ASH 2024 | QuANTUM-First: impact of co-mutations on quizartinib outcomes in FLT3-ITD+ AML

So as part of the analysis of the QuANTUM-First trial, we clearly want to see the impact of co-mutations on the benefit of quizartinib for overall survival, relapse-free survival, or complete remission rates. So we did a 38-gene panel on these patients at the time of diagnosis. We found that over 50% of the patients had a concomitant NPM1 mutation. 43% had a DNMT3A mutation. And about a third, 32%, had both NPM1 and a DNMT3A mutation. Now, the reason I’m focusing on that and we want to specifically look at that group of patients, as you may remember from the data published by Elli Papaemmanuil in the New England Journal, those two co-mutations, NPM1, DNMT3A with FLT3-ITD, really had the worst prognosis. And what we found when we looked specifically at the NPM1 mutated or the DNMT3A mutated patients, there was an improvement in overall survival and relapse-free survival by the addition of quizartinib in those. And in the combination in the patients who had both, we saw that as well. So the quizartinib seemed to be able to overcome the negative prognostic impact of having all three mutations there. Now, another topic along those lines that I’m particularly interested in is, how about the patients with myelodysplasia-related changes and mutations? There’s data out there that suggests that maybe this impacts on the outcomes of patients, especially, for example, with NPM1 mutations. What we found in this analysis is that the most common MDS-like mutations were RUNX1 and ASXL1, and then much less for all of the others. We could not see any impact of quizartinib when you look at all of the MDS-related mutations. So we lumped them all together. The hazard ratio was 1.0, so it didn’t favor quizartinib over placebo. I want to see more from that data because, in general, when I think about which patients are going to have MDS-related mutations, it’s typically older patients will have MDS-related mutations and then FLT3-ITD may be a secondary event in leukemogenesis. We know that the outcomes with quizartinib versus placebo were not as good in the older patients, where the hazard ratio basically was 0.9 in favor of quizartinib, but not statistically significant. What remains to be seen is, is there an interaction then between age and this mutational profile? Is it possible that the older patients who have an NPM1 mutation, DNMT3A, still will benefit even if they’re older? And yet the patients who have MDS-related mutations, maybe those are the ones who are older who will not benefit. I think we have to learn a lot more about the mutational profile in the younger and older patients. But the important part of that is I don’t believe we should just say quizartinib works only in the younger patients. I think that is a gross oversimplification. We have a lot more data mining to do from QuANTUM-First to see if there are other features in the older patients that are predictive of a benefit of quizartinib in that group.

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