Venetoclax promising for acute myelogenous leukemia

12 Aug 2016

Patients whose acute myelogenous leukemia (AML) had relapsed or was resistant to chemotherapy and those who were deemed unable to tolerate chemotherapy experienced responses to the selective BCL-2 inhibitor venetoclax (Venclexta), with complete remissions in some, according to phase 2 clinical trial data.

Venetoclax is a small molecule that belongs to a class of drugs called BH3 mimetics.  It binds with great affinity and selectivity to BCL-2, an antiapoptotic protein that plays a role in many blood cancers, commented Anthony Letai, MD, PhD, associate professor of medicine at Harvard Medical School and Dana-Farber Cancer Institute, in Boston, Massachusetts, senior author of the study.  BCL-2 proteins keep the AML cells alive by binding to proapoptotic proteins. Venetoclax binds to BCL-2 and frees the proapoptotic proteins, thus rapidly and irreversibly forcing the AML cell to undergo apoptosis, he explained.

The lead author of the study is Marina Konopleva, MD, PhD, professor in the Department of Leukaemia and the Department of Stem Cell Transplantation at The University of Texas MD Anderson Cancer Center in Houston.

In April 2016, venetoclax was approved by the U.S. FDA for the treatment of certain patients with chronic lymphocytic leukemia (CLL).

Clinical trial details & results

The study investigators recruited 32 patients with AML with a median age of 71 years to this multicenter, single-arm trial evaluating 800 mg daily oral venetoclax. 26 patients received at least four weeks of therapy.

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 and found that 12 patients had mutations in IDH genes, and six had a high BCL-2-sensitive protein index.

The analysis of the results revealed that:

  • The overall response rate was 19%; two patients had complete response and four had complete response with incomplete blood count recovery (CRi).
  • The median duration of therapy in responders was 144.5 days
  • The median duration of complete response was 48 days.
  • All patients discontinued therapy due to progressive disease or an adverse event, or for other reasons.
  • The four patients who had CRi had IDH mutations in their cancer cells.

Response to the drug correlated with biomarker results, including indices of BCL-2 protein expression and BH3 profiling, 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," he added.

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Evidence of exceptional sensitivity even among pretreated patients

Adverse events were as expected and included nausea, diarrhea and vomiting, febrile neutropenia, and hypokalemia.

"There has been research into apoptosis [cell death] for decades now. It has long been a goal of the field to see the work translated into actual improved care of cancer patients. AML is a disease in which new therapies are desperately needed, and based on published preclinical work, this type of cancer seemed to be an excellent target for the BCL-2 inhibitor venetoclax," said Letai.

"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," he added.

"It is also worth noting that in this age of precision medicine, dominated by genomics, this is an example of the importance of functional precision medicine. CLL and AML lack genetic abnormalities related to BCL-2. Instead, their vulnerability to BCL-2 inhibition was identified using functional studies. This is support that functional studies need to be part of any mature precision medicine project," Letai noted.

No clinical response for the majority of the patients

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

As limitations to the study, most patients did not meet the criteria of a clinical response, and in those who did respond, the response was not as durable as expected, Letai said. Further, the predictive biomarker assays were performed retrospectively.

Subsequent studies will need to perform biomarker studies while blinded to clinical data, he added.

Source: eCancer News

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