Venetoclax, bendamustine, and rituximab in patients with relapsed or refractory NHL: a phase 1b dose-finding study

Abstract

Background

Venetoclax is a selective, potent inhibitor of the anti-apoptotic BCL-2 protein approved for treatment of chronic lymphocytic leukemia. We conducted a dose-finding study of venetoclax in combination with bendamustine-rituximab (BR) in patients with relapsed/refractory non-Hodgkin's lymphoma (NHL).

Patients and methods

BR was given for 6 cycles at standard doses. Intermittent and continuous oral venetoclax administration was explored at 50mg–1200mg daily doses. Co-primary objectives included safety, pharmacokinetics, maximum tolerated dose (MTD), and recommended phase 2 dose (RP2D); secondary objective was preliminary efficacy.

Results

Sixty patients were enrolled: 32 with follicular lymphoma (FL), 22 with diffuse large B-cell lymphoma (DLBCL), and 6 with marginal zone lymphoma (MZL). Nausea (70%), neutropenia (68%), diarrhea (55%), and thrombocytopenia (52%) were the most frequent adverse events (AEs). Most common grade 3/4 AEs were neutropenia (60%) and lymphopenia (38%). Serious AEs were reported in 24 patients; the most frequent were febrile neutropenia and disease progression (8% each). Five patients died from either disease progression (n = 4) or respiratory failure (n = 1). MTD was not reached; RP2D for venetoclax-BR combination was established as 800 mg daily continuously. Venetoclax pharmacokinetic exposure with and without BR was comparable. For all patients, overall response rate (ORR) was 65%. Median duration of overall response (DOR), overall survival (OS), and progression-free survival (PFS) was 38.3 months (95% confidence interval (CI): 10.4–NR), not yet reached, and 10.7 months (95% CI: 4.3–21.0), respectively.

Conclusions

This study established the safety profile of venetoclax in combination with BR, and results demonstrated tolerability and preliminary efficacy of the combination. Additional follow-up is needed to better determine the future role of BR plus venetoclax in the treatment of relapsed/refractory B-cell NHL.