Skip to main content
SpringerLink
Log in

Venetoclax: A Review in Relapsed/Refractory Chronic Lymphocytic Leukemia

  • Adis Drug Evaluation
  • Published:
Targeted Oncology Aims and scope Submit manuscript

Abstract

Venetoclax (Venclyxto®; Venclexta®) is a first-in-class, oral, selective B cell lymphoma-2 (BCL-2) inhibitor. The drug is approved in numerous countries, including those of the EU and in the USA, for the treatment of adults with relapsed or refractory (RR) chronic lymphocytic leukemia (CLL); the specific indication(s) for venetoclax may vary between individual countries. Venetoclax monotherapy or combination therapy with rituximab was an effective treatment, provided durable responses, and had a manageable safety profile in pivotal clinical trials in adults with RR CLL, including in patients with adverse prognostic factors. In combination with 6 cycles of rituximab, venetoclax (fixed 24 months’ treatment) was more effective than bendamustine plus rituximab (6 cycles) in prolonging progression-free survival (PFS) and inducing undetectable minimal residual disease (uMRD) in peripheral blood (PB) and bone marrow (BM), with these benefits sustained during 36 months’ follow-up. Hence, with its novel mechanism of action and convenient oral once-daily regimen, venetoclax monotherapy or fixed 24-month combination therapy with rituximab represents an important option for treating RR CLL, including in patients with del(17p) or TP53 mutation and those failing a B cell receptor (BCR) inhibitor and/or chemotherapy.

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

Similar content being viewed by others

References

  1. Sharma S, Rai KR. Chronic lymphocytic leukemia (CLL) treatment; so many choices, such great options. Cancer. 2019;125:1432–40.

    Article  PubMed  Google Scholar 

  2. Hanna KS. Updates in the management of chronic lymphocytic leukemia/small lymphocytic leukemia. J Oncol Pharm Pract. 2019. https://doi.org/10.1177/1078155219853030.

    Article  PubMed  Google Scholar 

  3. Gaidano G, Rossi D. The mutational landscape of chronic lymphocytic leukemia and its impact on prognosis and treatment. Hematol Am Soc Educ Program. 2017;2017(1):329–37.

    Article  Google Scholar 

  4. Von Tresckow J, Eichhorst B, Bahlo J, et al. The treatment of chronic lymphatic leukemia. Dtsch Arzebl Int. 2019;116:41–6.

    Google Scholar 

  5. Abrisqueta P, Crespo M, Bosch F. Personalizing treatment for chronic lymphocytic leukemia. Exp Rev Haematol. 2011;4(1):27–35.

    Article  Google Scholar 

  6. Khan N, Kahl B. Targeting BCL-2 in hematologic malignancies. Targeted Oncol. 2018;13(3):257–67.

    Article  Google Scholar 

  7. Anderson MA, Deng J, Seymour JF, et al. The BCL2 selective inhibitor venetoclax induces rapid onset apoptosis of CLL cells in patients via a TP53-independent mechanism. Blood. 2016;127(25):3215–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Adams CM, Clark-Garvey S, Porcu P, et al. Targeting the Bcl-2 family in B cell lymphoma. Front Oncol. 2019;8:636.

    Article  PubMed  PubMed Central  Google Scholar 

  9. AbbVie Ltd. Venclyxto (Venetoclax): summary of product characteristics. 2019. http://www.medicines.org.uk/. Accessed 24 Aug 2019.

  10. AbbVie. Venclexta® (Venetoclax tablets): US prescribing information. 2019 https://www.rxabbvie.com/pdf/venclexta.pdf. Accessed 24 Aug 2019.

  11. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology (NCCN Guidelines®): chronic lymphocytic leukaemia/small lymphocytic lymphoma. Version 5.2019. 2019. http://www.nccn.org. Accessed 13 Jun 2019.

  12. 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.

