In the first-line treatment of higher-risk myelodysplastic syndromes (MDS), the combination of venetoclax with azacitidine fell short of the primary endpoint of a reduction in mortality compared with azacitidine plus placebo, despite some notable secondary outcomes, a primary analysis of the phase 3 VERONA study showed.

“What we have learned from this preliminary analysis is that, unfortunately, the combination of venetoclax with azacitidine did not show an improvement in overall survival,” said first author Guillermo Garcia-Manero, MD, of the University of Texas MD Anderson Cancer Center, Houston, in presenting the findings at the Society of Hematologic Oncology (SOHO) 2025 annual meeting.

“That said, the combination resulted in higher overall response rates in this patient population, and this was actually particularly seen in those patients with more than 5% blasts, and we also demonstrated that we could deliver this combination in a safe way.”

Approximately half of patients with MDS (43%) present with higher-risk forms, and even with the standard of care treatment with the hypomethylating agent azacitidine, their prognosis can be poor, with a median survival of only approximately 1.5 years.

Most patients present with one or more mutations, increasing their risk for progression to acute myeloid leukemia (AML) or death, and most are not eligible for the only known potentially curative treatment of allogeneic stem cell transplantation, underscoring the need for more effective treatment options.

The combination of a hypomethylating agent with the oral BCL-2 inhibitor venetoclax has shown important benefits in AML and is in fact the standard of care in that disease, and hopes of important benefits of the regimen in higher-risk MDS were raised in a previous phase 1b study presented at the 2024 American Society of Hematology Annual Meeting in San Diego last December.

That study of 107 patients with treatment-naive MDS showed a promising overall response rate of 80.4% and survival extending to about 26 months with the venetoclax/azacitidine treatment combination, with a manageable safety profile. 

To further investigate the effects in a randomized, double-blind study, Garcia-Manero and colleagues conducted the current VERONA trial, enrolling a larger pool of 509 treatment-naive patients with higher-risk MDS who were stem cell transplant-eligible or ineligible.

The patients were randomly assigned to a regimen of either oral venetoclax 400 mg or placebo once daily on days 1 through 14, with both groups receiving intravenous or subcutaneous azacitidine 75 mg/m² for 7 days in each 28-day cycle.

Those with therapy-related MDS or myelodysplastic/myeloproliferative neoplasms were excluded from the trial.

About 92% of the patients had a median age of 72 years and an Eastern Cooperative Oncology Group Performance Status of less than 1, and 72.5% had high or very high baseline revised international prognostic scoring system risk. Approximately a quarter of patients had the TP53 mutation.

Patients had a median duration of treatment of about 6 months and received a median of approximately six cycles.

At a median follow-up of 41.2 months, no significant differences were observed in the primary outcome between the groups, with a median overall survival of 22.1 months in the venetoclax/azacitidine group (n = 256) and 21.68 months in the azacitidine/placebo group (n = 253; hazard ratio, 0.908; P < .38).

Deaths occurred in 65.2% and 66.8% of the patients in the venetoclax/azacitidine and placebo/azacitidine groups, respectively. The leading cause of death was progressive disease occurring, in 39.2% and 40.7% of patients in the venetoclax/azacitidine and placebo/azacitidine groups, respectively, followed by adverse events in 11% and 10.6%.

However, the secondary endpoint of modified overall response rate was significantly higher in the venetoclax/azacitidine group than in the placebo/azacitidine group (76.6% vs 57.7%; P < .0001).

The rate of marrow complete response was also more favorable in the venetoclax/azacitidine arm than in the placebo arm (57.8% vs 37.5%), and the complete response rates were 18.0% and 20.2%, respectively.

The venetoclax/azacitidine arm also showed a trend towards a higher modified overall response in the subgroup of patients with bone marrow blasts between 5% and 20% and other specific mutations.

“Patients with a lower percentage of blasts, ie, less than 5%, actually did not seem to do as well as we expected, and this constituted nearly a quarter of patients in the study,” Garcia-Manero noted.

No New Safety Signals

The most common grade 3 or higher adverse events in the venetoclax/azacytidine group compared with the placebo/azacytidine group were neutropenia (76.9% vs 58.9%) and thrombocytopenia (63.5% vs 52%).

Fatal adverse events occurred in 7.1% with the venetoclax/azacytidine group vs 8.1% with the placebo/azacytidine group, with no new safety signals observed.

“When we were designing this trial, one of the questions we had was whether it is possible that this [combination] could be associated with more cytopenias and therefore possibly more mortality and inferior outcomes,” Garcia-Manero said. “But we did not see that. There were basically no new safety signals that were observed in this trial.”

Despite the lack of a benefit in mortality rates, Garcia-Manero noted that the improvements in response rates observed in the venetoclax/azacitidine group are “quite important, because we have seen some variations in response criteria that may or may not have been fully accepted by some of us.”

“We need to learn from this experience and better understand issues [such as] whether an HMA [hypomethylating agent] is always the proper backbone therapy in this group of patients — are there second-generation BCL inhibitors that we should be using?” Garcia-Manero added. “I think we need to be more precise in how we select patients in these kinds of trials for this specific type of intervention, such as with BCL-2 inhibition.”

“From this data, we are going to be able to build the next generation of studies that hopefully will allow us to improve the outcomes of patients with this complex disease,” he added in a SOHO meeting news report.

With Previous Combo Failures, Hopes Were High

Commenting on the study, Valeria Santini, MD, associate professor of hematology at the University of Florence Medical School, in Florence, Italy, who co-moderated the session, noted that with no alternative to azacitidine for patients with higher-risk MDS, “there were a lot of expectations for the VERONA trial.”

“There have been at least five trials with a combination of different agents with different mechanisms of action compared with azacitidine alone, but all have failed to show a prolongation of overall or event-free survival,” she told Medscape Medical News.

While the venetoclax/azacitidine combination has shown favorable survival benefits in AML, the findings underscore the differences from MDS.

“What we are learning is that we have to think about MDS differently from AML — this is important to stress,” Santini said. “There is a trend of considering MDS to be an earlier form of AML, and in some cases, [the two] can be overlapping, such as when there is a TP53 mutation.”

“But in other cases, MDS is not really similar to AML, due to differences in behavior; the microenvironment is different, and other considerations,” she explained.

Importantly, “the number of blasts is not enough to define the biology of the disease,” she underscored. “The count of blasts cannot be enough to consider an MDS to be like AML.”

Santini agreed that further evaluation should shed better light on potential benefits of the venetoclax/azacitidine combination in key patient subtypes, “but not as a general treatment for higher-risk MDS.”

The study was supported by AbbVie and Genentech. Garcia-Manero reported receiving research support from AbbVie and Genentech. Santini had no disclosures.