Navigating the Paradigm Shift in Chronic Lymphocytic Leukemia Treatment from Chemotherapy to Targeted Therapies
DOI:
https://doi.org/10.58931/cht.2024.3s01-244Abstract
The shift from traditional chemotherapy to more targeted therapies has been a landmark change in chronic lymphocytic leukemia (CLL) treatment. This transformation has implications for treatment efficacy, tolerability, and patient quality of life, along with implications for the Canadian oncology community at large, which must rapidly adapt to these advancements. This rapid development underscores the importance of continued responsiveness in medical practice, including more collaborative work with Canadian institutions and provincial cancer care to deliver these transformative therapies to patients. This review aims to offer practical guidance, from a Canadian perspective, for clinicians in treatment selection in the era of targeted therapies.
References
Owen C, Banerji V, Johnson N, Gerrie A, Aw A, Chen C, Robinson S. Canadian evidence-based guideline for frontline treatment of chronic lymphocytic leukemia: 2022 update. Leuk. Res. 2023 Jan 5:107016. doi: 10.1016/j.leukres.2023.107016
Jaramillo S, Agathangelidis A, Schneider C, Bahlo J, Robrecht S, Tausch E, Bloehdorn J, Hoechstetter M, Fischer K, Eichhorst B, Goede V. Prognostic impact of prevalent chronic lymphocytic leukemia stereotyped subsets: analysis within prospective clinical trials of the German CLL Study Group. Haematologica. 2020 Nov 11;105(11):2598. doi: 10.3324/haematol.2019.231027
Kater AP, Eichhorst B. Inhibiting BTK in Chronic Lymphocytic Leukemia. NEJM. 2023 Jul 6;389(1):83-6. Doi: 10.1056/NEJMe2302721
O’Brien SM, Brown JR, Byrd JC, Furman RR, Ghia P, Sharman JP, et al. Monitoring and managing BTK inhibitor treatment-related adverse events in clinical practice. Front Oncol. 2021 8;11:720704. doi: 10.3389/fonc.2021.720704
Souers AJ, Leverson JD, Boghaert ER, Ackler SL, Catron ND, Chen J, Dayton BD, Ding H, Enschede SH, Fairbrother WJ, Huang DC. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat. Med. 2013 Feb;19(2):202-8. doi: 10.1038/nm.3048
Fischer K, Al-Sawaf O, Bahlo J, Fink AM, Tandon M, Dixon M, Robrecht S, Warburton S, Humphrey K, Samoylova O, Liberati AM. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. NEJM. 2019 Jun 6;380(23):2225-36. doi: 10.1056/NEJMoa1815281
Morton LM, Curtis RE, Linet MS, Schonfeld SJ, Advani PG, Dalal NH, et al. Trends in risk for therapy-related myelodysplastic syndrome/acute myeloid leukemia after initial chemo/immunotherapy for common and rare lymphoid neoplasms, 2000–2018. EClinicalMedicine. 2023 Jul 1;61. doi: 10.1016/j.eclinm.2023.102060
Shanafelt TD, Wang XV, Hanson CA, Paietta EM, O’Brien S, Barrientos J, et al. Long-term outcomes for ibrutinib–rituximab and chemoimmunotherapy in CLL: updated results of the E1912 trial. Blood. 2022 14;140(2):112-120. doi: 10.1182/blood.2021014960
Hillmen P, Pitchford A, Bloor A, Broom A, Young M, Kennedy B, et al. Ibrutinib and rituximab versus fludarabine, cyclophosphamide, and rituximab for patients with previously untreated chronic lymphocytic leukaemia (FLAIR): interim analysis of a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2023 1;24(5):535-552. doi: 10.1016/S1470-2045(23)00144-4
Eichhorst B, Niemann CU, Kater AP, Fürstenau M, von Tresckow J, Zhang C, et l. First-line venetoclax combinations in chronic lymphocytic leukemia. N Engl J Med. 2023 11;388(19):1739-1754. doi: 10.1056/NEJMoa2213093
Tam CS, Allan JN, Siddiqi T, Kipps TJ, Jacobs R, Opat S, et al. Fixed-duration ibrutinib plus venetoclax for first-line treatment of CLL: primary analysis of the CAPTIVATE FD cohort. Blood. 2022 2;139(22):3278-3289. doi: 10.1016/S1470-2045(22)00293-5
Chatterjee A, van de Wetering G, Goeree R, Owen C, Desbois AM, et al. A probabilistic cost-effectiveness analysis of venetoclax and obinutuzumab as a first-line therapy in chronic lymphocytic leukemia in Canada. PharmacoEcon Open. 2023;7(2):199-216. doi: 10.1007/s41669-022-00375-x
Kater AP, Owen C, Moreno C, Follows G, Munir T, Levin MD, et al. Fixed-duration ibrutinib-venetoclax in patients with chronic lymphocytic leukemia and comorbidities. N Engl J Med Evid. 2022 28;1(7).
