Adding Venclexta to Chemotherapy Improves Survival in Some with AML Who Are Ineligible for Standard Treatment

Adding the targeted drug Venclexta (venetoclax) to the chemotherapy Vidaza (azacitidine) improved survival and the complete remission rate compared with Vidaza alone in certain previously untreated patients with acute myeloid leukemia (AML), according to data published in The New England Journal of Medicine.

The drug was also found to be safe in patients with the blood cancer who participated in the VIALE-A trial conducted by researchers at The University of Texas MD Anderson Cancer Center in Houston.

While most patients with AML are treated with intensive chemotherapy and/or a stem cell transplant, some are not eligible for those therapies. The trial studied patients who were ineligible because of coexisting health conditions, an age of 75 or older, or both.

"A large portion of patients with AML, including those older than 75 or those who have medical comorbidities, cannot tolerate existing treatment strategies, and the patients with AML who are ineligible for intensive chemotherapy often experience poor prognoses," Dr. Courtney D. DiNardo, lead investigator and associate professor of leukemia at MD Anderson, said in a press release by the institution. "We launched the VIALE-A trial to evaluate whether we could safely use a combination therapy to treat this critical patient population."

Venclexta is an inhibitor of B-cell lymphoma-2, blocking the protein’s activity to prevent it from helping cancer cells to survive. Vidaza is a hypomethylating drug that switches off the protein DNA methyltransferase, stimulating certain genes to fight cancer.

In the multi-institution trial, 431 patients were divided into groups, with 286 receiving the combination of Venclexta plus Vidaza and 145 receiving Vidaza alone. The median age of the patients in each group was 76. The primary goal of the study was to evaluate whether the combination improved overall survival (OS), or the time from the beginning of treatment until death, compared with Vidaza alone. An additional goal was to assess the safety of the combination therapy.

With a median follow-up of 20.5 months, the addition of Venclexta to Vidaza resulted in a median OS of 14.7 months compared with 9.6 months in patients receiving Vidaza alone, the authors reported. In addition, they wrote, 66.4% of patients receiving the combination therapy achieved complete remission versus 28.3% with Vidaza alone.

The responses to treatment were both rapid and durable, the authors stated, noting that 43% of patients in the combination therapy group exhibited a response to treatment during the first cycle and the observed median duration of remission was 17.5 months.

Regarding safety, the researchers found that the two-drug combination had a similar side-effect profile to that of each drug separately. The most common side effects in both study groups were hematologic and gastrointestinal. In general, side effect rates were consistent between the two treatment groups, although higher frequencies of neutropenia (42% vs. 29%) and febrile neutropenia (42% vs.19%) were observed with the combination therapy compared with Vidaza alone. Nausea of any severity was also a frequent side effect (44% vs. 35%).

"The primary adverse events seen with azacitidine and venetoclax are related to increased cytopenias, including neutropenia and neutropenia-related infections," DiNardo said in the release. "Key management guidelines include dosing interruptions between cycles to allow for (blood) count recovery in the setting of a leukemia-free marrow, and the use of granulocyte colony-stimulating factor (after treatment) to improve neutrophil count once a patient is in remission."

This research is likely to be practice-changing for the treatment of some groups of patients with AML, according to MD Anderson.

However, "While this combination represents a key advance in AML therapy, improving both remission and survival rates in newly diagnosed patients with AML, many unfortunately will still relapse," DiNardo said in the release. "Our next steps include an evaluation of azacitidine and venetoclax as a backbone to which additional novel therapeutics (will be added for evaluation) in particularly high-risk populations."