Skip to main content

Advertisement

SpringerLink
Log in

BTK Inhibitors in Chronic Lymphocytic Leukemia

  • Chronic Lymphocytic Leukemias (N Jain, Section Editor)
  • Published:
Current Hematologic Malignancy Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

The treatment landscape of chronic lymphocytic leukemia (CLL) has dramatically changed over the last few years with the introduction of novel targeted agents. Physicians are now faced with several equally effective therapy options when treating patients with CLL. Here, we review the role of Bruton tyrosine kinase (BTK) inhibitors in treating patients with treatment-naïve and relapsed or refractory CLL. We review recent approvals of BTK inhibitors as well as reported and ongoing clinical trial data.

Recent Findings

The approval of ibrutinib rapidly led to a paradigm shift in the management of CLL. Randomized trials have now compared ibrutinib to several chemoimmunotherapy approaches, which were in favor of ibrutinib. Second-generation more selective BTK inhibitors, including acalabrutinib and zanubrutinib, have been developed, and recent data have led to the approval of acalabrutinib in CLL. Ongoing and future studies focus on either combining BTK inhibitors with other novel agents (e.g., venetoclax, obinutuzumab, or ublituximab) or developing next-generation non-covalent reversible BTK inhibitors that may be effective in treating patients with CLL harboring BTK-resistant mutations.

Summary

The field of CLL continues to evolve rapidly with new and evolving combination treatments and novel BTK agents, which will continue to change the standard of care for CLL.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Data Availability

N/A

Code Availability

N/A

Human and Animal Rights and Informed Consent

This article contains no studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Siegel RL, et al. Cancer Statistics, 2021. CA Cancer J Clin. 2021;71(1):7–33.

    Article  PubMed  Google Scholar 

  2. Smith A, et al. Incidence of haematological malignancy by sub-type: a report from the Haematological Malignancy Research Network. Br J Cancer. 2011;105(11):1684–92.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Tsimberidou AM, et al. Assessment of chronic lymphocytic leukemia and small lymphocytic lymphoma by absolute lymphocyte counts in 2,126 patients: 20 years of experience at the University of Texas M.D. Anderson Cancer Center. J Clin Oncol. 2007;25(29):4648–56.

    Article  PubMed  Google Scholar 

  4. Pflug N, et al. Development of a comprehensive prognostic index for patients with chronic lymphocytic leukemia. Blood. 2014;124(1):49–62.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Hallek M, et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood. 2018;131(25):2745–60.

    Article  PubMed  CAS  Google Scholar 

  6. Woyach JA, Johnson AJ, Byrd JC. The B-cell receptor signaling pathway as a therapeutic target in CLL. Blood. 2012;120(6):1175–84.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Duhren-von Minden M, et al. Chronic lymphocytic leukaemia is driven by antigen-independent cell-autonomous signalling. Nature. 2012;489(7415):309–12.

    Article  PubMed  CAS  Google Scholar 

  8. Herman SE, et al. Bruton tyrosine kinase represents a promising therapeutic target for treatment of chronic lymphocytic leukemia and is effectively targeted by PCI-32765. Blood. 2011;117(23):6287–96.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Tsukada S, et al. Deficient expression of a B cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia. Cell. 1993;72(2):279–90.

    Article  PubMed  CAS  Google Scholar 

  10. Vetrie D, et al. The gene involved in X-linked agammaglobulinaemia is a member of the src family of protein-tyrosine kinases. Nature. 1993;361(6409):226–33.

    Article  PubMed  CAS  Google Scholar 

  11. Pal Singh S, Dammeijer F, Hendriks RW. Role of Bruton’s tyrosine kinase in B cells and malignancies. Mol Cancer. 2018;17(1):57.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Woyach JA, et al. Resistance mechanisms for the Bruton’s tyrosine kinase inhibitor ibrutinib. N Engl J Med. 2014;370(24):2286–94.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Guha A, et al. Ventricular arrhythmias following ibrutinib initiation for lymphoid malignancies. J Am Coll Cardiol. 2018;72(6):697–8.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Brown JR, et al. Characterization of atrial fibrillation adverse events reported in ibrutinib randomized controlled registration trials. Haematologica. 2017;102(10):1796–805.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Dickerson T, et al. Hypertension and incident cardiovascular events following ibrutinib initiation. Blood. 2019;134(22):1919–28.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Xiao L, et al. Ibrutinib-mediated atrial fibrillation attributable to inhibition of C-terminal Src kinase. Circulation. 2020;142(25):2443–55.

