VERONA Trial Shows Mixed Results for Venetoclax-Azacitidine Combination in High-Risk MDS
核心洞察
The phase III VERONA trial failed to demonstrate overall survival improvement with venetoclax plus azacitidine compared to azacitidine alone in high-risk myelodysplastic syndromes (搜索).
Subgroup analyses revealed favorable trends in patients under 75 years and those with excess blasts, though these findings did not reach statistical significance.
The combination therapy showed significantly higher overall response rates and transfusion independence without causing unexpected toxicities compared to standard care.
The phase III VERONA trial evaluating venetoclax plus azacitidine in high-risk myelodysplastic syndromes (搜索) (MDS (搜索)) failed to meet its primary endpoint of overall survival improvement, but new subgroup analyses presented at the American Society of Hematology (ASH) 2025 meeting reveal potential benefits for select patient populations.
The randomized trial, sponsored by AbbVie (搜索) and involving 500 patients with intermediate, high, or very high-risk MDS (搜索) worldwide, showed no significant difference in overall survival between the venetoclax-azacitidine combination and azacitidine alone. However, detailed subgroup analyses have identified specific patient populations that may derive benefit from the combination therapy.
Subgroup Analysis Reveals Promising Trends
According to Dr. Jacqueline S. Garcia, principal investigator from Dana-Farber Cancer Institute, the venetoclax combination showed favorable trends in overall survival among patients under age 75 and those with excess blasts. While these trends did not reach statistical significance, they suggest potential therapeutic value in carefully selected populations.
"While we have observed trends suggesting that the study treatment might have been better for certain subgroups, there aren't enough patients in each subgroup to make a conclusion," Garcia explained.
The subgroup analysis also revealed positive trends toward higher overall responses with the venetoclax combination across multiple patient groups, including those aged 18-74 years, patients with excess blasts, those with higher cytogenetic risks, and patients with mutations in ASXL1 (搜索), TP53 (搜索), and RUNX1.
Response Rates and Safety Profile
Despite the lack of overall survival benefit, the venetoclax-azacitidine combination demonstrated significantly higher rates of overall response—a combined measure of complete remission, partial remission, and marrow complete response—compared to azacitidine alone. The combination also showed superior rates of blood and platelet transfusion independence.
Importantly, the safety profile remained manageable, with no new unexpected or excess toxicities observed. Febrile neutropenia rates were 23% in the venetoclax combination arm versus 16% in the control group, representing an acceptable safety margin.
Impact of Patient Population Heterogeneity
The trial's design may have contributed to the mixed results. While the foundational phase 1b trial primarily enrolled patients with high or very high-risk disease (86%) and excess blasts (90%), the VERONA trial included a more heterogeneous population with 28% intermediate-risk MDS (搜索) patients and 27% without excess blasts.
"In the VERONA trial, it is possible that signals of an improved benefit in patients with high-risk disease, those patients who really need escalated treatment, could be buried by responses in patients with intermediate disease who would have done well on either regimen," Garcia noted.
Transplant Outcomes and Future Directions
The combination therapy did not prevent or delay stem cell transplantation for eligible patients. Post-study stem cell transplant was received by 17% of patients in the venetoclax group at a median of 5.6 months, compared to 13% in the control group at 6.7 months. Prior to transplant, patients on venetoclax showed higher rates of complete response (25.6% vs 27.3%) and marrow complete response (60.5% vs 33.3%).
The findings highlight the complexity of treating MDS (搜索) and underscore the need for more targeted approaches. As Garcia emphasized, "Future MDS trials need to be designed to focus on the patient sub-groups that stand to benefit most."
Standard of care for high-risk MDS (搜索) has remained azacitidine or decitabine for two decades, with real-world survival of approximately 16-17 months. The urgent need for improved treatments, particularly for patients ineligible for stem cell transplantation, continues to drive research efforts in this challenging disease area.