Patients with acute myelogenous leukemia (AML) whose disease had relapsed or was resistant to chemotherapy and those who were unable to tolerate chemotherapy have shown clinical responses to venetoclax (Venclexta, AbbVie/Genentech), with complete remissions in some, according to new phase 2 data published in Cancer Discovery.
Venetoclax is a small-molecule B-cell lymphoma 2 (BCL-2) homology 3 (BH3) mimetic. It binds with great affinity and selectivity to BCL-2, an antiapoptotic protein that plays a role in many blood cancers, according to lead investigator Anthony Letai, MD, PhD, of Harvard Medical School. BCL-2 proteins keep AML cells alive by binding to proapoptotic proteins. Venetoclax binds to BCL-2 and frees the proapoptotic proteins, thereby forcing the AML cells to undergo apoptosis, he explained.
In April 2016, venetoclax was approved by the FDA for the treatment of certain patients with chronic lymphocytic leukemia (CLL). It is not indicated for patients with AML.
The investigators enrolled 32 adults (median age, 71 years) with AML into a multicenter, single-arm trial evaluating oral venetoclax (800 mg/day). Twenty-six patients received at least four weeks of therapy.
The overall response rate was 19%; two patients experienced a complete response (CR), and four had a CR with incomplete blood-count recovery (CRi). The median duration of therapy in responders was 144.5 days, and the median duration of CRs was 48 days. All of the patients discontinued therapy because of progressive disease, an adverse event, or other reasons.
The investigators performed cytogenetic analysis, BH3 profiling, and next-generation sequencing to look for AML-related genetic mutations in the patients’ samples collected at study entry. They found that 12 patients had mutations in isocitrate dehydrogenase (IDH) genes and that six had a high BCL-2–sensitive protein index.
The four patients who experienced CRi had IDH mutations in their cancer cells. Responses to venetoclax correlated with biomarker results, including indices of BCL-2 protein expression and BH3 profiling, Dr. Letai said. “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.”
Adverse events included nausea, diarrhea, vomiting, febrile neutropenia, and hypokalemia.
As limitations to the study, most patients did not meet the criteria of a CR, and in those who did respond, the response was not as durable as expected, Dr. Letai said. Further, the predictive biomarker assays were performed retrospectively. Subsequent studies will need to perform biomarker studies while blinded to the clinical data, he added.
The study was funded by AbbVie in collaboration with Genentech/Roche.