Study shows new cancer drug safe and promising for patients with acute myelogenous leukemia

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Venclexta, the first of a new class of drugs that targets cancer cells’ survival proteins, achieved responses – including some complete remissions – in patients with acute myelogenous leukemia (AML) who had relapsed or were resistant to or couldn’t tolerate chemotherapy.

These results of a single-arm phase II clinical trial by scientists from Dana-Farber Cancer Institute and M.D. Anderson Cancer Center were reported in Cancer Discovery, a journal of the American Association for Cancer Research.

Venclexta (venetoclax), a BCL-2 inhibitor, was approved in April for patients with a certain type of chronic lymphocytic leukemia (CLL). By blocking the activity of the BCL-2 survival protein, Venclexta forces cancer cells to self-destruct by the process known as apoptosis.

“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,” said Anthony Letai, MD, PhD, of Dana-Farber and Harvard Medical School. “This could be accomplished by a single oral dose of venetoclax daily and demonstrated the potential clinical activity of BCL-2 inhibition in AM.” said Letai. He and Marina Konopleva, MD, PhD, of M.D. Anderson led the trial involving 32 AML patients whose median age was 71. Twenty-six patients received at least four weeks of therapy.

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

Most patients did not meet the criteria of a clinical response, and in those who did respond, the response was usually not durable, Letai said. Nonetheless, the activity shown has spurred to initiation of several clinical studies in combination with other agents used in AML therapy.  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,” said Letai. He and the late Stanley Korsmeyer, MD, of Dana-Farber carried out research that laid much of the groundwork leading to development of BCL-2 inhibitors.

“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,” Letai said.

Venetoclax is a small molecule that binds with great affinity and selectivity to BCL-2, an antiapoptotic protein that plays a role in many blood cancers, Letai explained. BCL-2 proteins keep the AML cells alive by binding to proapoptotic proteins that normally cause abnormal cells to self-destruct. Venetoclax binds to BCL-2 and frees the proapoptotic proteins, thus rapidly and irreversibly forcing the AML cell to undergo apoptosis, he explained.

This study was funded by AbbVie in collaboration with Genentech/Roche; the two companies are jointly developing Venetoclax. Researchers also received a grant from The Leukemia & Lymphoma Society. 

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Acute Myeloid - AML
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