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Review

Current and emerging investigational venetoclax-based therapies in chronic lymphocytic leukemia

, ORCID Icon, , , , & show all
Pages 621-633 | Received 02 Feb 2021, Accepted 28 Apr 2021, Published online: 15 May 2021

References

  • Burger JA, Longo DL. Treatment of chronic lymphocytic leukemia. N Engl J Med. 2020 Jul 30;383(5):460–473.
  • Hallek M, Fischer K, Fingerle-Rowson G, et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet. 2010;376(9747):1164–1174.
  • Fischer K, Bahlo J, Fink AM, et al. Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial. Blood. 2016;127(2):208–215.
  • Thompson PA, Tam CS, O’Brien SM, et al. Fludarabine, cyclophosphamide, and rituximab treatment achieves long-term disease-free survival in IGHV-mutated chronic lymphocytic leukemia. Blood. 2016;127(3):303–309.
  • 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):928–942.
  • 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):1101–1110.
  • Byrd JC, Brown JR, O’Brien S, et al., RESONATE Investigators. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 371(3): 213–223. 2014.
  • Burger JA, Tedeschi A, Barr PM, et al., Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 373(25): 2425–2437. 2015.
  • Woyach JA, Ruppert AS, Heerema NA, et al., Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL. N Engl J Med. 379(26): 2517–2528. 2018.
  • 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.
  • Woyach JA, Ruppert AS, Guinn D, et al. BTKC481S-mediated resistance to ibrutinib in chronic lymphocytic leukemia. J Clin Oncol. 2017;35(13):1437–1443.
  • Quinquenel A, Fornecker LM, Letestu R, et al. Prevalence of BTK and PLCG2 mutations in a real‑life CLL cohort still on ibrutinib after three years: a FILO group study. Blood. 2019;134(7):641–644.
  • 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):1973–1980.
  • Coutre S, Choi M, Furman RR, et al. Venetoclax for patients with chronic lymphocytic leukemia who progressed during or after idelalisib therapy. Blood. 1704–1711;2018(15):131.
  • 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.
  • Roberts AW, Ma S, Kipps TJ, et al. Efficacy of Venetoclax in relapsed chronic lymphocytic leukaemia is influenced by disease and response variables. Blood. 2019;134(2):111–122.
  • Fischer K, Al-Sawaf O, Bahlo J, et al., Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 380(23): 2225–2236. 2019.
  • Kater AP, Arslan O, Demikran F, et al. Efficacy of Venetoclax in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia: primary endpoint analysis of the international phase 3b Trial (VENICE I). EHA25 Virtual. June11-21 2020; Abstract S156
  • Thijssen R, Slinger E, Weller K, et al. Resistance to ABT-199 induced by microenvironmental signals in chronic lymphocytic leukemia can be counteracted by CD20 antibodies or kinase inhibitors. Haematologica. 2015;100(8):e302–e306.
  • 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):230–240.
  • Molica S. The evolving role of time-limited targeted therapy in chronic lymphocytic leukemia. Expert Rev Anticancer Ther. 2020;20(12):1015–1019.
  • Seymour JF, Kipps TJ, Eichhorst B, et al., Venetoclax-rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 378(12): 1107–1120. 2018.
  • Kater AP, Kipps TJ, Eichhorst B, et al. Five-Year Analysis of Murano Study Demonstrates Enduring Undetectable Minimal Residual Disease (uMRD) in a Subset of Relapsed/Refractory Chronic Lymphocytic Leukemia (R/R CLL) Patients (Pts) Following Fixed-Duration Venetoclax-Rituximab (VenR) Therapy (Tx). The 62nd ASH Annual Meeting and Exposition; (Virtual Meeting), December 5-8, 2020. Abstract 215.
  • Lew TE, Anderson MA, Lin VS, et al. Undetectable peripheral blood MRD should be the goal of venetoclax in CLL, but attainment plateau after 24 months. Blood Adv. 2020;4(1):165–173.
  • Mato AR, Roeker LE, Eyre TA, et al. A retrospective comparison of venetoclax alone or in combination with an anti-CD20 monoclonal antibody in R/R CLL. Blood Adv. 2019;3(10):1568–1573.
