ASH 2024 | Insights into several sub-studies of the QuANTUM-First trial of quizartinib in FLT3-ITD+ AML

There are several sub-studies on the QuANTUM-First study. The QuANTUM-First study was the randomized Phase III study of newly diagnosed FLT3 ITD AML patients receiving intensive chemotherapy, consolidation plus or minus quizartinib, including a maintenance phase of 3 years, or they called it continuation, but to the clinician it’s maintenance. And the first is… and I should say also that weaving through all of these abstracts is measurable residual disease, MRD, using a highly sensitive FLT3 ITD-specific MRD assay that detects very low levels of the disease. 

So, in the first abstract, which is, I call it the maintenance abstract, there’s a question of is maintenance really necessary? Once you’re done with induction, consolidation, you’ve had your FLT3 inhibitor, are you done? And we thought we could use MRD to tell us perhaps patients who still had MRD needed ongoing quizartinib. But it turns out, first of all, most patients in the trial did not go to allotransplant. And therefore, we had a significant number of patients who were entering the so-called maintenance phase. First of all, there was a pronounced overall survival benefit for being on the quizartinib arm in the maintenance phase, highlighting the fact that the QuANTUM-First trial outlined a complete therapy of induction, consolidation, and the three years of maintenance. B) MRD did not predict benefit. Patients who were MRD negative clearly still benefited from the drug. So the MRD assay was not picking up all of the residual disease in this trial, and I have a suspicion that is because we were not doing first whole bone marrow aspirates as we have done in other trials. So in other words, probably the quality of sample going in was not as good, I suspect. 

And the reason I can kind of say that is I’m gonna skip to the third abstract, which is the deep dive into the QuANTUM-First and the MRD. Two points, one, when we detected MRD by this assay, in the vast, vast majority of cases, it was identifying the ITD mutation by length that was seen at diagnosis. So it was clearly specific for the disease. Number two, if you use peripheral blood versus bone marrow, you lost a number, about a third of samples became negative using peripheral blood. So bone marrow is more sensitive, which is what we’ve known, and I suspect, to be honest, a high-quality bone marrow aspirate is really what’s essential. 

So then the more prominent finding out of that trial being presented in the so-called commutation study. And here we looked at the incidence and impact of the commutations in that trial. Not surprisingly, NPM1 and DNMT3A were the dominant commutations, and the so-called triple mutation of DNMT3A, NPM1, and a FLT3-ITD predicts for remarkable benefit and call it exquisite sensitivity of this disease to FLT3 inhibition. So that is kind of the take-home point, the so-called triple mutation of a chromatin modifier, NPM1 and a FLT3-ITD defines a subset of AML that specifically needs a FLT3 inhibitor for best outcome.

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