Comparison between Time-Limited,Venetoclax-Based and Continuous Bruton Thyrosine Kinase Inhibitors-Based Therapy in the Upfront Treatment of Chronic Lymphocytic Leukemia (CLL):a Systematic Review and Network Meta-Analysis

Background: Targeted agents (TAs) have shown impressive activity in the upfront treatment of chronic lymphocytic leukemia (CLL). However, TAs have rarely been compared in head-to-head clinical trials. With this background, a systematic literature review and network meta-analysis (NMA) was performed to estimate the relative efficacy of TAs approved by the FDA and/or EMA for upfront therapy of CLL (i.e., ibrutinib, acalabrutinib, and venetoclax).

Methods: A systematic search of MEDLINE, EMBASE, BioSciences Information Service, and the Cochrane Library databases was conducted. Eligible studies consisted of randomized controlled trials (RCTs) assessing the efficacy or safety of TAs in previously untreated CLL patients. Outcomes considered were hazard ratios for progression-free survival (PFS), odds ratios for overall response rate (ORR) and adverse event rates. A given treatment was considered more effective than another one when a 95 % upper confidence interval (CI) for relative risk (RR) did not cross the value 1.0 (equivalent to a Bayesian probability for this pairwise comparison p≥97.5%).

Results: Among relevant RCTs, 6 met criteria of low risk for bias according to the Cochrane Handbook for Systematic Reviews of Interventions and were selected for analysis. Three studies were excluded because they lacked a common comparator arm (i.e., RESONATE2, ALLIANCE,and ECOG-ACRIN). Three trials were suitable for the base-case network analysis (i.e., ILLUMINATE, ELEVATE-TN, and CLL14). In aggregate, these trials included1336 patients and evaluated the combination of ibrutinib-obinutuzumab (IO) (ILLUMINATE trial;n=113), venetoclax-obinutuzumab (VO) (CLL14 trial;n=216) and acalabrutinib (A) single agent (ELEVATE-TN trial; n=179). Chlorambucil-obinutuzumab (CO) was the control arm across these studies (n=504). Since results of A plus obinutuzumab (AO)(n=179) in the ELEVATE-TN trial were based on a post-hoc analysis they were not included in the NMA.

In terms of PFS, fixed-effect analyses comparing VO to IO (RR 1.52[0.82-2.81]), A to IO (RR 0.87 [0.47-1.61]) and A to VO (RR 0.57[0.32-1.03]) revealed that the upper limit of 95% CI for RR did exceed the 1.0 value (Fig 1). This implies a lack of significant difference in PFS for IO, VO, and acalabrutinib. Similarly, no differences with respect to ORR were found in the indirect comparison of different TAs: VO vs. IO (RR 0.98 [0.61-1.59]), A vs. IO (RR 0.90[0.55-1.48]) and A vs. VO (RR 0.92[0.60-1.40]). The analysis of treatment side effects was performed comparing in aggregate all adverse events (AEs). No differences in the frequency of AEs was observed across different TAs: VO vs. IO (RR 1.00 [0.63-1.58]), A vs. IO (RR 1.01[0.62-1.63]) and A vs. VO (RR 1.01[0.68-1.52]). The same applied when the analysis was restricted to events with grade 3-4 toxicity: VO vs. IO (RR 1.05[0.64-1.73]), A vs. IO (RR 0.73[0.43-1.24]) and A vs. VO (RR 0.69[0.44-1.09]).

Conclusions: This systematic review and network meta-analysis did not identify significant differences in PFS between BTKi-and time-limited venetoclax-based treatments in CLL upfront therapy. Further trials are needed to ascertain the pros and cons of different targeted treatments. Meanwhile, treatment selection in routine clinical practice should be based on drugs’ safety, cost, availability, and treatment objectives.