    Article  PubMed  CAS  Google Scholar 

  17. Kohrt HE, et al. Ibrutinib antagonizes rituximab-dependent NK cell-mediated cytotoxicity. Blood. 2014;123(12):1957–60.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Tam CS, et al. A randomized phase 3 trial of zanubrutinib vs ibrutinib in symptomatic Waldenström macroglobulinemia: the ASPEN study. Blood. 2020;136(18):2038–50.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Yazdy MS, et al. Toxicities and outcomes of acalabrutinib-treated patients with chronic lymphocytic leukemia: a retrospective analysis of real world patients. Blood. 2019;134(Supplement_1):4311–4311.

    Article  Google Scholar 

  20. Calquence met primary efficacy endpoint in head-to-head trial against ibrutinib in chronic lymphocytic leukaemia. News release. AstraZeneca. Published January 25, 2021. Accessed January 25, 2021. https://www.astrazeneca.com/content/astraz/media-centre/press-releases/2021/calquence-met-primary-endpoint-against-ibrutinib.html

  21. Caron F, et al. Current understanding of bleeding with ibrutinib use: a systematic review and meta-analysis. Blood Adv. 2017;1(12):772–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Atkinson BT, Ellmeier W, Watson SP. Tec regulates platelet activation by GPVI in the absence of Btk. Blood. 2003;102(10):3592–9.

    Article  PubMed  CAS  Google Scholar 

  23. Senis YA, Mazharian A, Mori J. Src family kinases: at the forefront of platelet activation. Blood. 2014;124(13):2013–24.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. •• Byrd JC, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369(1):32–42. Practice changing. Trial lead to approval of ibrutinib in R/R CLL.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. •• Byrd JC, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371(3):213–23. First phase 3 randomized trial showing superiority of ibrutinib over ofatumumab plus chlorambucil among patients with R/R CLL

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Munir T, 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Coutre SE, et al. Long-term safety of single-agent ibrutinib in patients with chronic lymphocytic leukemia in 3 pivotal studies. Blood Adv. 2019;3(12):1799–807.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Huang SJ, et al. Comparison of real-world treatment patterns in chronic lymphocytic leukemia management before and after availability of ibrutinib in the province of British Columbia Canada. Leuk Res. 2020;91:7.

    Article  CAS  Google Scholar 

  29. Roeker LE, et al. Allogeneic stem cell transplantation (alloHSCT) for chronic lymphocytic leukemia (CLL) in the era of novel agents. Blood. 2019;134(Supplement_1):3321.

    Article  Google Scholar 

  30. Burger JA, et al. Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL/SLL: 5 years of follow-up from the phase 3 RESONATE-2 study. Leukemia. 2020;34(3):787–98.

    Article  PubMed  CAS  Google Scholar 

  31. •• Tedeschi A, et al. Results from the international, randomized phase 3 study of ibrutinib versus chlorambucil in patients 65 years and older with treatment-naive CLL/SLL (RESONATE-2 (TM)). Blood. 2015;126(23):5. Practice changing. Showed superiority of single-agent ibrutinib over chlorambucil in older patients with untreated CLL without 17p deletion.

    Article  Google Scholar 

  32. Moreno C, 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.

    Article  PubMed  CAS  Google Scholar 

  33. Sharman JP, et al. Ublituximab plus ibrutinib versus ibrutinib alone for patients with relapsed or refractory high-risk chronic lymphocytic leukaemia (GENUINE): a phase 3, multicentre, open-label, randomised trial. Lancet Haematol. 2021;8:e254–66.

    Article  PubMed  Google Scholar 

  34. •• Shanafelt TD, et al. Ibrutinib-rituximab or chemoimmunotherapy for chronic lymphocytic leukemia. N Engl J Med. 2019;381(5):432–43. Practice changing. Showed superiority of ibrutinib plus rituximab over chemoimmunotherapy (FCR) in fit, untreated CLL patients who were 70 years of age or younger and without evidence of 17p deletion

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Shanafelt TD, et al. Ibrutinib and rituximab provides superior clinical outcome compared to FCR in younger patients with chronic lymphocytic leukemia (CLL): extended follow-up from the E1912 trial. Blood. 2019;134(Supplement_1):33.

