Comparison of venetoclax plus rituximab with B-cell receptor inhibitors in patients with relapsed/refractory chronic lymphocytic leukemia: a systematic review and network Meta-analysis

In the last few years, therapy for chronic lymphocytic leukemia (CLL) has undergone a revolution, with the initial approval of ibrutinib, idelalisib with rituximab, and venetoclax, followed, more recently, by the increasing indications of ibrutinib as frontline therapy [1–4]. With the array of treatment options available, especially in the setting of relapsed/refractory (R/R) disease, the therapeutic decision process is complex. There are now multiple standard of care options in patients with R/R CLL. A randomized study comparing three registered targeted agents (TAs) is highly unlikely to be performed. Currently, with no evidence of comparative efficacy, the choice of TA in routine clinical practice is often based on expected toxicity profile in a given patient rather than a clear understanding in of relative efficacy. To support evidence-based decision making in the setting of R/R CLL, we performed a network meta-analysis (NMA) that synthesizes direct and indirect evidence and enable a comparison of all TA approved in this setting. Relevant randomized clinical trials were identified by a systematic literature review in MEDLINER . The studies were included if they met all of the following eligibility criteria: [1] randomized controlled trials of R/R CLL patients; [2] the trials must explore the effectiveness of B-cell receptor (BCR) or B-cell lymphoma 2 (BCL2) pathway inhibitors with a comparison arm; [3] the trials must provide information on progression-free survival (PFS) and overall survival (OS). The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement was utilized as a reporting guideline (Supplementary Figure S1) [5]. Two reviewers (S.M. and D.G.) independently assessed the eligibility of all identified citations and extracted data from original trial reports. Efficacy endpoints with consistent definitions, including PFS and OS, were extracted and synthesized in the random effects NMA. A graphical approach aimed at visually synthesizing the experimental evidence by presenting the relative risk (RR) values of direct and indirect comparisons has been used [6]. A treatment was considered more effective than another when a 95 %confidence interval (CI) for RR did not cross the value 1.0 (equivalent to a Bayesian probability for this pairwise comparison p 97.5%). Among relevant randomized controlled trials (RCTs), eight met criteria of low risk for bias according to the Cochrane Handbook for Systematic Reviews of Interventions and were selected for inclusion in the present analysis [1–3,7–11] (Supplementary Table S1). Only 3 trials were suitable for the base-case network analysis [3,8,9]. In aggregate, these trials included 1383 patients and evaluated the combination of ibrutinibbendamustine-rituximab (BR) (HELIOS study; n1⁄4 289) [12], idelalisib-BR (n1⁄4 207) [11] and venetoclax-rituximab (VR) (MURANO study; n1⁄4 194) [3] and which used BR as a the common reference treatment in the control arm for all 3 trials (n1⁄4 693) [3,8,9]. The five trials excluded from the base-case analysis evaluated ibrutinib single agent in two studies (n1⁄4 301) [1,10], duvelisib in one study (n1⁄4 160) [11] and idelalisib in association with rituximab or ofatumumab in the remaining two studies (n1⁄4 284) [2,7]. These studies were excluded from NMA because they lacked a commonly used standard of therapy as comparator. Specifically, the control arm was rituximab [n1⁄4 164] or ofatumumab [n1⁄4 442] [1,2,7,10,11], not generally considered a standard of care for R/R CLL. Compared with idelalisib-BR, both ibrutinib-BR (Relative Risk [RR], 0.61; 95% Confidence Interval [CI], 0.40–0.92) and VR (RR, 0.52; 95% CI, 0.31–0.85) were associated with significant reductions in risk of progression. In contrast, no difference in terms of PFS could be found