    Article  CAS  PubMed  Google Scholar 

  13. Vogler M, Dinsdale D, Dyer MJS, et al. ABT-199 selectively inhibits BCL2 but not BCL2L1 and efficiently induces apoptosis of chronic lymphocytic leukaemic cells but not platelets. Br J Haematol. 2013;163(1):139–42.

    Article  CAS  PubMed  Google Scholar 

  14. Vandenberg CJ, Cory S. ABT-199, a new Bcl-2-specific BH3 mimetic, has in vivo efficacy against aggressive Myc-driven mouse lymphomas without provoking thrombocytopenia. Blood. 2013;121(12):2285–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Cao Y, Yang G, Hunter ZR, et al. The BCL2 antagonist ABT-199 triggers apoptosis, and augments ibrutinib and idelalisib mediated cytotoxicity in CXCR15(Wild-type) and CXCR15(WHIM) mutated Waldenstrom macroglobulinaemia cells. Br J Haematol. 2015;170(1):134–8.

    Article  CAS  PubMed  Google Scholar 

  16. Ackler S, Oleksijew A, Chen J, et al. Clearance of systemic hematologic tumors by venetoclax (Abt-199) and navitoclax. Pharmacol Res Perspect. 2015;3(5):e00178.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Peirs S, Matthijssens F, Goossens S, et al. ABT-199 mediated inhibition of BCL-2 as a novel therapeutic strategy in T-cell acute lymphoblastic leukemia. Blood. 2014;124(25):3738–47.

    Article  CAS  PubMed  Google Scholar 

  18. Ko TK, Chuah CTH, Huang JWJ, et al. The BCL2 inhibitor ABT-199 significantly enhances imatinib-induced cell death in chronic myeloid leukemia progenitors. Oncotarget. 2014;5(19):9033–8.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Touzeau C, Dousset C, Le Gouill S, et al. The Bcl-2 specific BH3 mimetic ABT-199: a promising targeted therapy for t(11;14) multiple myeloma. Leukemia. 2014;28(1):210–2.

    Article  CAS  PubMed  Google Scholar 

  20. Phillips DC, Xiao Y, Lam LT, et al. Loss in MCL-1 function sensitizes non-Hodgkin’s lymphoma cell lines to the BCL-2-selective inhibitor venetoclax (ABT-199). Blood Cancer J. 2015;5:e368.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Tessoulin B, Papin A, Gomez-Bougie P, et al. BCL-2 family dysregulation in B-cell malignancies: from gene expression regulation to a targeted therapy biomarker. Front Oncol. 2019;8:645.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Birkinshaw RW, Gong JN, Luo CS, et al. Studies of BCL-2 in complex with venetoclax reveal the molecular basis of resistance mutations. Nat Commun. 2019;10(1):2385.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Tausch E, Close W, Dolnik A, et al. Venetoclax resistance and acquired BCL2 mutations in chronic lymphocytic leukemia. Haematology. 2019. https://doi.org/10.3324/haematol.2019.222588.

    Article  Google Scholar 

  24. Blombery P, Anderson MA, Gong JN, et al. Acquisition of the recurrent Gly101Val mutation in BCL-2 confers resistance to venetoclax in patients with progressive chronic lymphocytic leukemia. Cancer Discov. 2019;9(3):342–53.

    Article  PubMed  Google Scholar 

  25. Fresquet V, Rieger M, Carolis C, et al. Acquired mutations in BCL2 family proteins conferring resistance to the BH3 mimetic ABT-199 in lymphoma. Blood. 2014;123(26):4111–9.

    Article  CAS  PubMed  Google Scholar 

  26. Freise KJ, Dunbar M, Jones AK, et al. Venetoclax does not prolong the QT interval in patients with hematological malignancies: an exposure-response analysis. Cancer Chemother Pharmacol. 2016;78(4):847–53.

    Article  CAS  PubMed  Google Scholar 

  27. Salem AH, Agarwal SK, Dunbar M, et al. Pharmacokinetics of venetoclax, a novel BCL-2 Inhibitor, in patients with relapsed or refractory chronic lymphocytic leukemia or non-Hodgkin lymphoma. J Clin Pharmacol. 2017;57(4):484–92.

