Efficacy and biological correlates of response in a phase II study of venetoclax monotherapy in patients with acute myelogenous leukemia

M Konopleva, DA Pollyea, J Potluri, B Chyla, L Hogdal… - Cancer discovery, 2016 - AACR
M Konopleva, DA Pollyea, J Potluri, B Chyla, L Hogdal, T Busman, E McKeegan, AH Salem
Cancer discovery, 2016AACR
We present a phase II, single-arm study evaluating 800 mg daily venetoclax, a highly
selective, oral small-molecule B-cell leukemia/lymphoma-2 (BCL2) inhibitor in patients with
high-risk relapsed/refractory acute myelogenous leukemia (AML) or unfit for intensive
chemotherapy. Responses were evaluated following revised International Working Group
(IWG) criteria. The overall response rate was 19%; an additional 19% of patients
demonstrated antileukemic activity not meeting IWG criteria (partial bone marrow response …
Abstract
We present a phase II, single-arm study evaluating 800 mg daily venetoclax, a highly selective, oral small-molecule B-cell leukemia/lymphoma-2 (BCL2) inhibitor in patients with high-risk relapsed/refractory acute myelogenous leukemia (AML) or unfit for intensive chemotherapy. Responses were evaluated following revised International Working Group (IWG) criteria. The overall response rate was 19%; an additional 19% of patients demonstrated antileukemic activity not meeting IWG criteria (partial bone marrow response and incomplete hematologic recovery). Twelve (38%) patients had isocitrate dehydrogenase 1/2 mutations, of whom 4 (33%) achieved complete response or complete response with incomplete blood count recovery. Six (19%) patients had BCL2-sensitive protein index at screening, which correlated with time on study. BH3 profiling was consistent with on-target BCL2 inhibition and identified potential resistance mechanisms. Common adverse events included nausea, diarrhea and vomiting (all grades), and febrile neutropenia and hypokalemia (grade 3/4). Venetoclax demonstrated activity and acceptable tolerability in patients with AML and adverse features.
Significance: Venetoclax monotherapy demonstrated clinical activity in patients with AML (relapsed/refractory or unfit for intensive chemotherapy) with a tolerable safety profile in this phase II study. Predictive markers of response consistent with BCL2 dependence were identified. Clinical and preclinical findings provide a compelling rationale to evaluate venetoclax combined with other agents in AML. Cancer Discov; 6(10); 1106–17. ©2016 AACR.
See related commentary by Pullarkat and Newman, p. 1082.
This article is highlighted in the In This Issue feature, p. 1069
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