In a phase Ib study reported in The Lancet Oncology, Seymour et al found that the combination of the BCL2 inhibitor venetoclax (Venclexta) and the anti-CD20 monoclonal antibody rituximab (Rituxan) was highly active in patients with relapsed or refractory chronic lymphocytic leukemia (CLL).
In the dose-escalation study, 49 patients with relapsed or refractory CLL (n = 48) or small lymphocytic lymphoma (n = 1) received daily venetoclax at doses escalated to a target of 200 to 600 mg, followed by monthly rituximab at 375 mg/m² in month 1 and 500 mg/m² in months 2 to 6. Drug cessation was permitted for patients with a complete response (including complete response with incomplete marrow recovery) or negative bone marrow minimal residual disease.
Analyses were per protocol for all patients who started treatment and included all patients who received at least one dose of venetoclax. Data are pooled across dose cohorts. At the time of analysis, patients were still receiving treatment with ongoing follow-up. Of 28 patients who had prior fludarabine-based therapy, 9 were refractory to treatment; of 45 patients who received prior rituximab-containing therapy, 21 were refractory to treatment.
Response was observed in 42 of 49 patients (86%), including a complete response in 25 patients (51%). Two-year estimates of progression-free survival and ongoing response were 82% and 89%, respectively.
Negative marrow–minimal residual disease was observed in 20 of 25 patients (80%) with a complete response and in 28 (57%) of all patients. Treatment was stopped in 13 responders; among them, each of 11 patients with minimal residual disease–negative response remained progression-free off therapy. In 2 patients with a minimal residual disease–positive complete response, disease progression occurred after 24 months off therapy, with response regained after reinitiation of venetoclax.
The most common grade 1 or 2 adverse events were upper respiratory tract infection (57%), diarrhea (55%), and nausea (51%). Grade 3 or 4 adverse events occurred in 37 patients (76%), with the most common being neutropenia (53%), thrombocytopenia (16%), anemia (14%), febrile neutropenia (12%), and leukopenia (12%). The most common serious adverse events were pyrexia (12%), febrile neutropenia (10%), lower respiratory tract infection (6%), and pneumonia (6%).
Clinical tumor-lysis syndrome occurred in 2 patients who started venetoclax at 50 mg, with 1 patient dying. No clinical tumor-lysis syndrome was observed in the subsequent 32 treated patients after enhanced prophylaxis measures were instituted and the starting venetoclax dose was reduced to 20 mg.
No maximum tolerated dose was identified. The recommended venetoclax dose for the phase II study is 400 mg in combination with rituximab.
The investigators concluded: “The depth and durability of responses observed with the combination offer an attractive potential treatment option for patients with relapsed or refractory [CLL] and could allow some patients to maintain response after discontinuing therapy, a strategy that warrants further investigation in randomised studies.”
The study was funded by AbbVie and Genentech.
John F. Seymour, MBBS, of the Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia, is the corresponding author of The Lancet Oncology article.
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