Network meta-analysis of upfront fixed-duration therapies in chronic lymphocytic leukemia

Molica, Stefano; Allsup, David; Giannarelli, Diana

Abstract

The emergence of Bruton's tyrosine kinase (BTK) inhibitors marked a significant advancement in chronic lymphocytic leukemia (CLL) management, especially for high-risk patients. 1 Ibrutinib, the pioneering BTK inhibitor, has undergone extensive study. The final analysis of the RESONATE-2 study confirms its sustained survival benefit for first-line CLL treatment with up to 10 years of follow-up. 2 Despite its efficacy, prolonged administration of BTK inhibitors can lead to cardiovascular toxicities and emergence of therapy resistance mutations. 3,4 Time-limited CLL-directed therapies, inspired by venetoclax's unique attributes in inducing deep therapeutic responses, aim to address continuous therapy limitations. 5 Venetoclax combined with anti-CD20 monoclonal antibodies in fixed-duration (FD) regimens, showcased in relapsed/refractory CLL with MURANO and in frontline with CLL14 and CLL13 trials, sustain responses with manageable toxicity across CLL patient profiles. 6-9 By harnessing the synergistic potential of venetoclax and ibrutinib (VI), which combines agents with distinct mechanisms of action and non-overlapping toxicities, researchers aim to attain deeper and persistent treatment responses without associated therapy resistance. 10-14 This combination has recently received approval from the European Medicines Agency (EMA) for frontline treatment of CLL. 15 This approval is based on pivotal findings from the Phase 3 GLOW study, which demonstrated superior PFS in patients treated with VI compared with those treated with chlorambucil-obinutuzumab, and from the FD cohort of the Phase 2 CAPTIVATE study. 10,11 However, the choice between FD therapies remains challenging due to the lack of head-to-head comparative data. Results from the ongoing CLL17 trial (NCT04608318), which is comparing continuous BTK inhibitor therapy with FD regimens, including VI and venetoclax-obinutuzumab (VO), are eagerly anticipated. To provisionally support evidence-based decision-making, we performed a network meta-analysis (NMA) comparing all approved FD therapies in the setting of treatment-naïve (TN) CLL patients. Relevant randomized clinical trials were identified through a systematic review of the literature in MEDLINE. To be included, studies had to meet the following criteria: (1) to be randomized controlled trials (RCTs) focusing on FD therapy in TN CLL patients; (2) to investigate the effectiveness of FD therapy with venetoclax as its core component; and (3) to provide data on both progression-free survival (PFS) and overall survival (OS). Reporting of the systematic review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. 16 Two reviewers (S.M. and D.G.) independently assessed the eligibility of all identified citations and extracted data from original trial reports. Consistent efficacy end-points, such as PFS and OS, were extracted and synthesized in the random effects NMA. The quality and certainty of the evidence for all outcomes with sufficient data were assessed using the recommended strategies developed by the Grading of Recommendations, Assessment , Development and Evaluation (GRADE) working group 17 (Supplementary Materials). A graphical method was employed to visually synthesize the experimental evidence by presenting the hazard ratio (HR) values of direct and indirect comparisons. A treatment was considered more effective than another if the 95% confidence interval (CI) for HR did not encompass the value 1.0 (which corresponds to a

Citation

Molica, S., Allsup, D., & Giannarelli, D. (online). Network meta-analysis of upfront fixed-duration therapies in chronic lymphocytic leukemia. American Journal of Hematology, https://doi.org/10.1002/ajh.27437

• Journal Article Type: Letter
• Acceptance Date: Jul 8, 2024
• Online Publication Date: Jul 23, 2024
• Deposit Date: Jul 23, 2024
• Publicly Available Date: Jul 24, 2025
• Journal: American Journal of Hematology
• Print ISSN: 0361-8609
• Electronic ISSN: 1096-8652
• Publisher: Wiley
• Peer Reviewed: Peer Reviewed
• DOI: https://doi.org/10.1002/ajh.27437
• Public URL: https://hull-repository.worktribe.com/output/4741885