084/MJHID.2025.053.
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