  • Al-Sawaf O, Zhang C, Robrecht S, et al. Clonal Dynamics after Venetoclax-Obinutuzumab Therapy: novel Insights from the Randomized, Phase 3 CLL14 Trial. The 62nd ASH Annual Meeting and Exposition; (Virtual Meeting), December 5-8, 2020. Abstract 127.
  • Tausch E, Schneider C, Robrecht S, et al. Prognostic and predictive impact of genetic markers in patients with CLL treated with obinutuzumab and venetoclax. Blood. 2020;135(26):2402–2412.
  • Al-Sawaf O, Lilienweiss E, Bahlo J, et al. High efficacy of venetoclax plus obinutuzumab inpatients with complex karyotype and chronic lymphocytic leukemia. Blood. 2020;135(11):866–870.
  • Al-Sawaf O, Zhang C, Tandon M, et al. Venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (CLL14): follow-up results from a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2020;21(9):1188–1200.
  • Jain N, Keating M, Thompson P, et al. Ibrutinib and venetoclax for first-line treatment of CLL. N Engl J Med. 2019;380(22):2095–2103.
  • Hillmen P, Rawstron AC, Brock K, et al., Ibrutinib plus venetoclax in relapsed/refractory chronic lymphocytic leukemia: the CLARITY study. J Clin Oncol. 37(30): 2722–2729. 2019.
  • Munir T, Boucher RH, Webster N, et al. Continued Long Term Responses to Ibrutinib + Venetoclax Treatment for Relapsed/Refractory CLL in the Blood Cancer UK TAP Clarity Trial. The 62nd ASH Annual Meeting and Exposition; (Virtual Meeting) December 5-8, 2020. Abstract 124.
  • 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. The 62nd ASH Annual Meeting and Exposition; (Virtual Meeting), December 5-8, 2020. Abstract 123.
  • Fürstenau M, Eichhorst B. Novel agents in chronic lymphocytic leukemia: new combination therapies and strategies to overcome resistance. Cancers (Basel). 2021 Mar 16;13(6):1336.
  • Rogers KA, Huang Y, Ruppert AS, et al. Phase Ib study of obinutuzumab, ibrutinib, and venetoclax in relapsed and refractory chronic lymphocytic leukemia. Blood. 2018;132(15):1568–1572.
  • Rogers KA, Huang Y, Ruppert AS, et al. Three-Year Follow-up from a Phase 2 Study of Combination Obinutuzumab, Ibrutinib, and Venetoclax in Chronic Lymphocytic Leukemia. The 62nd ASH Annual Meeting and Exposition; (Virtual Meeting), December 5-8, 2020. Abstract 1305.
  • Huber H, Edenhofer S, Von Tresckow J, et al. CLL2-GIVE, a prospective, open-label, multicenter phase-ii trial of obinutuzumab (GA101, G), ibrutinib (I), plus venetoclax (VE) in untreated patients with CLL with 17p deletion / TP53 mutation. EHA25 Virtual Meeting; June 11-21, 2020. Abstract S157.
  • Lampson BL, Tyekucheva S, Crombie JL, 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). The 61st ASH Annual Meeting and Exposition;(Virtual Meeting), December 6-10, 2019. Abstract 32.
  • Soumerai JD, Mato AR, Carter J, et al. Initial results of a multicenter, investigator initiated study of MRD driven time limited therapy with zanubrutinib, obinutuzumab, and venetoclax. J Clin Oncol. 2020 May 20;38(15_suppl):8006.
  • Guarente V, Sportoletti P. Lessons, challenges and future therapeutic opportunities for PI3K Inhibition in CLL. Cancers (Basel). 2021 Mar 13;13(6):1280.
  • Barr PM, Ma S, Cs Z, et al. A Phase 1/2 Study of Umbralisib, Ublituximab, and Venetoclax (U2-Ven) in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL). Blood. 2020 November;136(Supplement1):41–42. Abstr 3137
  • Blombery P, Anderson MA, Gong J-N, et al. Acquisition of the recurrent Gly101Val mutation in BCL2 confers resistance to venetoclax in patients with progressive chronic lymphocytic leukemia. Cancer Discov. 2019;9(3):342–353.
