Venetoclax Drug Shows Promising Results in Patients With Leukemia

by Sheela Philomena on  August 15, 2016 at 9:09 AM Cancer News
RSS Email Print This Page Comment
Font : A-A+

Acute myelogenous leukemia (AML) patients experienced responses to venetoclax (Venclexta) with complete remission in some people, reveal clinical trial data.

Journal in Which the Study was Published: Cancer Discovery , a journal of the American Association for Cancer Research.
Venetoclax Drug Shows Promising Results in Patients With Leukemia
Venetoclax Drug Shows Promising Results in Patients With Leukemia

Authors: Senior author: Anthony Letai, MD, PhD, associate professor of medicine at Harvard Medical School and Dana-Farber Cancer Institute, in Boston, Massachusetts; Lead author: Marina Konopleva, MD, PhD, professor in the Department of Leukemia and the Department of Stem Cell Transplantation at The University of Texas MD Anderson Cancer Center in Houston

Background: 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, Letai said. 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.

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

How the Study Was Conducted: 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. Twenty-six 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.

Results: The overall response rate was 19 percent; two patients had complete response (CR) and four had complete response with incomplete blood count recovery (CRi). The median duration of therapy in responders was 144.5 days, and the median duration of CR 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.

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

Authors' Comments: "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.

"Marina and I both identified evidence that AML would be a good target for BCL-2 inhibition some years ago. When we realized that we were working on the same idea, we made the conscious decision to collaborate rather than compete," Letai said. "Combining our work made progress more rapid, and provided more material to convince AbbVie to initiate a program of venetoclax in AML."

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."

Limitations: 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: Eurekalert

Post your Comments

Comments should be on the topic and should not be abusive. The editorial team reserves the right to review and moderate the comments posted on the site.
* Your comment can be maximum of 2500 characters
Notify me when reply is posted
I agree to the terms and conditions

Related Links

More News on:

Drug Toxicity Leukemia Chronic Myeloid Leukemia Acute Myeloid Leukemia Acute Lymphoblastic Leukemia Signature Drug Toxicity Multiple Myeloma Drugs Banned in India Bone Marrow Transplantation Hairy Cell Leukemia 

News A - Z


News Search

Medindia Newsletters

Subscribe to our Free Newsletters!

Terms & Conditions and Privacy Policy.

Stay Connected

  • Available on the Android Market
  • Available on the App Store


News Category

News Archive