    Article  CAS  PubMed  Google Scholar 

  28. Salem AH, Agarwal SK, Dunbar M, et al. Effect of low- and high-fat meals on the pharmacokinetics of venetoclax, a selective first-in-class BCL-2 Inhibitor. J Clin Pharmacol. 2016;56(11):1355–61.

    Article  CAS  PubMed  Google Scholar 

  29. Reda G, Cassin R, Dovrtelova G, et al. Venetoclax penetrates in cerebrospinal fluid and may be effective in CLL with central nervous system involvement [abstract]. Haematologica. 2019;104(5):e222–3.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Jones AK, Freise KJ, Agarwal SK, et al. Clinical predictors of venetoclax pharmacokinetics in chronic lymphocytic leukemia and non-Hodgkin’s lymphoma patients: a pooled population pharmacokinetic analysis. AAPS J. 2016;18(5):1192–202.

    Article  CAS  PubMed  Google Scholar 

  31. Deng R, Gibiansky L, Lu T, et al. Bayesian population model of the pharmacokinetics of venetoclax in combination with rituximab in patients with relapsed/refractory chronic lymphocytic leukemia: results from the MURANO study. Clin Pharmacokinet. 2019. https://doi.org/10.1007/s40262-019-00788-8.

    Article  PubMed  Google Scholar 

  32. Salem AH, Dave N, Marbury T, et al. Pharamcokinetics of the BCL-2 inhibitor venetoclax in subjects with hepatic impairment. Clin Pharmacokinet. 2019. https://doi.org/10.1007/s40262-019-00746-4.

    Article  PubMed  Google Scholar 

  33. Salem AH, Hu B, Freise KJ, et al. Evaluation of the pharmacokinetic interaction between venetoclax, a selective BCL-2 inhibitor, and warfarin in healthy volunteers. Clin Drug Invest. 2017;37:303–9.

    Article  CAS  Google Scholar 

  34. Agarwal SK, Hu B, Chien D, et al. Evaluation of rifampin’s transporter inhibitory and CYP3A inductive effects on the pharmacokinetics of venetoclax, a BCL-2 inhibitor: results of a single- and multiple-dose study. J Clin Pharmacol. 2016;56(11):1335–43.

    Article  CAS  PubMed  Google Scholar 

  35. Agarwal SK, Salem AH, Danilov AV, et al. Effect of ketoconazole, a strong CYP3A inhibitor, on the pharmacokinetics of venetoclax, a BCL-2 inhibitor, in patients with non-Hodgkin lymphoma. Br J Clin Pharmacol. 2017;83(4):846–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Stilgenbauer S, Eichhorst B, Schetelig J, et al. Venetoclax for patients with chronic lymphocytic leukemia with 17p deletion: results from the full population of a phase II pivotal trial. J Clin Oncol. 2018;36(19):1973–80.

    Article  CAS  PubMed  Google Scholar 

  37. Stilgenbauer S, Eichhorst B, Schetelig J, et al. Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study. Lancet Oncol. 2016;17(6):768–78.

    Article  CAS  PubMed  Google Scholar 

  38. 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.

    Article  CAS  PubMed  Google Scholar 

  39. Coutre S, Choi M, Furman RR, et al. Venetoclax for patients with chronic lymphocytic leukemia who progressed during or after idelalisib therapy. Blood. 2018;131(15):1704–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Roberts AW, Davids MS, Pagel JM, et al. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374(4):311–22.

    Article  CAS  PubMed  Google Scholar 

  41. Freise KJ, Jones AK, Eckert D, et al. Impact of venetoclax exposure on clinical efficacy and safety in patients with relapsed or refractory chronic lymphocytic leukemia. Clin Pharmacokinet. 2017;56(5):515–23.

    Article  PubMed  Google Scholar 

  42. Cochrane T, Chagorova T, Robak T, et al. Venetoclax improves quality of life for patients with relapsed/refractory chronic lymphocytic leukemia [abstract]. Blood. 2018;132(Suppl 1):4858.

