The following article features coverage from the European Hematology Association 2020 virtual meeting. Click here to read more of Cancer Therapy Advisor‘s conference coverage.

The addition of venetoclax to azacitidine was associated with a 34% reduction in risk of death compared with placebo plus azacitidine, according to results of a phase 3 trial of adult patients with treatment-naive acute myeloid leukemia (AML) ineligible for intensive induction chemotherapy presented at the Virtual Edition of the 25th European Hematology Association (EHA) Annual Congress.

Older patients and those with comorbidities who are diagnosed with AML are frequently ineligible for treatment with standard induction therapy involving administration of intensive chemotherapy, and instead receive less intensive treatments, including low-dose cytarabine or a hypomethylating agent, such as azacitidine or decitabine. However, the likelihood of achieving a complete remission (CR) is much lower for patients receiving less intensive therapy compared with intensive therapy.

Venetoclax is an oral BCL-2 inhibitor that was approved by the U.S. Food and Drug Administration (FDA) in 2018 in combination with azacitidine, decitabine, or low-dose cytarabine through the Accelerated Approval Program based on results of 2 nonrandomized studies conducted in adult patients newly diagnosed AML aged 75 years of older or those with comorbidities that made them ineligible to receive standard intensive induction therapy.2

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This placebo-controlled, randomized, confirmatory, phase 3 trial (VIALE-A; Identifier: NCT02993523) compared the efficacy and safety of azacitidine plus venetoclax with azacitidine plus placebo in adult patients with newly diagnosed AML ineligible for intensive induction therapy due to age of 75 years or older or comorbidity. Overall survival (OS) was the primary study endpoint with key secondary study endpoints including rates CR + CR with incomplete count recovery (CRi), CR + CR with partial hematologic recovery (CRh), CR + CRi and CR + CRh rates at cycle 2, event-free survival (EFS), CR + CRi and OS by molecular subgroup, transfusion independence rate, and safety.

At baseline, the 431 patients enrolled in the study had a median age of 76 years, as well as an Eastern Cooperative Study Group (ECOG) performance of 2/3, and disease characterized by secondary AML in approximately nearly one-half and approximately one-quarter of patients, respectively.

The study population was stratified according to age, cytogenetic risk, and region and were then randomly assigned in a 2:1 ratio to receive azacitidine plus venetoclax (286 patients) or azacitidine plus placebo (145 patients)

At a median follow-up of 20.5 months, median OS was 14.7 months and 9.6 months in the venetoclax-containing versus the placebo-containing arm, respectively (hazard ratio [HR], 0.66; 95% CI, 0.52-0.85; P <.001).

The CR + CRi rate was 66.4% vs 28.3% (P <.001), and the CR + CRi rate at the start of cycle 2 was 43.4% vs 7.6% (P <.001) for study arms treated with and without venetoclax, respectively. Notably, in the subgroups of patients defined by specific mutations, patients receiving venetoclax-containing therapy had substantially higher rates of CR + CRi compared with those receiving placebo plus azacitidine as follows: IDH1/2 (75% vs 11%), FLT3 (72% vs 36%), NPM1 (67% vs 24%), and TP53 (55% vs 0%), and this pattern was also observed across other subgroups, including those defined by patient age, cytogenetic risk, AML subtype, and level of bone marrow blasts.

The median number of cycles of study drug was 7.0 for those receiving venetoclax plus azacitidine and 4.5 for patients treated with placebo plus azacitidine, and the median time to first CR or CRi was 1.3 months and 2.8 months for those treated with and without venetoclax, respectively. Hence, responses to the combination of venetoclax and azacitidine occurred quickly. In addition, the median duration of CR + CRi was 17.5 months and 13.4 months in study arms treated with or without venetoclax, respectively.

Findings for some of the other key secondary study endpoints for patients receiving venetoclax vs placebo included the following: CR + CRh rate (64.7% vs 22.8%; P <.001) and median EFS (9.8 months vs 7.0 months; HR, 0.63; 95% CI, 0.50-0.80; P <.001). In addition, the percentage of patients with a transfusion-free interval with respect to both red blood cells and platelets for at least 8 weeks was 58% in the study arm treated with venetoclax and 34% for those receiving the placebo-containing therapy (P <.001).

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Regarding safety, gastrointestinal adverse events (AEs), including nausea, constipation, diarrhea, and vomiting, were common in both study arms. Serious AEs included febrile neutropenia (30% vs 10%) and pneumonia (17% vs 22%) for patients treated with and without venetoclax, respectively. Laboratory tumor lysis syndrome occurred in 1% of patients in the venetoclax-containing arm, and the rates of early mortality were similar in the 2 study arms: 7% and 6% for those treated with venetoclax and placebo, respectively. While AEs leading dose interruption were common for patients treated with the combination of venetoclax plus azacitidine (72%), and were mostly related to ongoing cytopenias, AEs leading to dose discontinuation occurred in only 24% of patients receiving this treatment.

In her concluding remarks, Courtney D. DiNardo, MD, from the University of Texas MD Anderson Cancer Center in Houston, Texas, stated that “the combination of azacitidine and venetoclax is associated with statistically significant and clinically meaningful improvements in OS, response rates, duration of remission, and transfusion independence, representing a true paradigm shift in the treatment of our older patients with AML.”

Editor’s note: This article was updated on 8/25/20.

Disclosures: Research funding for this study was provided by AbbVie, Inc. and Genentech, Inc.

Read more of Cancer Therapy Advisor‘s coverage of the EHA virtual meeting by visiting the conference page.


  1. DiNardo C, Jones 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: Virtual Edition of the 25th European Hematology Association (EHA) Annual Congress; June 2020. Abstract LB2601.
  2. Venetoclax (Venclexta) [package insert]. North Chicago, IL: AbbVie Inc.; 2020.