Phase 3 VIALE-A Trial Finds Venetoclax, Azacitidine Combo Safe, Improves Survival in AML

September 2, 2020

The combination was found to be safe and improved overall survival over azacitidine alone in certain patients with acute myeloid leukemia.

According to results from the phase 3 VIALE-A trial, the combination use of venetoclax (Venclexta) and azacitidine (Vidaza) was safe and improved overall survival (OS) over azacitidine alone in certain patients with acute myeloid leukemia (AML).1

The trial findings were presented in the virtual 25th European Hematology Association (EHA) Annual Congress and also published in The New England Journal of Medicine.

“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,” Courtney D. DiNardo, MD, lead investigator and associate professor of Leukemia at The University of Texas MD Anderson Cancer Center, said in a press release.2 “We launched the VIALE-A trial to evaluate whether we could safely use a combination therapy to treat this critical patient population.”

The randomized, double-blind, multicenter, placebo-controlled phase 3 study included patients with confirmed AML who were ineligible for intensive induction therapy due to medical comorbidities and/or were 75 years of age or older. However, those who had received prior treatment with a hypomethylating agent for an antecedent hematologic disorder were excluded.

Patients were randomized 2:1 to receive either azacitidine plus venetoclax or azacitidine plus placebo. The primary end point was a comparison of OS between the 2 arms.

As of January 4, 2020, 431 patients had been enrolled, including 286 in the azacitidine plus venetoclax arm and 145 in the azacitidine plus placebo arm. With a median follow-up of 20.5 months, the median OS was 14.7 months in azacitidine-venetoclax arm compared to 9.6 months in the azacitidine-placebo arm (HR, 0.66; 95% CI, 0.52-0.85, P < .001), respectively, representing a 34% reduction in risk of death.

Hematological adverse events (AEs) of grade 3 or higher in the azacitidine-venetoclax and the azacitidine-placebo arms included thrombocytopenia (45% vs 38%, respectively), neutropenia (42% vs 29%), febrile neutropenia (42% vs 19%), anemia (26% vs 20%), and leukopenia (21% vs 12%). Further, all grade gastrointestinal AEs were common, including nausea (44% vs 35%, respectively), constipation (43% vs 39%), diarrhea (41% vs 33%), and vomiting (30% vs 23%).

Notable serious AEs of grade 3 or higher the azacitidine-venetoclax and the azacitidine-placebo arms were febrile neutropenia (30% vs 10%, respectively) and pneumonia (16% vs 22%xw). Moreover, laboratory tumor lysis syndrome was rare at 1% in the azacitidine plus venetoclax arm. The 30-day mortality rates were 7% (n = 21) for the azacitidine-venetclax arm and 6% (n = 9) for the azacitidine-placebo arm.

“The primary adverse events seen with azacitidine and venetoclax are related to increased cytopenias, including neutropenia and neutropenia-related infections,” DiNardo explained. “Key management guidelines include dosing interruptions between cycles to allow for count recovery in the setting of a leukemia-free marrow, and the use of granulocyte colony-stimulating factor as an adjunct to improve neutrophil count once a patient is in remission.”

Though this research has the potential to be practice-changing for the treatment of some patients with AML, additional research is still necessary to determine how new therapies, including this combination therapy, can improve outcomes for all patients with AML.

“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,” said DiNardo. “Our next steps include an evaluation of azacytidine and venetoclax as a backbone to which additional novel therapeutics are being evaluated in particularly high-risk populations.”

References:

1. DiNardo C, Jonas B, Pullarkat V, et al. A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY OF VENETOCLAX WITH AZACITIDINE VS AZACITIDINE IN TREATMENT-NAÏVE PATIENTS WITH ACUTE MYELOID LEUKEMIA INELIGIBLE FOR INTENSIVE THERAPY-VIALE-A. Presented at the virtual 25th European Hematology Association (EHA) Annual Congress. Abstract #: LB2601.

2. Combination therapy significantly improves survival outcomes for patients with acute myeloid leukemia [news release]. Houston. Published August 12, 2020. Accessed August 27, 2020. https://www.newswise.com/articles/combination-therapy-significantly-improves-survival-outcomes-for-patients-with-acute-myeloid-leukemia?sc=sphr&xy=10021790