The U.S. Food and Drug Administration (FDA) approved a novel targeted drug to treat acute myelogenous leukemia (AML) in older patients, a segment of the blood cancer population in dire need of improved therapies.
In a phase 3 clinical trial, researchers showed that the oral drug, venetoclax (or Venclexta), when given along with azacitidine, could extend survival in newly diagnosed patients with AML who were 75 years or older or had other medical conditions that made them poor candidates for intensive chemotherapy.
The venetoclax combination for such patients had been granted accelerated approval by the FDA in 2018. Full approval, which came in October 2020, awaited positive results of the phase 3 VIALE-A trial, published in the New England Journal of Medicine (NEJM) this past August. The study showed that venetoclax plus azacitidine reduced the risk of death by 34% compared to azacitidine alone, yielding median overall survival of 14.7 months vs 9.6 months.
Treatment with venetoclax plus azacitidine also had significantly higher rates of composite complete remission — 66% vs 28% with azacitidine alone. (Composite complete remission is complete remission — meaning the leukemia is gone and the bone marrow has completely recovered — plus complete remission in which the leukemia is gone, but the bone marrow has not completely recovered.)
A welcome approval for older patients
AML, an aggressive blood cancer, affects primarily older individuals and has a low survival rate.
“We do have regimens that can induce remissions in AML, but they can be very toxic and poorly tolerated by people who are over 60 or 65,” says Anthony Letai, MD, PhD, a medical oncologist at Dana-Farber and an author on the clinical trial report.
Venetoclax is the first of a class of drugs that target BCL-2, a “survival protein” in cancer cells that enables them to escape the built-in “self-destruct” program, or apoptosis, that is triggered in abnormal cells. By blocking BCL-2 activity, venetoclax renders the cancer cells more vulnerable to self-destruction.
The study of BCL-2 and ways to target it for cancer therapy has a long history at Dana-Farber. A pioneer in the field was the late Stanley Korsmeyer, MD, and Letai was a member of his laboratory before heading his own now. Venetoclax has proved highly effective in other blood cancers, chiefly chronic lymphocytic leukemia (CLL) and has a more benign side effect profile than some other agents.
Sold as Venclexta, the drug was developed by AbbVie and Roche, but much of the early work was done by Letai and other Dana-Farber researchers.
“This trial wouldn’t exist without the preclinical and early clinical work that started out at Dana-Farber,” says Letai.
Venetoclax won its first approval for treating certain patients with chronic lymphocytic leukemia (CLL). Subsequently, Letai and another oncologist, Marina Konopleva, at M.D. Anderson Cancer Center, led a clinical trial of venetoclax in AML. The results were promising, but it was thought that a combination approach would be better. A series of trials led to the studies of venetoclax and azacitidine in older AML patients, setting the stage for the phase 3 trials and the FDA approval.
Jacqueline Garcia, MD, an author on the NEJM report, says a test known as BH3 profiling developed at Dana-Farber should be valuable in identifying patients who will respond to venetoclax.