Venetoclax Plus Azacitidine Fails to Provide OS Advantage in Treatment-Naive, Higher-Risk MDS

The addition of venetoclax (Venclexta) to azacitidine (Vidaza) did not generate a median overall survival (OS) benefit vs placebo plus azacitidine in previously untreated patients with revised International Prognostic Scoring System (IPSS-R) intermediate- and high-risk myelodysplastic syndrome (MDS).

Findings from the phase 3 VERONA trial (NCT04401748), which were presented at the 2025 SOHO Annual Meeting, showed that in the combination arm, the median OS was 22.18 months (95% CI, 17.28-27.27) vs 21.68 months (95% CI, 17.81-23.79) in the placebo arm (HR, 0.908; 95% CI, 0.733-1.126; P = .38).

The modified overall response rate (ORR) in the venetoclax/azacitidine arm was 76.2% (95% CI, 70.5%-81.3%). The marrow complete response (CR) rate was 57.8%, the partial response (PR) rate was 0.4%, and the CR rate was 18.0%. In the placebo arm, the modified ORR was 57.7% (95% CI, 51.4%-63.9%), the marrow CR rate was 37.5%, and the CR rate was 20.2%.

The overall hematological improvement rate in the combination arm was 49.4% (95% CI, 43.0%-55.8%) compared with 41.2% (95% CI, 35.0%-47.6%) in the placebo arm (P = .0723). The transfusion independence rates were 55.7% (95% CI, 47.1%-64.1%) vs 33.6% (95% CI, 25.7%-42.1%), respectively (P = .0003). The median duration of transfusion independence was 183 days vs 294 days, respectively.

“Subgroup analyses [showed] venetoclax plus azacitidine trended toward a modified overall response benefit vs placebo plus azacitidine for patients with more than 5% to less than 20% bone marrow blasts [who had] ASXL1, TP53, and RUNX1 mutations at baseline,” Guillermo Garcia-Manero, MD, chair ad interim in the Department of Leukemia in the Division of Cancer Medicine, fellowship program director in the Department of Leukemia, and the Dr. Kenneth B. McCredie Chair in Clinical Leukemia Research at The University of Texas MD Anderson Cancer Center in Houston, said during the presentation.

What was the design of the VERONA trial?

A total of 509 patients were randomly assigned 1:1 to the combination or placebo arm. Patients were given venetoclax at 400 mg by mouth daily on days 1 to 14 plus azacitidine at 75 mg/m2 intravenously or subcutaneously for 7 of the first 9 days. Dosing in the placebo plus azacitidine arm matched the combination arm’s dosing. Patients continued treatment until relapse, progressive disease, hematopoietic stem cell transplant (HSCT), or unacceptable toxicity. Patients then transitioned to follow-up.

Patients were stratified by IPSS-R score, HSCT eligibility, and geographic region. The primary end point was OS, and key secondary end points included modified ORR, overall hematologic improvement, and CR rate.

Patients were eligible for treatment if they were 18 years or older, had newly diagnosed MDS, had an IPSS-R score of 3 or more, and were HSCT eligible without prearranged HSCT.

What were the baseline characteristics of patients in the VERONA trial?

Between the combination and placebo arms, respectively, the median ages were 72 years (range, 31-86) and 72 years (range, 25-92) years. In these respective arms, 63.3% vs 65.6% of patients were male, 72.7% vs 71.9% of patients were White, 43.8% vs 43.9% of patients were from Europe, and 54.7% vs 52.2% of patients had an ECOG performance status of 1. Additional baseline characteristics across these respective arms included 37.5% vs 39.1% of patients having a high IPSS-R risk score, 80.5% vs 81.4% of patients deemed ineligible for HSCT, and 30.0% vs 33.5% of patients having ASXL1 mutations.

The median follow-up was 41.2 months, the median duration of treatment was 6.4 months, and the median number of treatment cycles received was 6.

What were the safety outcomes with venetoclax plus azacitidine in the VERONA trial?

No new safety signals were observed. The most common any-grade treatment-emergent adverse effects (AEs) included neutropenia (77.3% vs 60.2%), thrombocytopenia (66.3% vs 58.9%), anemia (44.7% vs 38.2%), and constipation (42.4% vs 50.4%) in the combination and placebo arms, respectively.

Serious AEs leading to treatment discontinuation occurred in 41.6% of patients in the combination arm and 55.3% of those in the placebo arm. Dose interruption was noted in 78.8% vs 67.9% of patients, respectively. Dose reduction of venetoclax/placebo occurred in 12.5% vs 6.9% of patients, respectively, and azacitidine dose reductions were reported in 48.6% vs 27.2% of patients, respectively.

AEs leading to death included disease progression (venetoclax/azacitidine arm, 1.6%; control arm, 0.8%), septic shock (1.2%; 0.8%), sepsis (0.4%; 0.8%), and acute myeloid leukemia transformation (0.4%; 0.8%). The most common causes of death were disease progression (39.2% vs 40.7%) and AEs (10.6% vs 11.4%).

Reference

Garcia-Manero G, Platzbecker U, Fenaux P, et al. Primary analysis of the randomized phase 3 VERONA study of venetoclax plus azacitidine versus placebo with azacitidine in patients with treatment-naïve, intermediate and higher-risk myelodysplastic syndromes. Presented at: 2025 SOHO Annual Meeting; September 3-6, 2025; Houston, TX;. Abstract MDS-1497.