Safety and efficacy of venetoclax and ibrutinib in relapsed/refractory chronic lymphocytic leukemia: A systematic review and meta-analysis.

Abstract

e19035 Background: Chronic lymphocytic leukemia (CLL) is considered to be the most common leukemia in adults and remains incurable but newer oral targeted agents have improved options for patients unwilling or ineligible for chemo-immunotherapy. Ibrutinib is a BTK inhibitor which heightens the dependence of CLL cells on BCL-2, increasing sensitivity to venetoclax and accelerating cell death. We performed this meta-analysis to assess efficacy and safety of this combination in relapsed (2nd Line and beyond) settings. Methods: A systematic search of PubMed, Embase, Google Scholar, and Cochrane (CENTRAL) was conducted, covering the period from January 2014 to December 2024, for clinical trials (PROSPERO ID: CRD420250585791). Primary outcomes were progression free survival (PFS), minimal residual disease in bone marrow (MRD-BM), and serious adverse effects (SAEs) and the secondary were total adverse effects (TAEs), overall survival (OS), and overall response rate (ORR). The pooled risk ratio (RR) with 95% CIs for outcomes were calculated using a random-effects model. Subgroup analysis was performed on primary outcomes that minimized inter-study variability in PFS and MRD results. RevMan 5.1 was used for all analyses, with statistical significance set below 0.05. This review was in accordance with PRISMA guidelines. Results: Five RCTs involving 443 participants were included and the results were assessed on primary and secondary outcomes. Venetoclax and ibrutinib significantly improved PFS in patients who used it for a fixed duration (RR = 0.86, P = 0.0008). Rate of MRD negativity was higher in patients with wild type p53. The combination therapy achieved significantly higher MRD-negativity than reported for either as a single agent. Serious adverse events (SAEs) were reduced with combination therapy (P = 0.003). Secondary outcomes showed exceptional ORR to this regimen (ORR (P = 0.01)) with low heterogeneity (I² = 23%). This dual regimen appears to have an acceptable risk of atrial fibrillation and hypertension (P < 0.00001). Conclusions: Our study identified venetoclax and ibrutinib combined regimen to be a reasonable option in increasing PFS in patients utilizing fixed duration regimens, especially those with lower burden of TP53 mutation. Safety Profile for cardio-vascular side effects in an elderly population is tolerable. Further studies with larger participant numbers are needed to solidify these findings.