Barr PM, Owen C, Robak T, Tedeschi A, Bairey O, Burger JA, et al. Up to 8-year follow-up from RESONATE-2: first-line ibrutinib treatment for patients with chronic lymphocytic leukemia. Blood Adv. 2022 14;6(11):3440-3450. doi: 10.1182/bloodadvances.2021006434
Jones J, Mato A, Coutre S, Byrd JC, Furman RR, Hillmen P, et al. Evaluation of 230 patients with relapsed/refractory deletion 17p chronic lymphocytic leukaemia treated with ibrutinib from 3 clinical trials. Br J Haematol. 2018;182(4):504-512. doi: 10.1111/bjh.15421
Woyach JA, Ruppert AS, Heerema NA, Zhao W, Booth AM, Ding W, et al. Long-term results of alliance A041202 show continued advantage of Ibrutinib-based regimens compared with bendamustine plus rituximab (BR) chemoimmunotherapy. Blood. 2021 23;138:639. doi: 10.1182/blood-2021-153146
Chanan-Khan A, Cramer P, Demirkan F, Fraser G, Silva RS, Grosicki S, et al. Ibrutinib combined with bendamustine and rituximab compared with placebo, bendamustine, and rituximab for previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma (HELIOS): a randomised, double-blind, phase 3 study. Lancet Oncol. 2016 1;17(2):200-211. doi: 10.1016/S1470-2045(15)00465-9
Sharman JP, Egyed M, Jurczak W, Skarbnik A, Pagel JM, Flinn IW, et al. ELEVATE-TN: at 5 years, progression-free survival with high tolerability maintained in treatment-naïve CLL patients [Internet]. American Society of Clinical Oncology (ASCO) 2022 Annual meeting: June 3-7, 2022; Chicago, Illinois. The Medical Xchange [cited 2023 Aug 29]. Available from: https://themedicalxchange.com/en/2022/06/21/2447-at-5-years-progression-free-survival-with-high-tolerability-maintained-in-treatment-naive-cll-patients/
Sharman JP, Egyed M, Jurczak W, Skarbnik A, Pagel JM, Flinn IW, 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-naïve chronic lymphocytic leukemia. Leukemia. 2022;36(4):1171-1175. doi: 10.1038/s41375-021-01485-x
Tam CS, Brown JR, Kahl BS, Ghia P, Giannopoulos K, Jurczak W, 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 1;23(8):1031-1043. doi: 10.1016/S1470-2045(22)00293-5
Shadman M, Munir T, Robak T, et al. Zanubrutinib vs bendamustine + rituximab in patients with treatment-naïve chronic lymphocytic leukemia/small lymphocytic lymphoma: extended follow-up of the SEQUOIA study. Presented at: 17th International Conference on Malignant Lymphoma; June 13-17, 2023. Lugano, Switzerland. Abstract 154.
Munir T, Brown JR, O’Brien S, Barrientos JC, Barr PM, Reddy NM, 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. doi: 10.1002/ajh.25638
Byrd JC, Hillmen P, Ghia P, Kater AP, Chanan-Khan A, Furman RR, O’Brien S, Yenerel MN, Illés A, Kay N, Garcia-Marco JA. Acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia: results of the first randomized phase III trial. J. of Clin. Onc. 2021 Nov 1;39(31):3441-52.