  • Lucas F, Larkin K, Gregory CT, et al. Novel BCL2 mutations in venetoclax-resistant, ibrutinib-resistant CLL patients with BTK/PLCG2 mutations. Blood. 2020;135(24):2192–2195.
  • Guièze R, Liu VM, Rosebrock D, et al. Mitochondrial reprogramming underlies resistance to BCL-2 inhibition in lymphoid malignancies. Cancer Cell. 2019;36(4):369–384.
  • Brander DM, Seymour JF, Kipps TJ, et al. Durability of responses on continuous therapy and following drug cessation with venetoclax and rituximab: long-term follow-up analysis of a phase 1b study in patients with relapsed CLL [abstract]). The 61st ASH Annual Meeting and Exposition; (Virtual Meeting) December 6-10, 2019. Abstract 3036.
  • Thompson M, Allan JN, Sail K, et al. Venetoclax Re-Treatment of Chronic Lymphocytic Leukemia (CLL) Patients after a Previous Venetoclax-Based Regimen. The 62nd ASH Annual Meeting and Exposition;(Virtual Meeting), December 5-8, 2020. Abstract 3136.
  • Harrup RA, Owen C, D’Rozario J, et al. Efficacy of Subsequent Novel Targeted Therapies, Including Repeated Venetoclax-Rituximab (VenR), in Patients (Pts) with Relapsed/Refractory Chronic Lymphocytic Leukemia (R/R CLL) Previously Treated with Fixed-Duration Venr in the Murano Study. The 62nd ASH Annual Meeting and Exposition;(Virtual Meeting), December 5-8, 2020. Abstract 3139.
  • Mato AR, Roeker LE, Jacobs R, et al. Assessment of the efficacy of therapies following venetoclax discontinuation in CLL reveals BTK inhibition as an effective strategy. Clin Cancer Res. 2020;26(14):3589–3596.
  • Mato AR, Pagel JM, Coombs CC, et al. LOXO-305, A Next Generation, Highly Selective, Non-Covalent BTK Inhibitor in Previously Treated CLL/SLL: results from the Phase 1/2 BRUIN Study. The 62nd ASH Annual Meeting and Exposition; (Virtual Meeting), December 5-8, 2020. Abstract 542.
  • Bjge B, Smith S, Smith S. LOXO-305, a next generation reversible BTK inhibitor, for overcoming acquired resistance to irreversible BTK inhibitors. Clin Lymphoma Myeloma Leuk. 2018;18:S216.
  • Mato AR, Shah NN, Md J. W, et al Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): a phase 1/2 study. Lancet. 2021;397(10277):892–901.
  • Ta E, Aa K, 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):656–669.
  • 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):1353–1363.
  • Thompson MC, Mato AR. Treatment of relapsed chronic lymphocytic leukemia after venetoclax. Hematology Am Soc Hematol Educ Program. 2020 Dec 4;2020(1):18–23.
  • Garner LM, Kline T, Miller J, et al. Impact of Adherence to Ibrutinib on Clinical Outcomes in Real-World Patients With Chronic Lymphocytic Leukemia. J Adv Pract Oncol. 2021;12(1):20–28.
  • Barr PM, Brown JR, Hillmen P, et al. Impact of ibrutinib dose adherence on therapeutic efficacy in patients with previously treated CLL/SLL. Blood. 2017;129(19):2612–2615.
  • Mato AR, Sharman JP, Biondo JML, et al. The impact of early discontinuation/dose modification of venetoclax on outcomes in patients with relapsed/refractory chronic lymphocytic leukemia: post-hoc analyses from the phase III MURANO study. Haematologica Early view Dec. 2020;17.
  • Hafezi S, Targeting RM. BCL-2 in Cancer: advances, Challenges, and Perspectives. Cancers (Basel). 2021 Mar 14;13(6):1292.
  • Molica S, Giannarelli D, Montserrat E. Comparison Between Venetoclax-based and Bruton Tyrosine Kinase Inhibitor-based Therapy as Upfront Treatment of Chronic Lymphocytic Leukemia (CLL): a Systematic Review and Network Meta-analysis. Clin Lymphoma Myeloma Leuk. 2020;S2152-2650(20):30579–30586.