    Article  Google Scholar 

  43. Wierda W, Sail K, Potluri J, et al. Impact of venetoclax on the quality of life of CLL patients relapsed/refractory to B-cell receptor (BCR) signaling pathway inhibitor treatment [abstract no. BSH18-PO-081]. Br J Haematol. 2018;181(Suppl 1):88–9.

    Google Scholar 

  44. Wierda W, Sail K, Noe L, et al. Impact of venetoclax on the quality of life of patients with relapsed/refractory chronic lymphocytic leukemia: results of a phase 2, open-label study of venetoclax (ABT-199/GDC-0199) monotherapy [abstract no. E1466]. Haematologica. 2017;102(Suppl 2):599.

    Google Scholar 

  45. Seymour JF, Kipps TJ, Eichhorst B, et al. Venetoclax–rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2018;378(12):1107–20.

    Article  CAS  PubMed  Google Scholar 

  46. Seymour JF, Ma S, Brander DM, et al. Venetoclax plus rituximab in relapsed or refractory chronic lymphocytic leukaemia: a phase 1b study. Lancet Oncol. 2017;18(2):230–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Brander DM, Seymour JF, Ma S, et al. Durability of responses on continuous therapy and following drug cessation in deep responders with venetoclax and rituximab [abstract]. Blood. 2018;132(Suppl 1):183.

    Article  Google Scholar 

  48. Kater AP, Seymour JF, Hillmen P, et al. Fixed duration of venetoclax–rituximab in relapsed/refractory chronic lymphocytic leukemia eradicates minimal residual disease and prolongs survival: post-treatment follow-up of the MURANO phase III study. J Clin Oncol. 2019;37(4):269–77.

    Article  CAS  PubMed  Google Scholar 

  49. Eyre TA, Kirkwood AA, Gohill S, et al. Efficacy of venetoclax monotherapy in patients with relapsed chronic lymphocytic leukaemia in the post-BCR inhibitor setting: a UK wide analysis. Br J Haematol. 2019;185(4):656–69.

    Article  CAS  PubMed  Google Scholar 

  50. Bouclet F, Calleja A, Dilhuydy MS, et al. Outcome of patients receiving venetoclax for chronic lymphocytic leukemia (CLL) in real-life clinical practice: results of the French ATU program on behalf of the Filo Group [abstract]. Blood. 2018;132(Suppl 1):5549.

    Article  Google Scholar 

  51. Innocenti I, Morelli F, Autore F. Venetoclax in CLL patients who progress after B-cell receptor inhibitor treatment: a retrospective multi-centre Italian experience. Br J Haematol. 2019. https://doi.org/10.1111/bjh.16123.

    Article  PubMed  Google Scholar 

  52. Mato AR, Hill BT, Lamanna N, et al. Optimal sequencing of ibrutinib, idelalisib, and venetoclax in chronic lymphocytic leukemia: results from a multicenter study of 683 patients. Ann Oncol. 2017;28(5):1050–6.

    Article  CAS  PubMed  Google Scholar 

  53. Mato AR, Thompson M, Allan JN, et al. Real-world outcomes and management strategies for venetoclax-treated chronic lymphocytic leukemia patients in the United States. Haematologica. 2018;103(9):1511–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Nabhan C, Klink A, Samp J, et al. Management, adverse events, and outcomes of 282 CLL patients (PTS) treated with venetoclax (VEN) in the real world [abstract no. PF342]. HemaSphere. 2018;2(Suppl 1):122–3.

    Google Scholar 

  55. Davids MS, Hallek M, Wierda W, et al. Comprehensive safety analysis of venetoclax monotherapy for patients with relapsed/refractory chronic lymphocytic leukemia. Clin Cancer Res. 2018;24(18):4371–9.

