Venetoclax (ABT-199/GDC-0199) plus Bendamustine/Rituximab in Relapsed/Refractory NHL: Results of a Dose-Escalation Study
Venetoclax is a selective, potent, oral inhibitor of antiapoptotic protein BCL-2 that has demonstrated single-agent activity in patients with relapsed or refractory non-Hodgkin lymphoma (NHL) and showed preclinical evidence of increasing the efficacy of bendamustine/rituximab (BR). At the ASH 2015 meeting, De Vos and colleagues reported the results of an ongoing phase 1, open-label, multicenter, dose-escalation study of venetoclax in combination with BR in patients relapsed/refractory NHL.1
At the time of this analysis, 48 patients were enrolled in 10 dose-escalation cohorts using the standard 3+3 dose- escalation design to receive venetoclax (50-800 mg) following 3 dosing schedules (3-, 7-, and 28-day) plus standard BR treatment for 6 cycles, following which they may continue venetoclax monotherapy for up to 2 years. Of these, 27 (57%) patients were diagnosed with follicular lymphoma (FL), 15 (32%) with diffuse large B-cell lymphoma (DLBCL), and 5 (11%) with marginal zone lymphoma (MZL). Patients had received a median of 3 (range, 1-8) prior therapies. Overall, 22 (47%) patients discontinued treatment, mainly due to progressive disease (n = 13); 4 withdrew due to adverse events (AEs). Seventeen patients completed 6 cycles of treatment; of these, 14 continued to monotherapy. In the venetoclax plus BR combination part of the study, the most common all-grade AEs were nausea (58%), thrombocytopenia (50%), neutropenia (56%), constipation (38%), anemia (38%), diarrhea (44%), fatigue (38%), hyperglycemia (33%), and lymphocyte count decrease (28%). Grade 3/4 AEs were reported in 79% of patients, mostly hematologic in nature including neutropenia (48%), lymphocyte count decrease (35%), thrombocytopenia (21%), anemia (15%), and leukopenia (17%). The most frequent serious AE was febrile neutropenia (8%). Following 2 dose-limiting toxicities of febrile neutropenia and thrombocytopenia in cohort 5 (200 mg; 28/28d), a protocol amendment was done mainly to recommend granulocyte colony-stimulating factor (G-CSF) prophylaxis during venetoclax therapy. Of the 48 patients evaluable for response, 31 achieved an objective response, including 13 complete responses and 18 partial responses. Of these, objective responses were achieved by 38% of patients with DLBCL, 78% of those with FL, and 80% of MZL. Based on these preliminary results, venetoclax plus BR appears to show promising activity and a tolerable safety profile in a heavily pretreated patient population.
- De Vos S, et al. ASH 2015. Abstract 255.