ASH 2025 | Interpreting findings from the VERONA trial in MDS: factors influencing the lack of survival benefit

I would say VERONA was a really important study. It taught us how we should try to adjust how we run clinical trial protocols for high-risk MDS in 2025. We’ve evolved how we take care of MDS patients and our expectations. So I would say the punchline is the addition of venetoclax to azacitidine is not for everybody, mostly because we don’t see a change of survival benefit. However, there are a lot of details that have not yet emerged that require additional analyses, and we might have to learn from ongoing and recently presented real-world data to really supplement what the trial could not offer or provide yet. So as an example, during the life expectancy of this clinical trial of VERONA, which was a trial for intermediate and high-risk patients, we found that it did not meet its primary endpoint of overall survival. It was essentially the same 22 versus 21 months for study versus standard of care azacitidine. We learned a few things. One, the combination regimen was not as toxic as everyone was worried about. The rate of febrile neutropenia was 23% versus 17%, which tells us we can take care of our patients. The scheduling was very safe. Importantly, there was no early treatment mortality, which was excellent. During the life expectancy of the clinical trial, our recommendations for higher risk MDS changed. And so based on BMT CTN or a randomized study in the transplant setting, we learned that what our patients should get in frontline is really transplantation. So during the process of the clinical trial, our expectations have adjusted and have increased for patients with high-risk MDS, meaning the chemotherapy or cytoreductive regimen that we give is merely a bridge or what we provide en route to a transplant for patients. Now, the majority of patients may not be eligible based on age or comorbidity, but it is something that we learned. So in this clinical trial, VERONA, we did see that despite not meeting the survival endpoint, we learned several things. One, there was a better modified overall response that included complete remission, which was the same in both cohorts, partial remission, and marrow complete remission. The marrow complete remission is a bit of a topical concept in itself because we removed it from the IWG 2023 response criteria. But the idea is that that means it’s less than 5% blast and could represent an opportunity to then transplant somebody who has adequate disease control. And so in this clinical trial, we saw that the modified or overall response was higher with the study arm. And if we’re wondering why didn’t it translate to survival, I think it’s several things. So one is patients were not as sick with study treatment. And so there is a chance, because it’s overall survival, that people got additional therapies afterwards that might have led to them being able to have a longer survival, meaning our first regimen did not make them too sick, and so they could get a second-line therapy if indicated. A second thing that we found is that, unfortunately, while we wanted to focus on higher-risk MDS patients, we included intermediate risk as well. And while they’re very worthy of investigation, what we know about venetoclax is it’s really a blast reducer. And that’s what we learned in the acute myeloid leukemia setting. In MDS, it’s a stem cell disease, and it is a different beast when it’s less than 5% blast versus those with excess blast. When you look at the forest plot curves, when we look at multi-variable analyses, we’re able to appreciate that with the study arm, by overall response, we see that it trends in favor of the combination. And when we take a look, it was not powered for overall response that yeah it was a secondary endpoint but when we look at the forest plots for overall survival it trended with a hazard ratio 0.8 just barely crossing over one for those with greater than five percent blasts. So my hope was if we had patients that were truly high risk, higher or excess blasts, I think that we have not fully answered the question in the context of this randomized clinical trial because it’s underpowered for this. To ask the question of whether or not those with excess blasts greater than 10%, greater than 5%, or those with high or very high risk disease, do they benefit from a combination approach? I would argue that there’s certainly flirtation of that based on the trends. It just did not meet significance. So I would say across the board, I don’t universally recommend giving venetoclax. I would be very strategic on individual use. If it’s being used to bridge someone to a transplant, I think it could be worthwhile to consider because it does not add more toxicity. But if it’s used as a sole agent, I don’t think that it’s necessary at this time from what we know. The last thing I’ll say is what we’ve learned with the additional follow-up is only about 19% of patients went to transplant. That really speaks to that we had a really higher risk patient population that was older. When we look at the transplant data, it looks like patients are doing well overall. What we need a little bit more analyses on, which we hope to do for the manuscript, is to show were there any differences based on the first-line regimen that they received. All I can tell you is that from what we know with the data available is that on this trial, after their first treatment assignment, twice as many patients in the azacitidine placebo group did end up getting venetoclax at the end of the day. That might have helped to contribute to the curves over getting close to each other and not being significantly different, meaning they eventually got venetoclax despite not getting it in the beginning. A second thing that was presented at the SOHO meeting in September is that for patients on the study arm, because it was doublet and there’s a little bit more myelosuppression or lower cell counts, there was a bit more azacitidine reduction. So did we potentially underdose patients on the study arm because the other arm was placebo and so we had to dose reduce azacitidine in the protocol. I think there was a lot of factors from inclusion of intermediate risk, patients getting post-trial venetoclax, the reduction of the azacitidine in the combination arm that contributed potentially to the survival benefit being unseen.

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