Venetoclax/Azacitidine Yields No OS Improvement in Intermediate/High Risk MDS

The modified overall response rate was higher with venetoclax/azacitidine vs placebo/azacitidine in patients with intermediate/high risk MDS.

The combination of venetoclax (Venclexta) plus azacitidine did not improve overall survival (OS) compared with placebo plus azacitidine in patients with revised international prognostic scoring system intermediate and high-risk myelodysplastic syndrome (MDS), according to results from the phase 3 VERONA trial (NCT04401748), presented at the 2025 Society of Hematologic Oncology Annual Meeting.

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 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.

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

A total of 509 patients were randomly assigned 1:1 to either the combination or placebo arms. 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. 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 revised international prognostic scoring system, HSCT eligibility, and geographic region. The primary end point was OS, and key secondary end points included mOR, overall hematologic improvement, and CR.

Patients were eligible for treatment if they were older than 18, had newly diagnosed MDS, and a revised international prognostic scoring system of 3 or more, and HSCT eligible without prearranged HSCT.

Between the combination and placebo arms, the median age was 72 (range, 31-86) and 72 (range, 25-92) years, 63.3% vs 65.6% were male, 72.7% vs 71.9% were White, 43.8% vs 43.9% were from Europe, and 54.7% vs 52.2% had an ECOG performance status of 1. Additional characteristics included 37.5% vs 39.1% having a high revised international prognostic scoring system risk, 80.5% vs 81.4% did not have baseline eligibility for HSCT, and 30.0% vs 33.5% had ASXL1 mutations.

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

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%) between 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% in the placebo arm, dose interruption was noted in 78.8% vs 67.9%, and dose reduction of venetoclax/placebo in 12.5% vs 6.9% while azacitidine was 48.6% vs 27.2%.

AEs leading to death included disease progression (1.6% vs 0.8%), septic shock (1.2% vs 0.8%), sepsis (0.4% vs 0.8%), and acute myeloid leukemia transformation (0.4% vs 0.8%) in the combination and placebo arms, respectively. The most common cause of death was 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 the 2025 Society of Hematologic Oncology Annual Meeting, Houston, TX; September 3-6, 2025. Abstract MDS-1497.