ISSN (print) 1997-6933     ISSN (online) 2500-2139
Vol. 16 No. 1 (2023), REVIEWS
Vol. 16 No. 1 (2023)
REVIEWS

Combination of Ibrutinib and Venetoclax in the Therapy of Chronic Lymphocytic Leukemia: A Review of the Latest Data from Clinical Studies

Published 20.02.2024
A.A. Petrenko
SP Botkin City Clinical Hospital, 5 2-i Botkinskii pr-d, Moscow, Russian Federation, 125284; Russian Medical Academy of Postgraduate Education, 2/1 Barrikadnaya ul., Moscow, Russian Federation, 125993
Mariya Igorevna Kislova
SP Botkin City Clinical Hospital, 5 2-i Botkinskii pr-d, Moscow, Russian Federation, 125284
E.A. Dmitrieva
SP Botkin City Clinical Hospital, 5 2-i Botkinskii pr-d, Moscow, Russian Federation, 125284
E.A. Nikitin
SP Botkin City Clinical Hospital, 5 2-i Botkinskii pr-d, Moscow, Russian Federation, 125284; Russian Medical Academy of Postgraduate Education, 2/1 Barrikadnaya ul., Moscow, Russian Federation, 125993
V.V. Ptushkin
SP Botkin City Clinical Hospital, 5 2-i Botkinskii pr-d, Moscow, Russian Federation, 125284; Russian Medical Academy of Postgraduate Education, 2/1 Barrikadnaya ul., Moscow, Russian Federation, 125993; NI Pirogov Russian National Research Medical University, 1 Ostrovityanova ul., Moscow, Russian Federation, 117997
2023-1
PDF_2023-16-1_37-45 (Russian)

Keywords

ibrutinib
BTK inhibitors
venetoclax
BCL-2 inhibitors
targeted agents
chronic lymphocytic leukemia

How to Cite

Petrenko A.A., Kislova M.I., Dmitrieva E.A., Nikitin E.A., Ptushkin V.V. Combination of Ibrutinib and Venetoclax in the Therapy of Chronic Lymphocytic Leukemia: A Review of the Latest Data from Clinical Studies. Clinical Oncohematology. 2024;(1):37–45. doi:10.21320/2500-2139-2023-16-1-37-45.
ACM ACS APA ABNT Chicago Harvard IEEE MLA Turabian Vancouver AMA ГОСТ

Download Citation

Endnote/Zotero/Mendeley (RIS) BibTeX

Keywords

Abstract

New Bruton’s tyrosine kinase (BTK) inhibitors caused drastic modifications in the therapy of chronic lymphocytic leukemia (CLL). Ibrutinib, the first in its class BTK inhibitor, showed high efficacy in many clinical studies. However, the treatment with BTK inhibitors as monotherapy must not be discontinued. Ibrutinib monotherapy inevitably leads to BTK inhibitor resistance and severe adverse events, which often results in treatment failure. Inhibitor BCL-2 venetoclax combined with BTK inhibitor can increase the therapy efficacy due to the synergetic effect of these agents on different CLL cell populations. Combined therapy potentially providing fixed-duration treatment can yield deeper responses. The present review focuses on ibrutinib and venetoclax combination, summarizes the latest data from clinical studies, and deals with feasibility of combined therapy in terms of its efficacy and safety profile.

PDF_2023-16-1_37-45 (Russian)

