In the phase III VIALE-A trial reported in The New England Journal of Medicine, Courtney D. DiNardo, MD, and colleagues found that venetoclax plus azacitidine significantly improved overall survival vs azacitidine alone in previously untreated patients with acute myeloid leukemia (AML) who were ineligible for standard induction therapy due to coexisting conditions or age.

Courtney D. DiNardo, MD

Study Details

In the double-blind trial, 431 patients (intent-to-treat population) from sites in 27 countries were randomly assigned 2:1 between February 2017 and May 2019 to receive azacitidine plus venetoclax (n = 286) or azacitidine plus placebo (n = 145). Patients were considered to be ineligible for standard induction therapy if they were aged 75 or older, or had at least one of the following coexisting conditions:

• History of congestive heart failure for which treatment was warranted or an ejection fraction of ≤ 50% or chronic stable angina
• A diffusing capacity of the lung for carbon monoxide of ≤ 65% or forced expiratory volume in 1 second of ≤ 65%
• Eastern Cooperative Oncology Group performance status of 2 or 3.

Patients with favorable cytogenetic risk were excluded from the trial. In both groups, the median age was 76 years. All patients received standard azacitidine at 75 mg/m² subcutaneously or intravenously on days 1 through 7 in 28-day cycles, and either venetoclax at a target dose of 400 mg or placebo once daily. The primary endpoint was overall survival.

Overall Survival

Median follow-up was 20.5 months. Median overall survival was 14.7 months in the azacitidine/venetoclax group vs 9.6 months in the control group (hazard ratio [HR] = 0.66, 95% confidence interval [CI] = 0.52–0.85, P < .001).

Complete remission was observed in 36.7% vs 17.9% of patients (P < .001) and median duration of complete remission was 17.5 months vs 13.3 months. Complete remission/complete remission with incomplete hematologic recovery was observed in 66.4% vs 28.3% of patients (P < .001), and median duration of composite complete remission was 17.5 months vs 13.4 months.

Among 214 vs 110 patients with de novo AML, median overall survival was 14.1 months vs 9.6 months (HR = 0.67, 95% CI = 0.51–0.90). Among 72 vs 35 patients with secondary AML, median overall survival was 16.4 months vs 10.6 months (HR = 0.56, 95% CI = 0.35–0.91). Among 182 vs 89 patients with intermediate cytogenetic risk, median overall survival was 20.8 months vs 12.4 months (HR = 0.57, 95% CI = 0.41–0.79). Among 104 vs 56 patients with poor cytogenetic risk, median overall survival was 7.6 months vs 6.0 months (HR = 0.78, 95% CI= 0.54–1.1). Median event-free survival was 9.8 months vs 7.0 months (HR = 0.63, P < .001).

Adverse Events

Grade ≥ 3 hematologic adverse events were more common in the azacitidine/venetoclax group, including thrombocytopenia (45% vs 38%), neutropenia (42% vs 28%), febrile neutropenia (42% vs 19%), anemia (26% vs 20%), and leukopenia (21% vs 12%). Gastrointestinal adverse events of any grade were common in both groups, including nausea (44% vs 35%), constipation (43% vs 39%), diarrhea (41% vs 33%), and vomiting (30% vs 23%). Infections of any grade occurred in 85% vs 67% of patients. Serious adverse events occurred in 83% vs 73%, including grade ≥ 3 febrile neutropenia in 30% vs 10% and pneumonia in 16% vs 22%.

The investigators concluded, “In previously untreated patients who were ineligible for intensive chemotherapy, overall survival was longer and the incidence of remission was higher among patients who received azacitidine plus venetoclax than among those who received azacitidine alone. The incidence of febrile neutropenia was higher in the venetoclax/azacitidine group than in the control group.”

Disclosure: The study was funded by AbbVie and Genentech. For full disclosures of the study authors, visit nejm.org.