Venetoclax Monotherapy Safe and Clinically Active in Acute Myelogenous Leukemia

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A phase II study has found venetoclax (Venclexta) to be clinically active in patients with high-risk relapsed/refractory acute myelogenous leukemia (AML) or those unfit for intensive chemotherapy, with an overall response rate of 19% and a tolerable safety profile. The study results, which were reported by lead author Marina Konopleva,
, Associate Professor in the Departments of Leukemia and Stem Cell Transplantation at The University of MD Anderson Cancer Center in Houston, Texas, and colleagues in Cancer Discovery, support evaluating venetoclax in combination with other agents in patients with AML.

Venetoclax is a highly selective, oral bioavailable BCL-2 inhibitor that has shown activity in BCL-2–dependent leukemia and lymphoma cell lines and has demonstrated promising clinical activity as a single agent in the treatment of chronic lymphocytic leukemia (CLL). In April 2016, the U.S. Food and Drug Administration approved venetoclax for the treatment of patients with CLL who have the 17p deletion and who have been treated with at least one prior therapy.

A total of 32 patients with relapsed/refractory AML or those unfit for intensive chemotherapy were enrolled in this phase II open-label, single-arm, multicenter study between December 31, 2013, and April 5, 2014. The patients had a median age of 71 years. Pretreatment bone marrow aspirates or peripheral blood samples for BCL-2 family protein mutational analysis were collected at study entry and analyzed.

A stepwise ramp-up of oral venetoclax dosing was used to achieve the target dose of 800 mg. Twenty-six patients received at least 4 weeks of therapy.

Study Findings

The patients’ responses to venetoclax 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). A total of 12 patients (38%) had isocitrate dehydrogenase 1/2 mutations, of whom 4 (33%) achieved complete response or complete response with incomplete blood cell count recovery. Six patients (19%) had BCL2-sensitive protein index at screening, which correlated with time on study. BH3 profiling was consistent with on-target BCL-2 inhibition and identified potential resistance mechanisms.

Common adverse events included nausea, diarrhea and vomiting (all grades), and febrile neutropenia and hypokalemia (grade 3/4).

“We believe that venetoclax will soon become an equal partner to standard-of-care chemotherapy in elderly patients with AML when used in combination with hypomethylating agents and other approaches,” said Dr. ­Konopleva, in a statement. “Planned studies will test the hypothesis that venetoclax may likewise improve outcomes in younger AML patients when combined with high-dose chemotherapy.”

Funding for this study was provided by AbbVie and Genentech.

Konopleva M, et al: Cancer Discov 6:1106-1117, 2016.