References

  1. Brown JR, Hallek MJ, Pagel JM. Chemoimmunotherapy Versus Targeted Treatment in Chronic Lymphocytic Leukemia: When, How Long, How Much, and in Which Combination? Am Soc Clin Oncol Educ Book. 2016;35:e387–е398. doi: 10.1200/EDBK_159018.
  2. Eichhorst B, Fink AM, Bahlo J, et al. First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): an international, open-label, randomised, phase 3, non-inferiority trial. Lancet Oncol. 2016;17(7):928–42. doi: 10.1016/S1470-2045(16)30051-1.
  3. Goede V, Fischer K, Busch R, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med. 2014;370(12):1101–10. doi: 10.1056/NEJMoa1313984.
  4. Hallek M, Shanafelt TD, Eichhorst B. Chronic lymphocytic leukaemia. 2018;391(10129):1524–37. doi: 10.1016/S0140-6736(18)30422-7.
  5. Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369(1):32–42. doi: 10.1056/NEJMoa1215637.
  6. de Rooij MF, Kuil A, Geest CR, et al. The clinically active BTK inhibitor PCI-32765 targets B-cell receptor- and chemokine-controlled adhesion and migration in chronic lymphocytic leukemia. 2012;119(11):2590–4. doi: 10.1182/blood-2011-11-390989.
  7. Herman SE, Mustafa RZ, Jones J, et al. Treatment with Ibrutinib Inhibits BTK- and VLA-4-Dependent Adhesion of Chronic Lymphocytic Leukemia Cells In Vivo. Clin Cancer Res. 2015;21(20):4642–51. doi: 10.1158/1078-0432.CCR-15-0781.
  8. 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(11):3440–50. doi: 10.1182/bloodadvances.2021006434.
  9. Shanafelt TD, Wang XV, Kay NE, et al. Ibrutinib-Rituximab or Chemoimmunotherapy for Chronic Lymphocytic Leukemia. N Engl J Med. 2019;381(5):432–43. doi: 10.1056/NEJMoa1817073.
  10. 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):2517–28. doi: 10.1056/NEJMoa1812836.
  11. Moreno C, Greil R, Demirkan F, et al. Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in first-line treatment of chronic lymphocytic leukaemia (iLLUMINATE): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019;20(1):43–56. doi: 10.1016/S1470-2045(18)30788-5.
  12. 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(12):1353–63. doi: 10.1002/ajh.25638.
  13. Byrd JC, Brown JR, O’Brien S, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371(3):213–23. doi: 10.1056/NEJMoa1400376.
  14. 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):2425–37. doi: 10.1056/NEJMoa1509388.
  15. Byrd JC, Furman RR, Coutre SE, et al. Three-year follow-up of treatment-naive and previously treated patients with CLL and SLL receiving single-agent ibrutinib. Blood. 2015;125(16):2497–506. doi: 10.1182/blood-2014-10-606038.
  16. Davids MS, Brander DM, Kim HT, et al. Ibrutinib plus fludarabine, cyclophosphamide, and rituximab as initial treatment for younger patients with chronic lymphocytic leukaemia: a single-arm, multicentre, phase 2 trial. Lancet Haematol. 2019;6(8):e419–e428. doi: 10.1016/S2352-3026(19)30104-8.
  17. Souers AJ, Leverson JD, Boghaert ER, et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med. 2013;19(2):202–8. doi: 10.1038/nm.3048.
  18. 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(23):2225–36. doi: 10.1056/NEJMoa1815281.
  19. 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(34):4042–54. doi: 10.1200/JCO.20.00948.
  20. 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(36):4049–60. doi: 10.1200/JCO.21.01181.
  21. Kittai AS, Woyach JA. uMRD: “the” endpoint or “an” endpoint for CLL? Blood. 2022;140(8):797–8. doi: 10.1182/blood.2022016927.
  22. Chen SS, Chang BY, Chang S, et al. BTK inhibition results in impaired CXCR4 chemokine receptor surface expression, signaling and function in chronic lymphocytic leukemia. Leukemia. 2016;30(4):833–43. doi: 10.1038/leu.2015.316.
  23. Cervantes-Gomez F, Lamothe B, Woyach JA, et al. Pharmacological and Protein Profiling Suggests Venetoclax (ABT-199) as Optimal Partner with Ibrutinib in Chronic Lymphocytic Leukemia. Clin Cancer Res. 2015;21(16):3705–15. doi: 10.1158/1078-0432.CCR-14-2809.
  24. Kater AP, Slinger E, Cretenet G, et al. Combined ibrutinib and venetoclax treatment vs single agents in the TCL1 mouse model of chronic lymphocytic leukemia. Blood Adv. 2021;5(23):5410–4. doi: 10.1182/bloodadvances.2021004861.
  25. Slinger E, Thijssen R, Kater AP, Eldering E. Targeting antigen-independent proliferation in chronic lymphocytic leukemia through differential kinase inhibition. Leukemia. 2017;31(12):2601–7. doi: 10.1038/leu.2017.129.
  26. Haselager MV, Kater AP, Eldering E. Proliferative Signals in Chronic Lymphocytic Leukemia; What Are We Missing? Front Oncol. 2020;10:592205. doi: 10.3389/fonc.2020.592205.
  27. Ondrisova L, Mraz M. Genetic and Non-Genetic Mechanisms of Resistance to BCR Signaling Inhibitors in B Cell Malignancies. Front Oncol. 2020;10:591577. doi: 10.3389/fonc.2020.591577.