Ghia P, Pluta A, Wach M, Lysak D, Kozak T, Simkovic M, 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 1;38(25):2849-2861. doi: 10.1200/JCO.19.03355
Brown JR, Eichhorst B, Hillmen P, Jurczak W, Kaźmierczak M, Lamanna N, et al. Zanubrutinib or ibrutinib in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2023 26;388(4):319-332. doi: 10.1056/NEJMoa2211582
Seymour JF, Kipps TJ, Eichhorst B, Hillmen P, D’Rozario J, Assouline S, et al. Venetoclax–rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2018 22;378(12):1107-1120. doi: 10.1056/NEJMoa1713976
Sharman JP, Coutre SE, Furman RR, Cheson BD, Pagel JM, Hillmen P, et al. Final results of a randomized, phase III study of rituximab with or without idelalisib followed by open-label idelalisib in patients with relapsed chronic lymphocytic leukemia. J Clin Oncol. 2019 6;37(16):1391-1402. doi: 10.1200/JCO.18.01460
Mato AR, Roeker LE, Jacobs R, Hill BT, Lamanna N, Brander D, et al. Assessment of the efficacy of therapies following venetoclax discontinuation in CLL reveals BTK inhibition as an effective strategy. Clin Cancer Res. 2020 15;26(14):3589-3596. doi: 10.1158/1078-0432.CCR-19-3815
Woyach JA, Furman RR, Liu TM, Ozer HG, Zapatka M, Ruppert AS, Xue L, Li DH, Steggerda SM, Versele M, Dave SS. Resistance mechanisms for the Bruton’s tyrosine kinase inhibitor ibrutinib. NEJM. 2014 Jun 12;370(24):2286-94. doi: 10.1056/NEJMoa1400029
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 Jul;31(7):1645-7.
Johnson AR, Kohli PB, Katewa A, Gogol E, Belmont LD, Choy R, Penuel E, Burton L, Eigenbrot C, Yu C, Ortwine DF. Battling Btk mutants with noncovalent inhibitors that overcome Cys481 and Thr474 mutations. ACS Chem. Bio. 2016 Oct 21;11(10):2897-907.
Burger JA, Landau DA, Taylor-Weiner A, Bozic I, Zhang H, Sarosiek K, Wang L, Stewart C, Fan J, Hoellenriegel J, Sivina M. Clonal evolution in patients with chronic lymphocytic leukaemia developing resistance to BTK inhibition. Nat. commun. 2016 May 20;7(1):11589.
Blombery P, Thompson ER, Lew TE, Tiong IS, Bennett R, Cheah CY, et al. Enrichment of BTK Leu528Trp mutations in patients with CLL on zanubrutinib: potential for pirtobrutinib cross-resistance. Blood Adv. 2022 25;6(20):5589-5592. doi: 10.1182/bloodadvances.2022008325
Wang E, Mi X, Thompson MC, Montoya S, Notti RQ, Afaghani J, et al. Mechanisms of resistance to noncovalent Bruton’s tyrosine kinase inhibitors. N Engl J Med. 2022 24;386(8):735-743. doi: 10.1056/NEJMoa2114110
Koenig KL, Huang Y, Dotson EK, Sheredy S, Bhat SA, Byrd JC, et al. Safety of venetoclax rapid dose escalation in CLL patients previously treated with B-cell receptor signaling antagonists. Blood Adv. 2020 13;4(19):4860-4863. doi: 10.1182/bloodadvances.2020002593
Ailawadhi S, Chen Z, Huang B, Paulus A, Collins MC, Fu LT, Li M, Ahmad M, Men L, Wang H, Davids MS. Novel BCL-2 Inhibitor Lisaftoclax in Relapsed or Refractory Chronic Lymphocytic Leukemia and Other Hematologic Malignancies: First-in-Human Open-Label Trial. Clin. Cancer Res. 2023 Jul 1;29(13):2385-93. doi: 10.1158/1078-0432.CCR-22-3321
Cheah CY, Tam CS, Lasica M, Verner E, Browett PJ, Anderson MA, Hilger J, Fang Y, Simpson D, Opat S. A Phase 1 Study with the Novel B-Cell Lymphoma 2 (Bcl-2) Inhibitor Bgb-11417 As Monotherapy or in Combination with Zanubrutinib (ZANU) in Patients (Pts) with CLL/SLL: Preliminary Data. Blood. 2022 Nov 15;140(Supplement 1):2321-3. doi: 10.1182/blood-2022-169662
Todorovic Z, Todorovic D, Markovic V, Ladjevac N, Zdravkovic N, Djurdjevic P, Arsenijevic N, Milovanovic M, Arsenijevic A, Milovanovic J. CAR T cell therapy for chronic lymphocytic leukemia: successes and shortcomings. Curr. Onc. 2022 May 18;29(5):3647-57.
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