    Article  Google Scholar 

  36. •• Woyach JA, et al. Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL. N Engl J Med. 2018;379(26):2517–28. Practice changing. Showed superiority of ibrutinib given alone or combined with rituximab over bendamustine plus rituximab in untreated CLL patients who were 65 years of age or older.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Burger JA, et al. Randomized trial of ibrutinib vs ibrutinib plus rituximab in patients with chronic lymphocytic leukemia. Blood. 2019;133(10):1011–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Deng J, 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Hillmen P, et al. Ibrutinib plus venetoclax in relapsed/refractory chronic lymphocytic leukemia: the CLARITY study. J Clin Oncol. 2019;37(30):2722–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Jain N, et al. Ibrutinib and venetoclax for first-line treatment of CLL. N Engl J Med. 2019;380(22):2095–103.

    Article  PubMed  CAS  Google Scholar 

  41. Tam CS, et al. Ibrutinib (Ibr) plus venetoclax (Ven) for first-line treatment of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL): results from the MRD cohort of the phase 2 CAPTIVATE study. Blood. 2019;134:35.

    Article  Google Scholar 

  42. Wierda WG, 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(Supplement 1):16–7.

    Article  Google Scholar 

  43. •• Ghia P, et al. ASCEND: phase III, randomized trial of acalabrutinib versus idelalisib plus rituximab or bendamustine plus rituximab in relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol. 2020;38(25):2849–61. Practice changing. Contributed to approval of acalabrutinib in patients with CLL.

    Article  PubMed  CAS  Google Scholar 

  44. Byrd JC, et al. Acalabrutinib in treatment-naive (TN) chronic lymphocytic leukemia (CLL): updated results from the phase 1/2 ACE-CL-001 study. Clin Lymphoma Myeloma Leuk. 2019;19:S283–S283.

    Article  Google Scholar 

  45. •• Sharman JP, et al. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzmab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. Lancet. 2020;395(10232):1278–91. Practice changing. Contributed to approval of acalabrutinib in patients with CLL.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Badillo M, et al. Acalabrutinib: managing adverse events and improving adherence in patients with mantle cell lymphoma. Clin J Oncol Nurs. 2020;24(4):392–8.

    Article  PubMed  Google Scholar 

  47. Lampson BL, et al. Preliminary safety and efficacy results from a phase 2 study of acalabrutinib, venetoclax and obinutuzumab in patients with previously untreated chronic lymphocytic leukemia (CLL). Blood. 2019;134:5.

    Article  Google Scholar 

  48. Tam C, et al. The BTK inhibitor, Bgb-3111, is safe, tolerable, and highly active in patients with relapsed/ refractory B-cell malignancies: initial report of a phase 1 first-in-human trial. Blood. 2015;126(23):4.

    Article  Google Scholar 

  49. Ou YC, et al. Evaluation of drug interaction potential of zanubrutinib with cocktail probes representative of CYP3A4, CYP2C9, CYP2C19, P-gp and BCRP. Br J Clin Pharmacol 2021;87(7):2926–36.

  50. Calquence (acalabrutinib) [prescribing Information]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; October 2017. https://medicalinformation.astrazeneca-us.com/home/prescribing-information/calquence-pi.html.

  51. Tam CS, et al. Phase 1 study of the selective BTK inhibitor zanubrutinib in B-cell malignancies and safety and efficacy evaluation in CLL. Blood. 2019;134(11):851–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Cull G, et al. Treatment with the Bruton tyrosine kinase inhibitor zanubrutinib (BGB-3111) demonstrates high overall response rate and durable responses in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): updated results from a phase 1/2 trial. Blood. 2019;134(Supplement_1):500.

    Article  Google Scholar 

  53. Xu W, et al. Treatment of relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma with the BTK inhibitor zanubrutinib: phase 2, single-arm, multicenter study. J Hematol Oncol. 2020;13(1):48.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Tam CS, et al. Zanubrutinib monotherapy for patients with treatment naive chronic lymphocytic leukemia and 17p deletion. Haematologica, 2020;106(9):2354–63.

  55. Liclican A, et al. Biochemical characterization of tirabrutinib and other irreversible inhibitors of Bruton’s tyrosine kinase reveals differences in on - and off - target inhibition. Biochim Biophys Acta Gen Subj. 2020;1864(4):129531.