  28. Haselager MV, Kielbassa K, Ter Burg J, et al. Changes in Bcl-2 members after ibrutinib or venetoclax uncover functional hierarchy in determining resistance to venetoclax in CLL. Blood. 2020;136(25):2918–26. doi: 10.1182/blood.2019004326.
  29. Deng J, Isik E, Fernandes SM, et al. Bruton’s tyrosine kinase inhibition increases BCL-2 dependence and enhances sensitivity to venetoclax in chronic lymphocytic leukemia. Leukemia. 2017;31(10):2075–84. doi: 10.1038/leu.2017.32.
  30. Gutierrez C, Wu CJ. Clonal dynamics in chronic lymphocytic leukemia. Blood Adv. 2019;3(22):3759–69. doi: 10.1182/bloodadvances.2019000367.
  31. Lu P, Wang S, Franzen CA, et al. Ibrutinib and venetoclax target distinct subpopulations of CLL cells: implication for residual disease eradication. Blood Cancer J. 2021;11(2):39. doi: 10.1038/s41408-021-00429-z.
  32. Zhang J, Lu X, Li J, Miao Y. Combining BTK inhibitors with BCL2 inhibitors for treating chronic lymphocytic leukemia and mantle cell lymphoma. Biomark Res. 2022;10(1):17. doi: 10.1186/s40364-022-00357-5.
  33. 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(34):3853–65. doi: 10.1200/JCO.21.00807.
  34. Wierda WG, Tam CS, Allan JN, et al. Ibrutinib (Ibr) Plus Venetoclax (Ven) for First-Line Treatment of Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL): 1-Year Disease-Free Survival (DFS) Results From the MRD Cohort of the Phase 2 CAPTIVATE Study. Blood. 2020;136(Suppl 1):16–7. doi: 10.1182/blood-2020-134446.
  35. Ghia P, Allan JN, Siddiqi T, et al. First-Line Treatment with Ibrutinib (Ibr) Plus Venetoclax (Ven) for Chronic Lymphocytic Leukemia (CLL): 2-Year Post-Randomization Disease-Free Survival (DFS) Results from the Minimal Residual Disease (MRD) Cohort of the Phase 2 Captivate Study. Blood. 2021;138(Suppl 1):68. doi: 10.1182/blood-2021-144544.
  36. 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(22):3278–89. doi: 10.1182/blood.2021014488.
  37. Allan JN, Wierda WG, Siddiqi T, et al. Primary analysis of the fixed-duration cohort from the phase 2 CAPTIVATE study of first-line ibrutinib+venetoclax for chronic lymphocytic leukemia/small lymphocytic lymphoma. EHA Library. 2021;324555:S147.
  38. Jain N, Keating M, Thompson P, et al. Ibrutinib and Venetoclax for First-Line Treatment of CLL. N Engl J Med. 2019;380(22):2095–103. doi: 10.1056/NEJMoa1900574.
  39. Jain N, Keating MJ, Thompson PA, et al. Combined Ibrutinib and Venetoclax for First-Line Treatment of Patients with Chronic Lymphocytic Leukemia (CLL): Focus on Long-Term MRD Results. Blood. 2021;138(Suppl 1):3720. doi: 10.1182/blood-2021-154454.
  40. Jain N, Keating M, Thompson P, et al. Ibrutinib Plus Venetoclax for First-line Treatment of Chronic Lymphocytic Leukemia: A Nonrandomized Phase 2 Trial. JAMA Oncol. 2021;7(8):1213–9. doi: 10.1001/jamaoncol.2021.1649.
  41. Kater A, Owen C, Moreno C, et al. Fixed-duration ibrutinib and venetoclax (I+V) versus chlorambucil plus obinutuzumab (CLB+O) for first-line (1L) chronic lymphocytic leukemia (CLL): primary analysis of the phase 3 GLOW study. EHA Library. 2021;330172:LB1902.
  42. 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. Blood. 2021;138(Suppl 1):70. doi: 10.1182/blood-2021-148666.
  43. Kater AP, Owen C, Moreno C, et al. Fixed-Duration Ibrutinib-Venetoclax in Patients with Chronic Lymphocytic Leukemia and Comorbidities. NEJM Evid. 2022;1(7). doi: 10.1056/EVIDoa2200006.
  44. 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(30):2722–9. doi: 10.1200/JCO.19.00894.
  45. Niemann CU, Levin M-D, Dubois J, et al. Venetoclax and ibrutinib for patients with relapsed/refractory chronic lymphocytic leukemia. Blood. 2021;137(8):1117–20. doi: 1182/blood.2020008608.
  46. Jain N, Keating MJ, Thompson PA, et al. Combined Ibrutinib and Venetoclax in Patients with Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia (CLL). Blood. 2019;134(Suppl_1):359. doi: 10.1182/blood-2019-131732.
  47. Scarfo L, Heltai S, Albi E, et al. Minimal residual disease-driven treatment intensification by sequential addition of ibrutinib to venetoclax in relapsed/refractory chronic lymphocytic leukemia: results of the monotherapy and combination phases of the IMPROVE study. Blood. 2020;136(Suppl 1):21–2.
  48. Thompson PA, Wang Y, Keating MJ, et al. Venetoclax Consolidation in Patients with High-Risk CLL Who Have Been on Ibrutinib More Than a Year Achieves a High Rate of Undetectable Minimal Residual Disease. Blood. 2021;138(Suppl 1):3723. doi: 1182/blood-2021-149919.
  49. Petrenko A, Kislova M, Dmitrieva E, et al. P654: Ibrutinib Plus Venetoclax in Patients With Complex Karyotype and Chronic Lymphocytic Leukemia. HemaSphere. 2022;6:552–3. doi: 10.1097/01.HS9.0000845500.06883.11.
Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.