Venetoclax Plus Azacitidine Misses OS End Point in Newly Diagnosed Higher-Risk MDS

Despite a strong biologic rationale for BCL-2 inhibition in higher-risk myelodysplastic syndromes (MDS) and interest in replicating the success of venetoclax (Venclexta)–based doublets in acute myeloid leukemia (AML), data from the phase 3 VERONA trial (NCT04401748) did not demonstrate an overall survival (OS) advantage with venetoclax plus azacitidine (Vidaza) vs placebo plus azacitidine in newly diagnosed higher-risk MDS, according to Guillermo Garcia-Manero, MD.

Findings from VERONA presented during the 2025 SOHO Annual Meeting showed that adding venetoclax plus azacitidine to frontline therapy for newly diagnosed higher-risk myelodysplastic syndromes did not translate into an OS improvement vs placebo plus azacitidine, and no clear OS benefit emerged across prespecified subgroups.¹ However, data from a subgroup analysis presented during the 2025 ASH Annual Meeting suggested a possible signal in select populations, with HRs numerically favoring venetoclax plus azacitidine in younger patients who were 18 to less than 75 years old (HR, 0.835; 95% CI, 0.630-1.107) and in those with excess blasts (≥ 5% to < 20% blasts; HR, 0.858; 95% CI, 0.676-1.090); outcomes were not improved in the TP53-mutated subgroup (HR, 1.064; 95% CI, 0.670-1.688).²

In an interview with OncLive®, Garcia-Manero noted that, “Unfortunately, we did not see an improvement in OS when we compared azacitidine [plus] venetoclax arm vs azacitidine. This was a double-blind, [large], internationally conducted trial, and despite the fact that the response rate was greater with the combination, we did not see that translating into an improvement in OS.”

Garcia-Manero is the interim chair of the Department of Leukemia, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center, in Houston.

OncLive: What was the clinical rationale for evaluating venetoclax plus azacitidine in treatment-naive, intermediate- and higher-risk MDS?

Garcia-Manero: VERONA was a study [which examined] the combination of venetoclax with azacitidine vs azacitidine in patients with high-risk MDS. The primary end point was OS. We’re trying to see if we can improve the survival of our patients, and the standard right now is single-agent azacitidine. The study followed the [phase 3] VIALE trial [NCT02993523] in AML, and there are some similarities between AML and MDS in terms of the role of BCL-2 inhibition. The reality is that we designed the study in parallel to VIALE. There’s a strong rationale for BCL-2 inhibition in high-risk MDS. We wanted to see if, as it happened in AML, if the combination of a hypomethylating agent with a BCL-2 inhibitor improved survival for our patients.

Did any patient subgroups show a clearer signal of benefit with venetoclax plus azacitidine?

[This is very] important, because the question is, how is it possible that this combination that is successful in AML, [a] very [closely related] disease that resulted in an increased response rate compared with single-agent hypomethylating agents [HMAs], did not result in improvement in survival? We believe that this is likely [due] to some subsets of small groups of patients on the trial.

For instance, if you look at VIALE, this was a study for older individuals unfit for chemotherapy, whereas VERONA was a study for all comers, so there was a significant fraction of patients who went for transplantation. It’s possible that some of the survival issues that we saw on the trial were related to the fact that patients on the monotherapy arm could have been rescued with single-agent azacitidine if they were transplanted.

It is [also] possible that patients [received] some type of salvage chemotherapy before transplant, even if they failed on a HMA or the combination. That’s probably very important. Second, with this kind of analysis, there is a natural crossover issue, where even if the study was double-blinded, it is likely that patients were treated at the time of failure by adding [a] BCL-2 inhibitor. Those are things that could have affected the survival significantly.

There are groups of patients that probably will not benefit from this type of approach, such as those who are TP53-mutated with a low percentage of blasts. If I was going to design this study again, I would restrict it to [a] group of patients who are a bit older and who are not transplant candidates.

How should the higher response rates with venetoclax plus azacitidine be interpreted, and should these results change current treatment decision-making in higher-risk MDS?

We need to see the full data to see if there are some subgroups [of patients] who benefited from the therapy. We saw some of this at ASH, but BCL-2 is very important in this disease, and we should continue to investigate these kinds of doublets. We should not accept that single-agent azacitidine is the standard of care for high-risk MDS. The [phase 3] GLORA-4 study [NCT06641414] of a second-generation BCL-2 inhibitor is ongoing, and there are other studies looking at other BCL-2 inhibitors in this disease.

We need to learn from the design of the VERONA to design [other] studies in a way that will be [successful]. It’s not about the drugs, it’s about the patients. [We need to] focus on the group of patients [who are] going to benefit from BCL-2 inhibition.

References

1. 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.
2. Garcia-Manero G, Platzbecker U, Fenaux, P et al. Subgroup analyses from the randomized, phase 3 VERONA study of venetoclax with azacitidine (Ven+Aza) versus placebo with azacitidine (Pbo+Aza) in patients with treatment-naïve, intermediate and higher-risk myelodysplastic syndromes (HR MDS). Blood. 2025;146(1):235. doi:10.1182/blood-2025-235