VERONA and the Future of High-Risk Myelodysplastic Syndromes: A Conversation With Dr. Jacqueline Garcia Free

In 2009, the international phase III AZA-001 trial demonstrated that treatment with azacitidine yielded a median overall survival of 24.5 months — a survival advantage over conventional care.²  Since then, no therapy has improved on these results (Table).^3-7  “Over the last ten years, we’ve seen an enormous number of promising agents in early-phase studies,” Dr. Garcia explained. “But when they’ve moved into phase III, the story has been much less encouraging.” Additionally, many studies and real-world data have failed to replicate AZA-001’s findings, reporting survival rates closer to 18 months.^8,9  Hopes for VERONA were high. Most active drugs for the treatment of higher-risk MDS are approved in the acute myeloid leukemia (AML) space. Venetoclax is already approved in AML with azacitidine, delivering higher remission rates and survival.¹⁰  A phase Ib study in high-risk MDS led by Dr. Garcia had shown promising activity and safety.¹¹ 

VERONA was a double-blind, randomized, international phase III trial comparing azacitidine plus venetoclax versus azacitidine plus placebo, with a primary endpoint of overall survival. Eligible patients had a Revised International Prognostic Scoring System score of greater than 3 (intermediate-, high-, or very high-risk).¹²  All were treatment-naive, aged 18 or older, and not immediate candidates for stem cell transplant, though they could proceed to transplant during or after study participation.

Treatment consisted of venetoclax 400 mg daily on days 1 to 14 of a 28-day cycle, alongside standard azacitidine dosing (75 mg/m² for seven of nine days). Dose modifications were built into the protocol to mitigate myelosuppression. Of note, the protocol prioritized reduction of the azacitidine backbone before venetoclax/placebo, which was necessary as the trial was double-blind.

A total of 509 patients were randomized: 256 to the study arm and 253 to control. Median age was in the early 70s, reflecting the demographics of higher-risk MDS, and most participants were male. Roughly 80% were enrolled outside the U.S., underscoring the study’s international reach.

About 60% of patients in both arms had high- or very high-risk disease, while a quarter were intermediate-risk. Blasts were capped below 20% to avoid overlap with AML, though as more than a third of patients in each arm had 10% to 19% blasts, it is possible they might meet the MDS/AML category under International Consensus Classification 2022 criteria (pending mutational profile).¹³ 

After a median follow-up of 41 months, no statistically significant overall survival difference emerged (22.2 months for study intervention vs. 21.7 months for control; hazard ratio = 0.908, p=0.3772). “For reasons not entirely clear, the patients in the control arm did very well,” Dr. Garcia said. “And so that is part of the challenge of interpreting the data. Why did we finally get the control arm closer to AZA-001? And why was the study arm insufficiently effective to show the survival difference?”

Secondary endpoints tell a more nuanced story, with the venetoclax arm demonstrating higher objective response rates, including marrow complete remission with hematologic improvement, some gains in transfusion independence, and trends toward improved responses in patients with greater than 5% blasts and those with ASXL1, RUNX1, or TP53 mutations. Safety was reassuring, with febrile neutropenia in 23.1% in the intervention group versus 15.9% in the control group; fatal adverse events were comparable. However, azacitidine dose reductions were almost twice as common in the venetoclax arm.

“I think the truth is that there isn’t one single explanation,” Dr. Garcia said. She pointed to several possibilities: inclusion of intermediate-risk patients or those with 5% blasts or less may have diluted benefit in the high-risk cohort; the Blood and Marrow Transplant Clinical Trials Network study 1102 (CTN 1102), published during the study, “confirmed the role of transplant for high-risk MDS, so we need to know if that influenced the outcome.”¹⁴  She also noted that more frequent azacitidine dose reductions in the intervention arm may have reduced efficacy. “We also need to look at the data to understand whether off-study, off-label venetoclax use in the control arm could have affected outcome, particularly in the U.S., where clinicians have adopted this regimen for MDS/AML overlap cases,” Dr. Garcia said.

“While we all really wanted to see this trial be the first of many future approvals, it tells us we need to really rethink how we run our trials,” Dr. Garcia said, highlighting two key takeaways for future studies. First, trials must differentiate between treatment goals. Some patients are candidates for curative transplant while others will never be eligible due to age or comorbidity. Trials may need separate strategies for these groups: bridging therapies versus long-term disease management. Second, in the era of the Molecular International Prognostic Scoring System risk classification,¹⁵  studies should incorporate molecular stratification and efficacy assessed within molecularly defined subgroups rather than broad populations.

For now, azacitidine monotherapy remains standard of care. The absence of futility or excess toxicity seen in VERONA potentially leaves the door open for use in subsets. “We do not have that data yet,” Dr. Garcia said. “But there are potential groups where there could still be a role for combination therapy.” Downstream analyses may identify a role for this regimen in patients with MDS/AML overlap or those molecular subsets known to benefit from venetoclax in AML (e.g., splicing mutations, secondary ontogeny mutations). For now, Dr. Garcia urged caution: “I would not be blanketly giving combination therapy for higher-risk MDS until we have further analyses.”

Despite disappointment, Dr Garcia remains optimistic. “We must learn from these large datasets — understand where we went wrong and which subgroups might still benefit,” she said. “There is still hope.”

Dr. Garcia also stressed the importance of early transplant referral: “The CTN 1102 study confirms that a transplant discussion should be happening for every patient who’s under 75. That is a very, very strong recommendation from my part.”

Meanwhile, the early-phase pipeline is active with novel targets including CLEC12A, MYB, and PI3K-gamma inhibitors. “Strong science is driving these programs,” Dr. Garcia said. “The challenge will be selecting the right patients and endpoints.”

VERONA may not have delivered the patient benefit that the MDS patients, advocates, and clinicians had hoped for, but it has provided crucial insights. Azacitidine plus venetoclax is safe and capable of delivering meaningful hematologic improvements in some — yet translating those gains into longer survival remains elusive.

Dr. Garcia’s final words reflect both realism and resilience: “I’m not giving up on high-risk MDS, and neither are my colleagues. We owe it to our patients to keep pushing forward with sharper trial designs and smarter use of molecular biology. That’s how we’ll move the needle.”

The full interview is available at ashpublications.org/thehematologist/pages/podcasts

Dr. Brierley indicated no relevant conflicts of interest.