  • Sheng Z, Song S, Yu M, et al. Comparison of acalabrutinib plus obinutuzumab, ibrutinib plus obinutuzumab and venetoclax plus obinutuzumab for untreated CLL: a network meta-analysis. Leuk Lymphoma. 2020;61(14):3432–3439.
  • Brander D, Islam P, Barrientos JC. Tailored Treatment Strategies for Chronic Lymphocytic Leukemia in a Rapidly Changing Era. Am Soc Clin Oncol Educ Book. 2019;39(39):487–498.
  • Smolewski P, Robak T. Current Treatment of Refractory/Relapsed Chronic Lymphocytic Leukemia: a Focus on Novel Drugs. Acta Haematol. 2020 Nov;25:1–15.
  • Prukova D, Andera L, Nahacka Z, et al. Co-targeting of BCL2 with venetoclax and MCL1 with S63845 is synthetically lethal in vivo in relapsed mantle cell lymphoma. Clin Cancer Res. 2019;25(14):4455–4465.
  • Wei AH, Roberts AW, Spencer A, et al. Targeting MCL-1 in hematologic malignancies: rationale and progress. Blood Rev. 2020;44:100672. Epub 2020 Feb 21.
  • Tron AE, Belmonte MA, Adam A, et al. Discovery of Mcl-1-specific inhibitor AZD5991 and preclinical activity in multiple myeloma and acute myeloid leukemia. Nat Commun. 2018;9(1):5341.
  • Luedtke DA, Su Y, Ma J, et al. Inhibition of CDK9 by voruciclib synergistically enhances cell death induced by the Bcl-2 selective inhibitor venetoclax in preclinical models ofacute myeloid leukemia. Signal Transduct Target Ther. 2020;5(17). 10.1038/s41392-020-0112-3.
  • Dey J, Deckwerth TL, Kerwin WS, et al. Voruciclib, a clinical stage oral CDK9 inhibitor, represses MCL-1 and sensitizes high-risk Diffuse Large B-cell Lymphoma to BCL2 inhibition. Sci Rep. 2017;7(1):18007.
  • Dreger P, Ghia P, Schetelig J, et al. High-risk chronic lymphocytic leukemia in the era of pathway inhibitors: integrating molecular and cellular therapies. Blood. 2018;132(9):892–902.
  • Wierda WG, Dorritie KA, Munoz J, et al. Transcend CLL 004: phase 1 cohort of lisocabtagene maraleucel (liso-cel) in combination with ibrutinib for patients with relapsed/refractory (r/r) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Presented at: the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition; (Virtual Meeting), December 5-9, 2020. Abstract 544.
  • Robinson HR, Qi J, Cook EM, et al. A CD19/CD3 bispecific antibody for effective immunotherapy of chronic lymphocytic leukemia in the ibrutinib era. Blood. 2018;132(5):521–532.
  • Van Der Horst HJ, De Jonge AV, Hiemstra IH, et al. Epcoritamab induces potent anti-tumor activity against malignant B-cells from patients with DLBCL, FL and MCL, irrespective of prior CD20 monoclonal antibody treatment. Blood Cancer J. 2021 Feb 18;11(2):38.
  • Cuneo A, Scarfo’ L, Reda G, et al. Chronic lymphocytic leukemia management in Italy during the COVID-19 pandemic: a Campus CLL report. Blood. 2020;136(6):763–766.
  • Scarfo L, Chatzikonstantinou T, Rigolin GM, et al. COVID-19 severity and mortality in patients with chronic lymphocytic leukemia: a joint study by ERIC. the European Research Initiative on CLL, and CLL Campus:Leukemia. Vol. 34. 9 2020 2354–2363.
  • [cited 2021 Feb 2]. Available from: https://www.hematology.org/covid-19/covid-19-and-cll. COVID-19 and CLL.
  • https://ehaweb.org/covid-19/covid-19-recommendations/recommendations-for-specific-hematologic-malignancies. COVID-19 and CLL: frequently Asked Questions (Produced by the EHA SWG on CLL (ERIC) and endorsed by EHA).
  • Roeker LE, Scarfo L, Chatzikonstantinou T, et al. Worldwide Examination of Patients with CLL Hospitalized for COVID-19. Presented at: the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition; December 5-9, 2020. Abstract 1590.

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