    Article  CAS  PubMed  Google Scholar 

  56. McBride A, Trifilio S, Baxter N, et al. Managing tumor lysis syndrome in the era of novel cancer therapies. Adv Pract. 2017;8(7):705–20.

    Google Scholar 

  57. Roeker LE, Fox CP, Eyre TA, et al. Tumor lysis, adverse events, and dose adjustments in 297 venetoclax-treated CLL patients in routine clinical practice. Clin Cancer Res. 2019;25(14):4264–70.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Burger JA, O’Brien S. Evolution of CLL treatment—from chemoimmunotherapy to targeted and individualized therapy. Nat Rev Clin Oncol. 2018;15(8):510–27.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  60. Hallek M. Chronic lymphocytic leukemia: 2019 update on diagnosis, risk stratification and treatment. Am J Hematol. 2019. https://doi.org/10.1002/ajh.25595.

    Article  PubMed  Google Scholar 

  61. Eichhorst B, Robak P, Montserrat E, et al. Chronic lymphocytic leukaemia: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015;26(Suppl 5):v78–84.

    Article  PubMed  Google Scholar 

  62. ESMO Guidelines Committee. Appendix 4: Chronic lymphocytic leukaemia: eUpdate published online 27 June 2017 (www.esmo.org/Guidelines/Haematological-Malignancies). Ann Oncol. 2017;28(Suppl 4):iv149–52.

    Google Scholar 

  63. Mato A, Follows G, Sail K, et al. Indirect treatment comparison of venetoclax plus rituximab with B-cell receptor inhibitors in patients with relapsed/refractory chronic lymphocytic leukemia [abstract no. PF358]. HemaSphere. 2018;2(Suppl):132.

    Google Scholar 

  64. Roberts AW, Ma S, Kipps TJ, et al. Efficacy of venetoclax in relapsed chronic lymphocytic leukemia is influenced by disease and response variables. Blood. 2019;134(2):111–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Hilal T, Betcher JA, Leis JF. Economic impact of oral therapies for chronic lymphocytic leukemia: the burden of novelty. Curr Hematol Malig Rep. 2018;13:237–43.

    Article  PubMed  Google Scholar 

  66. National Institute for Health and Care Excellence. Venetoclax with rituximab for previously treated chronic lymphocytic leukaemia: technology appraisal guidance ta561. 2019. http://www.nice.org.uk/. Accessed 25 June 2019.

Download references

Acknowledgements

During the peer review process, the manufacturer of venetoclax was also offered an opportunity to review this article. Changes resulting from comments received were made on the basis of scientific and editorial merit.

Author information

Authors and Affiliations

  1. Springer Nature, Mairangi Bay, Private Bag 65901, Auckland, 0754, New Zealand

    Lesley J. Scott

Authors
  1. Lesley J. Scott
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lesley J. Scott.

Ethics declarations

Funding

The preparation of this review was not supported by any external funding.

Conflict of interest

Lesley Scott is a salaried employee of Adis International Ltd./Springer Nature, is responsible for the article content and declares no relevant conflicts of interest.

Additional information

The manuscript was reviewed by:M. J. Braunstein, NYU Long Island School of Medicine, NYU Winthrop Hospital, Department of Medicine, Division of Haematology/Oncology, Mineola, NY, USA; T. Eyre, Oxford University Hospitals NHS Foundation Trust, Department of Haematology, Churchill Hospital, Oxford, UK; Y. Ge, Wayne State University School of Medicine, Department of Oncology, Detroit, MI, USA; J. F. Seymour, Peter MacCallum Cancer Center and Royal Melbourne Hospital, Department of Haematology, Melbourne, Victoria, Australia.

Enhanced material for this Adis Drug Evaluation can be found at https://adisjournals.figshare.com/s/dd9a375ae5aa5a191349.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Scott, L.J. Venetoclax: A Review in Relapsed/Refractory Chronic Lymphocytic Leukemia. Targ Oncol 14, 493–504 (2019). https://doi.org/10.1007/s11523-019-00673-1

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11523-019-00673-1

Search

Navigation