OBJECTIVES:

Venetoclax+rituximab (VEN+RTX) is a potent anti-leukemic therapy for relapsed/refractory chronic lymphocytic leukemia (R/R CLL), superior to bendamustine+rituximab (BEND+RTX) based on the results of the MURANO trial. However, the relative efficacy and safety of VEN+RTX compared to other treatment options remain unknown. This study aimed to compare VEN+RTX with other possible therapies for R/R CLL, including BTK and PI3K inhibitors, chemotherapy, and/or immunotherapy.

METHODS:

An extensive systematic review was performed in medical databases (MEDLINE, Embase, and The Cochrane Library) and other sources to identify randomized clinical trials for R/R CLL (PROSPERO: CRD42022304330). Data for the longest available follow-up from identified studies were used to compare progression-free survival (PFS), overall survival (OS), and serious adverse events (SAEs) in Bayesian network meta-analysis (NMA). The results of NMA were presented as hazard ratios (HR) or risk ratios (RR) with 95% credible intervals (CrI); SUCRA values were also calculated. Statistical analyses were performed in the R software using the GeMTC package.

RESULTS:

As a result of the systematic search, 15 studies were identified and included in the NMA. VEN+RTX significantly prolonged PFS compared to immuno(chemo)therapy (HR [95% CrI] for VEN+RTX vs. RTX: 0.08 [0.04; 0.16], vs. OFA: 0.11 [0.06; 0.20], vs. CLB+RTX: 0.13 [0.08; 0.23], physician's choice: 0.08 [0.04; 0.18]) and regimens based on PI3K inhibitors (HR [95% CrI] for VEN+RTX vs. IDE+OFA: 0.41 [0.20; 0.84], vs. IDE+RTX: 0.28 [0.15; 0.49], vs. IDE+BEND+RTX: 0.58 [0.39; 0.85], DUV: 0.20 [0.10; 0.40]). No significant differences were found in PFS for comparisons with BTK inhibitors (AKA, IBR, ZAN). Overall survival was similar between VEN+RTX and other therapies except for immunotherapy and the physician's choice. Rates of SAE were also significantly decreased compared to PI3Ki regimens.

CONCLUSIONS:

The results of NMA suggest that VEN+RTX is superior to all chemoimmunotherapy and PI3K regimens and has similar efficacy to BTK inhibitors in R/R CLL.