VIALE-A Trial Supports Survival Benefit of Venetoclax Plus Azacitidine in Elderly Patients With AML

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In the phase III VIALE-A trial, venetoclax added to azacitidine led to a significant and clinically meaningful improvement in response rates and overall survival, as compared with azacitidine alone, in treatment-naive predominantly elderly patients with acute myeloid leukemia (AML) ineligible for intensive therapy.1

According to Courtney D. DiNardo, MD, of The University of Texas MD Anderson Cancer Center, Houston, these “eagerly awaited” results come from the first phase III trial to show such a clear survival advantage in this patient population. The study met numerous secondary endpoints as well as its primary endpoint, said Dr. DiNardo, who presented this late-breaking abstract during the EHA25 Virtual Congress, the virtual edition of the 25th European Hematology Association Annual Congress. Median overall survival was 14.7 months with venetoclax/azacitidine and 9.6 months with azacitidine alone (hazard ratio = 0.66; P < .001), she reported.

Courtney D. DiNardo, MD

Courtney D. DiNardo, MD

The phase III randomized, double-blind, placebo-controlled VIALE-A study compared venetoclax/azacitidine with azacitidine/placebo in 431 treatment-naive patients who were ineligible for intensive induction therapy due to medical comorbidities and/or age ≥ 75. As Dr. DiNardo explained, this is a challenging population.

“For older patients with AML—due to their high-risk disease-related biology and medical comorbidities—the prognosis has remained poor. Lower-intensity treatments are reasonable treatment options for these patients, though unfortunately they are associated with low response rates and survival expectations of less than 1 year,” explained Dr. DiNardo. “In this setting, the oral BCL2 inhibitor venetoclax demonstrated impressive response rates and promising activity in clinical trials, leading to its accelerated approval in select countries, including the United States. These results are from the confirmatory phase III trial.”

Phase III VIALE-A Details

Patients, whose median age was 76, were randomly assigned 2:1 to venetoclax at 400 mg daily plus azacitidine at 75 mg/m2 on days 1 to 7 (n = 286) per 28-day cycle or to azacitidine alone (n = 145). The primary endpoint was overall survival. Secondary endpoints were rates of composite complete remission (complete remission/complete remission with incomplete hematologic recovery) by the initiation of cycle 2; complete remission; transfusion independence (red blood cells or platelets); compositive complete remission and overall survival in key molecular subgroups; and event-free survival.

Median follow-up was 20.5 months. Patients received a median of 7 cycles of the combination and 4.5 cycles of azacitidine alone.

Overall Survival Benefit

Multiple outcomes were improved with the combination therapy (Table 1). The primary endpoint, median overall survival, was 14.7 months with venetoclax/azacitidine and 9.6 months with azacitidine alone (hazard ratio = 0.66; P < .001).

“The 9.6-month overall survival with azacitidine alone is consistent with the 10-month overall survival in the AML-AZA001 study,2 which is often used as historical comparison for azacitidine in newly diagnosed older patients,” pointed out Dr. DiNardo.

The composite complete remission rate was 66% and 28%, respectively (P < .001), and the median duration of these responses was 17.5 and 13.4 months, respectively. Consistent with earlier studies of this combination, responses occurred quickly, at a median time of 1.3 months, with 43% of patients having a composite complete remission by the start of cycle 2.

“With the important caveat that many subgroups are quite small,” Dr. DiNardo said, “the combination was favored in virtually all subgroup analyses…across the board. Of note, this includes many of the most difficult-to-treat patients, such as those aged 75 and older and those with secondary AML…. We saw a doubling or more in response rates across all evaluated genomic subgroups.”

The combination led to composite complete remission rates in key mutational subsets, ranging from 55% for those with TP53 mutations to 75.4% for those with IDH1/2 mutations; the range with azacitidine alone was 0% to 36.4% in key molecular subsets.

Dr. DiNardo elaborated on the achievement of complete remission with partial hematologic recovery, which is defined as an absolute neutrophil count of at least 500/L and a platelet count of at least 50,000/L. “Although this is a new AML endpoint, many believe it is more clinically relevant, representing a degree of immune system recovery and peripheral count recovery that is meaningful to our patients,” she noted.

“The complete remission/complete remission with partial hematologic recovery rate of 64.7% is nearly superimposable to the complete remission/complete remission with incomplete hematologic recovery rate of 66% with the combination—and again, with a median time to complete remission/complete remission with partial hematologic recovery of 1 month and 40% of patients attaining this before cycle 2, versus 5.5% with azacitidine alone,” Dr. DiNardo elaborated.

Combination Generally Tolerated

The safety profile was generally consistent with the known safety profiles of venetoclax combined with azacitidine and the known safety profiles of the two medications alone. The most common grade 3 or 4 adverse events in patients receiving the combination were thrombocytopenia (45%), neutropenia (42%), febrile neutropenia (42%), anemia (26%), leukopenia (21%), pneumonia (20%), and hypokalemia (11%). Notable serious adverse events (grade ≥ 3) for the combination versus azacitidine alone were febrile neutropenia (30% vs 10%) and pneumonia (16% vs 22%). Gastrointestinal adverse events of all grades were common in both arms. Laboratory tumor-lysis syndrome was rare, occurring in three patients who received the combination therapy. The 30-day mortality rates were 7% and 6%, respectively.

“Of note, though dose interruptions were needed for nearly three-quarters of patients on the combination, this was typically due to ongoing cytopenia on day 28 of a given treatment cycle (often cycle 1), in the setting of a leukemia-free marrow,” related Dr. DiNardo. “Management guidelines were provided for cytopenias in this setting.” 

DISCLOSURE: Dr. DiNardo has served as a consultant to or received honoraria from Celgene, Notable Labs, AbbVie, Daiichi Sankyo, MedImmune, Jazz Pharmaceuticals, Agios, and Syros.


1. DiNardo C, Jonas B, Pullarkat V, et al: A randomized, double-blind, placebo-controlled study of venetoclax with azacitidine vs azacitidine in treatment-naive patients with acute myeloid leukemia ineligible for intensive therapy: VIALE-A. EHA25 Virtual Congress. LB2601.

2. Dombret H, Seymour JF, Butrym A, et al: International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood 126:291-299, 2015.


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