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EHA 2025 | The effect of baseline co-mutations on quizartinib efficacy in AML: an analysis of QuANTUM-First
Mark Levis, MD, PhD, Sidney Kimmel Comprehensive Cancer Center & Johns Hopkins School of Medicine, Baltimore, MD, discusses an analysis of data from the QuANTUM-First trial (NCT02668653) that aimed to identify the effect of baseline co-mutations in FLT3-ITD, NPM1, and either DNMT3A, TET2, WT1, IDH1, or IDH2, on the efficacy of quizartinib treatment in patients with acute myeloid leukemia (AML). Prof. Levis highlights that the combination of FLT3-ITD, NPM1, and epigenetic regulatory gene mutations confers unique sensitivity to quizartinib and that these findings may impact treatment selection in older patients with AML. This interview took place at the 30th Congress of the European Hematology Association (EHA) in Milan, Italy.
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Transcript
So this was really looking into trying to explain why certain demographic groups didn’t do as well in QuANTUM-First compared to others, specifically the older patient population. Patients under age 60 had a clear benefit from the addition of quizartinib to induction consolidation chemotherapy. Older patients clearly did not. But FLT3-ITD mutated AML is not one disease, it occurs with other mutations and they have specific clinical behaviors...
So this was really looking into trying to explain why certain demographic groups didn’t do as well in QuANTUM-First compared to others, specifically the older patient population. Patients under age 60 had a clear benefit from the addition of quizartinib to induction consolidation chemotherapy. Older patients clearly did not. But FLT3-ITD mutated AML is not one disease, it occurs with other mutations and they have specific clinical behaviors. So with this difference in older patients, we first looked at MDS-related genes and did not see any obvious association with one MDS-associated gene. However, we then looked at the concept of this triple mutation, DNMT3A-NPM1-FLT3-ITD. That had been reported to do very poorly with intensive chemotherapy alone, remarkably well with a FLT3 inhibitor in the salvage setting.
So when we looked at the QuANTUM-First data, we saw A, triple mutant patients, DNMT3A-NPM1-FLT3-ITD did very poorly on the placebo arm, more poorly than patients lacking the triple mutation on the placebo arm. So yes, we’ve confirmed it’s bad. B, Quizartinib versus placebo had a dramatic difference in these patients benefiting the triple mutation. And then we asked, okay, well, DNMT3A is a common founder mutation, but there are other associated epigenetic founder mutations not dissimilar in function – TET2, and the other components of the complementation group, WT1, IDH1, IDH2. So let’s look at those with an NPM1, with a FLT3-ITD and get a larger group. All of those seemed to benefit more dramatically with quizartinib. Finally, we turn back to our age question, oh, older patients who have this subtype of epigenetic regulator, DNMT3A, TET2, or whatever, NPM1, FLT3-ITD, actually do benefit from the addition of quizartinib versus placebo.
So it really gets to, you should not look at FLT3-ITD disease as a single entity, but what is the context it’s occurring in? The older patients with MDS, AML, with a FLT3-ITD probably shouldn’t be treated with intensive chemotherapy anyway, whereas a more fit but patient over age 65 who is fit enough for intensive, who has the triple, as we might call it, probably should get intensive therapy plus quizartinib.
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