ASH 2025 | Outcomes of HMA plus venetoclax in HR-MDS: an analysis from the icMDS validate database

First, I would like to talk a little bit about the multi-center retrospective analysis that we did as part of the Validate database, which is an international consortium of academic centers throughout the globe in nine countries, 32 centers that participated. And that’s a retrospective database that includes patients with higher-risk MDS who are treated with hypomethylating agents in the frontline setting. And for this particular analysis from the database, we looked at patients who were treated with either HMA monotherapy or a combination of HMA plus venetoclax. And that combination of HMA and venetoclax has really become the new standard of care for older patients or patients ineligible for intensive chemotherapy with newly diagnosed AML. And there’s also been a recent randomized Phase III trial in higher-risk MDS that compared azacitidine plus venetoclax versus azacitidine monotherapy. And that was the so-called VERONA trial. However, the efficacy of the combination with HMA venetoclax in a real-world setting is unknown. And to answer a little bit about the real-world efficacy of this combination, we conducted this analysis. And in our analysis, we had about 1,900 patients that were included. All were high-risk MDS patients that were treated with HMA-based therapy in a frontline setting. Among those 1,900 patients, there were about 1,700 that were treated with HMA monotherapy and 134 with HMA venetoclax. And then we looked at various different things, including the response rate, as well as overall survival, and then trying to tease out if there are any specific subgroups of patients that might benefit from the addition of venetoclax. First, in terms of the response rate, in line with other studies, the combination arm with HMA and venetoclax had higher response rates compared to HMA monotherapy. However, that did not apply to the true complete remission rate, which was similar in both arms. And this is also in line with what we’ve seen from the VERONA trial and other clinical trials of the combination. However, when we then looked at overall survival, both in unadjusted as well as in adjusted analysis, there was no difference in terms of overall survival with the addition of venetoclax to HMA monotherapy. And that was applied both to the median as well as to various different landmark analyses. And that was also true after we adjusted for different baseline disease and patient covariates as well as bone marrow transplant. We then finally tried to tease out if there are any specific patient subgroups that might benefit from the addition of venetoclax. One is TP53 mutant patients. As you may know, TP53 mutations in MDS are associated with adverse outcomes. And when we then looked at patients with TP53 mutant disease versus wild-type patients, we did notice that the benefit with the addition of venetoclax seemed to be limited to patients with TP53 wild-type disease. And that applied both to the response rate as well as to overall survival. And the other molecular subtype that has been associated with higher response rates to HMA venetoclax in the VERONA trial are ASXL1 mutations. So we looked at this in our analysis as well. And again, here we saw that similar to the entire cohort, patients independent of the ASXL1 mutation status benefited in terms of the response rate from the addition of venetoclax, but not in terms of overall survival. And then lastly, we looked at transplant status. And that’s a little bit of a difficult analysis because it was not a randomized clinical trial where we have standardized approaches to transplant. So you have to take this with a little bit of a grain of salt. But we did see that the median overall survival among transplant recipients was better for the combination with HMA venetoclax versus HMA monotherapy. And among non-transplanted patients, there was no difference again. So, yeah, I think putting this all together, I think this is an important study because it’s a large international sample of high-risk MDS patients with a very detailed molecular annotation that’s treated in a real-world practice. However, again, this is a retrospective analysis and not a prospective clinical trial, so we had limited availability of some of the variables and also the treatment schedules and those adjustments were not standardized. But I think it is well in line with the VERONA trial in terms of their overall survival outcomes. And we were currently looking more into certain specific subtypes. We are trying to tease out if there are subtypes of high-risk MDS patients that might benefit from the addition of venetoclax.

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