Venetoclax plus obinutuzumab is tolerable and active in both untreated and relapsed/refractory CLL.

  • Major finding: Venetoclax plus obinutuzumab is tolerable and active in both untreated and relapsed/refractory CLL.

  • Concept: The safety and dosing of BCL2 inhibitor and this anti-CD20 antibody were assessed in a phase Ib trial.

  • Impact: This combination may become standard-of-care treatment for patients with previously untreated CLL.

Treatment of patients with chronic lymphocytic leukemia (CLL) is limited by therapeutic resistance and disease relapse. Dual treatment with the BCL2 inhibitor venetoclax and the anti-CD20 antibody rituximab improves survival in patients with relapsed/refractory CLL, but preclinical data suggests that venetoclax combined with the type II anti-CD20 antibody obinutuzumab may more effectively deplete B cells. Flinn and colleagues evaluated the safety and preliminary activity of venetoclax plus obinutuzumab in patients with relapsed/refractory or previously untreated CLL in a single-arm, open-label phase Ib trial. The primary endpoints were the maximum tolerated dose (MTD) of venetoclax when combined with obinutuzumab and the safety and tolerability of the combination; efficacy measures and undetectable minimal residual disease (uMRD) were assessed as secondary and exploratory endpoints, respectively. In the dose-finding stage, a schedule of obinutuzumab followed by venetoclax initiation and a 400 mg dose of venetoclax were selected for the safety-expansion cohort, and the MTD was not reached. The combination had an acceptable safety profile in both patient populations, with no dose-limiting toxicities or incidence of clinical tumor lysis syndrome; adverse events were mostly low grade and the most common grade 3–4 adverse event was neutropenia. The overall response rate was 95% in patients with relapsed/refractory CLL and 100% in patients with previously untreated CLL, and the response rate was independent of cytogenetic risk factors and patient fitness. Complete response or complete response with incomplete marrow recovery was observed in 37% of patients with relapsed/refractory disease and 78% of patients with untreated disease, and the rate of uMRD in peripheral blood of patients with relapsed/refractory CLL and untreated patients was 64% and 91%, respectively. These findings demonstrate that venetoclax–obinutuzumab is tolerable and elicits high response rates in both relapsed/refractory and untreated CLL and suggest that this combination may represent a new standard treatment option in CLL.

Flinn IW, Gribben JG, Dyer MJS, Wierda W, Maris MB, Furman RR, et al. Phase 1b study of venetoclax–obinutuzumab in previously untreated and relapsed/refractory chronic lymphocytic leukemia. Blood 2019 Mar 12 [Epub ahead of print].

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