Venetoclax (VEN) is a selective, potent, orally bioavailable BCL-2 inhibitor. High overall response rates (ORR, 79%) and complete response (CR, 20%) rates were attained in a first-in-human dose-escalation study of VEN monotherapy in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (M12-175). The addition of monthly rituximab (months 1-6) in combination with VEN is being evaluated in an ongoing phase 1b dose-escalation study (M13-365). In this study, ORR was 86% (CR, 47%). Although entry criteria for the 2 studies were similar, patients in M12-175 were more heavily pretreated.
The aim of this study was to assess the effect of adding rituximab to VEN on ORR and the quality and duration of responses relative to VEN monotherapy using post hoc exploratory multivariate analyses.1
After selection of the final statistical model, 157 patients were evaluated for ORR from the 2 studies, 129 for CR, and 105 for duration of response. Analysis showed that combination therapy did not influence ORR relative to VEN monotherapy (odds ratio, 1.14 [95% confidence interval (CI), 0.43-3.02]; P = 0.79). CRs were more likely with combination therapy (odds ratio, 6.13 [95% CI, 2.44-15.44]; P = 0.001). Responses were also more durable with combination therapy versus VEN monotherapy (hazard ratio for progression, 0.37 [95% CI, 0.15-0.89]; P = 0.03).
These exploratory, cross-study, post hoc analyses show that combination use of VEN and rituximab, bulkiness of adenopathy, del(17p), del(11q), and dose of VEN were identified as response modifiers in the analysis of both trials. The combination had significantly higher CR rates and duration of response compared with VEN monotherapy.
VEN combined with rituximab is being compared with bendamustine and rituximab in the ongoing, phase 3 MURANO study.