Adding Venetoclax to Azacitidine Improves Response and Survival Rates in Treatment-Naïve AML

A combination of the hypomethylating agent azacitidine and the small-molecule BCL2 inhibitor venetoclax was associated with a 34% reduction in the risk of death, as well as higher response rates, compared with azacitidine alone in a treatment-naïve, predominantly elderly patient population with acute myeloid leukemia (AML) who were not considered candidates for intensive therapy.

This was according to results from a study presented as a late-breaking abstract at EHA25 Virtual, the 25th European Hematology Association Annual Congress, by Courtney DiNardo, MD, of the University of Texas MD Anderson Cancer Center. According to Dr. DiNardo, these findings indicate that the combination approach improves on azacitidine or decitabine monotherapy – currently widely used for older or frailer patients.

In the phase III, double-blinded, multicenter trial, Dr. DiNardo and colleagues enrolled patients with a confirmed diagnosis of AML who were considered to be poor candidates for intensive induction therapy with cytarabine and an anthracycline because of specific comorbidities or age older than 75 years. Eligible participants had treatment-naïve disease, except for prior hydroxyurea.

The patients were randomized (2:1) to:

  • azacitidine and venetoclax (n=286)
  • azacitidine and placebo (n=145)

The combination regimen consisted of azacitidine 75 mg/m2 administered subcutaneously or intravenously on days 1-7 of a 28-day cycle, and once-daily venetoclax 400 mg taken orally on days 1-28 with a 3-day ramp up during cycle 1.

The median age of the overall study cohort was 76 years (range = 49-91). During study follow-up of 20.5 months, patients received a median of 7.0 cycles (range = 1-30) of azacitidine plus venetoclax, compared with 4.5 cycles (range = 1-26) of azacitidine plus placebo.

The median overall survival (primary endpoint) was significantly higher with the combination therapy versus the azacitidine monotherapy (14.7 vs. 9.6 months; hazard ratio [HR] = 0.66; 95% CI 0.52-0.85; p<0.001), which translated to a 34% reduction in risk of death. During the first 30 days of treatment, 21 patients in the venetoclax group (7%) and 9 in the placebo group (6%) died.

The median event-free survival also was longer in the venetoclax group (9.8 vs. 7.0 months; p<0.001).

Complete response (CR) rates also were higher in the venetoclax group:

  • CR: 36.7% vs. 17.9% (p<0.001)
  • CR or CR with complete hematologic recovery (CRh): 64.7% vs. 22.8% (p<0.001)

These responses were achieved early for most patients, Dr. DiNardo noted, with a median time to first CR/CRh of 1 month in the venetoclax group. The median duration of CR/CRh also was longer in the venetoclax group: 17.8 months versus 13.9 months.

When looking at CR rates across subgroups, the investigators reported that venetoclax was associated with significantly higher CR/CRh rates in those with mutations in the following genes:

  • IDH1/2 (75.4% vs. 10.7%; p<0.001)
  • FLT3 (72.4% vs. 36.4%; p=0.021)
  • NPM1 (66.7% vs. 23.5%; p=0.012)
  • TP53 (55.3% vs. 0%; p<0.001)

Venetoclax also led to higher response rates across cytogenetic risk categories:

  • poor cytogenetic risk: 53% vs. 23%
  • intermediate cytogenetic risk: 74% vs. 32%

All patients experienced at least one treatment-emergent adverse event (AE), Dr. DiNardo reported, and hematologic AEs were common. The most common grade ≥3 hematologic AEs included thrombocytopenia (45% with venetoclax vs. 38% with placebo), neutropenia (42% vs. 29%), febrile neutropenia (42% vs. 19%), anemia (26% vs. 20%), and leukopenia (21% vs. 12%).

Gastrointestinal events were the most common nonhematologic AEs, and occurred at similar rates in both arms, she added.

Although serious AEs occurred more frequently in the venetoclax arm (83% vs. 73%), the researchers noted that this increase was not associated with an increase in early mortality. However, dose interruptions were common, with nearly three-quarters of venetoclax-treated patients requiring an interruption.

While this combination approach appears promising, Dr. DiNardo noted that treatment challenges remain in certain populations. “Patients with complex cytogenetics and TP53 mutations still have short-lived responses to azacitidine plus venetoclax,” she explained, “and I look forward to improvements in these most difficult-to-treat patient subgroups.”

Study authors report relationships with AbbVie, which sponsored this trial.


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 intensives therapy-Viale-A. Abstract LB2601. Presented as part of EHA25 Virtual, June 13, 2020.