Courtney D. DiNardo, MD, MSCE
In the phase III VIALE-A trial reported in The New England Journal of Medicine, Courtney D. DiNardo, MD, MSCE, of The University of Texas MD Anderson Cancer Center, 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 aged ≥ 75 years.1
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 ineligible for standard induction therapy if they were aged ≥ 75 years or had at least one of the following coexisting conditions: a 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%: or an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or 3. Patients with favorable cytogenetic risk were excluded from the trial. 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.
For the azacitidine/venetoclax vs azacitidine groups, median patient age was 76 years, with 61% ≥ 75 years vs 76 years, with 60% ≥ 75 years. Overall, 60% of patients in both groups were male, 75% vs 76% had de novo and 25% vs 24% secondary AML, and 45% vs 44% had an ECOG performance status of 2 or 3; 49% in both groups had a bone marrow blast count ≥ 50%, and 64% vs 61% had intermediate and 36% vs 39% had poor cytogenetic risk. Grade ≥ 3 cytopenias at baseline were anemia in 31% vs 36%, neutropenia in 72% vs 62%, and thrombocytopenia in 51% vs 50%. In addition, 50% vs 52% had red blood cell and 24% vs 22% platelet transfusion dependence at baseline, and 49% vs 45% had at least two factors for ineligibility to receive intensive therapy.
Overall Survival
Median follow-up was at 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. In patients with composite complete remission with measurable residual disease of < 1 residual blast per 1,000 leukocytes, overall survival at 24 months was 73.6% vs 63.6%.
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 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).
Red blood cell transfusion independence occurred in 59.8% of the azacitidine/venetoclax group vs 35.2% of the control group (P < .001), and platelet transfusion independence occurred in 68.5% vs 49.7% (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 and were grade ≥ 3 in 64% vs 51%. The most common grade ≥ 3 nonhematologic adverse events in the azacitidine/venetoclax group included pneumonia (20% vs 25% in control group), hypokalemia (11% vs 10%), and diarrhea (5% vs 3%).
Serious adverse events occurred in 83% vs 73% and were grade ≥ 3 in 82% vs 71%. The most common in the azacitidine/venetoclax group included febrile neutropenia (30% vs 10%, all grade ≥ 3), pneumonia (17% vs 22%; 16% vs 22% grade ≥ 3), sepsis (6% vs 6%, all grade ≥ 3), atrial fibrillation (5% vs 1%; 4% vs 1% grade ≥ 3), anemia (5% vs 4%, all grade ≥ 3), and neutropenia (5% vs 2%, all grade ≥ 3). Adverse events led to discontinuation of treatment in 24% vs 20% of patients and to interruption of treatment in 72% vs 57%.
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. Dr. DiNardo has received grant support, consulting fees, and honoraria from AbbVie, Agios Pharmaceuticals, Celgene, ImmuneOnc Therapeutics, and Daiichi Sankyo; grant support and honoraria from Novartis; honoraria from Bayer, Jazz Pharmaceuticals, and MedImmune; grant support from Calithera Biosciences, and advisory board fees from Notable Labs.
REFERENCE
1. DiNardo CD, Jonas BA, Pullarkat V, et al: Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N Engl J Med 383:617-629, 2020.
