BCL-2 Inhibitor Active In Relapsed/Refractory AML

Patients with relapsed or refractory acute myelogenous leukemia (AML) respond to single-agent treatment with the B-cell lymphoma-2 (BCL-2) inhibitor venetoclax (Venclexta), according to the results of a phase II clinical trial published in Cancer Discovery.  

Among 32 patients treated, 19% had measurable responses including two complete responses and four complete responses with incomplete blood count recovery (CRi). The median duration of therapy among responders was 144.5 days. The median duration of a complete response was 48 days.

“In this clinical trial, we found that even among pretreated patients whose AML was refractory to intensive chemotherapy there was evidence of exceptional sensitivity to selective BCL-2 inhibition, even to the point of complete remissions. This could be accomplished by a single oral dose of venetoclax daily and demonstrated the potential clinical activity of BCL-2 inhibition in AML,” said study author Anthony Letai, MD, PhD, an associate professor of medicine at Harvard Medical School and the Dana-Farber Cancer Institute, Boston, in a news release.

Venetoclax is a small molecule inhibitor of BCL-2, an antiapoptotic protein expressed in hematological tumors and plays a role in tumor survival and chemoresistance. BCL-2 is thought to facilitate AML cell survival by binding and inhibiting proapoptotic proteins. Venetoclax is thought to work by binding and inhibiting BCL-2, allowing apoptosis of the AML cells.

The drug was approved by the US Food and Drug Administration in April 2016, for treatment of patients with chronic lymphocytic leukemia (CLL) who have a chromosomal abnormality called 17p deletion and who have been treated with at least one prior therapy.

The current study is the first testing the BCL-2 inhibitor in AML patients and is based on laboratory data showing venetoclax is able to induce cell death of AML cell lines as well as primary AML cells derived from patients and in mouse xenograft models.

Patients on the trial had a median age of 71. Two patients were newly diagnosed, 30 patients had been treated with at least one prior therapy, and 13 patients had received at least three prior therapies. Patients received 800 mg of venetoclax daily in the single-arm study.

A total of 26 patients received at least 4 weeks of therapy. Eleven patients received escalated 1,200 mg daily doses of venetoclax after a lack of objective response to the 800 mg dose, but the higher dose did not demonstrate additional activity among these patients.

Of the 12 patients that had a mutation in either isocitrate dehydrogenase 1 or 2 (IDH1 or IDH2), four (33%) had a complete response or CRi.

Response to venetoclax correlated with BCL-2 protein expression and BH3 (one of the domains within the BCL-2 protein) profiling. “This is significant as it supports the mechanism of action of venetoclax as an on-target inhibitor of BCL-2. Moreover, it offers the possibility of using BH3 profiling as a potential predictive biomarker for clinical use of BH3 mimetics,” said Letai.

All patients discontinued venetoclax. Twenty-nine discontinued due to progressive disease, one due to terminal ileitis, one withdrew consent and another proceeded to allogeneic hematopoietic stem cell transplant after achieving stable disease.

Common adverse events included nausea, diarrhea, hypokalemia, vomiting, and headache. The most common high-grade adverse events were febrile neutropenia, hypokalemia, pneumonia, hypotension, and urinary tract infection. Serious adverse events occurred in 27 patients. Febrile neutropenia was the most common serious adverse event.

Venetoclax is also currently being studied in combination with chemotherapy for patients with AML.

The clinical trial was funded by AbbVie together with Genentech/Roche, the manufacturers of venetoclax.