    Article  PubMed  CAS  Google Scholar 

  56. Munakata W, et al. Phase I study of tirabrutinib (ONO-4059/GS-4059) in patients with relapsed or refractory B-cell malignancies in Japan. Cancer Sci. 2019;110(5):1686–94.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Walter HS, et al. A phase 1 clinical trial of the selective BTK inhibitor ONO/GS-4059 in relapsed and refractory mature B-cell malignancies. Blood. 2016;127(4):411–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Kutsch N, et al. A prospective, open-label, multicenter, phase 2 trial to evaluate the safety and efficacy of the combination of tirabrutinib (ONO/GS-4059) and entospletinib with and without obinutuzumab in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). Blood. 2019;134(Supplement_1):4297–4297.

    Article  Google Scholar 

  59. Kutsch N, et al. A prospective, open-label, multicenter, phase 2 trial to evaluate the safety and efficacy of the combination of tirabrutinib (ONO/GS-4059) and idelalisib with and without obinutuzumab in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). Blood. 2019;134(Supplement_1):3047.

    Article  Google Scholar 

  60. Woyach J, et al. Resistance to acalabrutinib in CLL is mediated primarily by BTK mutations. Blood. 2019;134:504.

    Article  Google Scholar 

  61. Reiff SD, et al. The BTK inhibitor ARQ 531 targets ibrutinib-resistant CLL and richter transformation. Cancer Discov. 2018;8(10):1300–15.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Brandhuber B, et al. LOXO-305, A next generation reversible BTK inhibitor, for overcoming acquired resistance to irreversible BTK inhibitors. Clin Lymphoma Myeloma Leuk. 2018;18:S216–S216.

    Article  Google Scholar 

  63. Gomez EB, et al. Loxo-305, a highly selective and non-covalent next generation BTK inhibitor, inhibits diverse BTK C481 substitution mutations. Blood. 2019;134(Supplement_1):4644–4644.

    Article  Google Scholar 

  64. Naeem AS, et al. LOXO-305: targeting C481S Bruton tyrosine kinase in patients with ibrutinib-resistant CLL. Blood. 2019;134(Supplement_1):478–478.

    Article  Google Scholar 

  65. Mato AR, et al. Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): a phase 1/2 study. Lancet. 2021;397(10277):892–901.

    Article  PubMed  CAS  Google Scholar 

  66. Woyach J, et al. Final results of phase 1, dose escalation study evaluating ARQ 531 in patients with relapsed or refractory B-cell lymphoid malignancies. Blood. 2019;134:4.

    Google Scholar 

  67. Kaptein A, et al. Potency and selectivity of BTK inhibitors in clinical development for B-cell malignancies. Blood. 2018;132(Supplement 1):1871–1871.

    Article  Google Scholar 

Download references

Acknowledgements

Editorial assistance was provided by the Moffitt Cancer Center’s Office of Scientific Writing by Dr. Paul Fletcher and Daley Drucker. No compensation was given beyond their regular salaries.

Author information

Authors and Affiliations

  1. Department of Malignant Hematology, Lymphoma Section, Moffitt Cancer Center, Tampa, FL, USA

    Sameh Gaballa & Javier Pinilla-Ibarz

  2. Tampa, USA

    Sameh Gaballa

Authors
  1. Sameh Gaballa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Javier Pinilla-Ibarz
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

SG drafted the first manuscript draft. JP reviewed and edited the manuscript. All authors approved the final manuscript.

Corresponding author

Correspondence to Sameh Gaballa.

Ethics declarations

Consent to Participate

N/A

Consent for Publication

N/A

Conflict of Interest

Sameh Gaballa reports: consulting/advisory fees from Beigene, TG therapeutics, Janssen, Celgene, Epizyme, and ADC therapeutics.

Pinilla-Ibarz reports: Consulting: Abbvie, Janssen, AstraZeneca and Takeda; Speaker Bureau: Abbvie, Janssen, AstraZeneca and Takeda; Research: TG therapeutics, MEI and Sunesis.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Chronic Lymphocytic Leukemias

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gaballa, S., Pinilla-Ibarz, J. BTK Inhibitors in Chronic Lymphocytic Leukemia. Curr Hematol Malig Rep 16, 422–432 (2021). https://doi.org/10.1007/s11899-021-00645-1

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11899-021-00645-1

Keywords

Search

Navigation