ASH 2025 | The prognostic impact of KMT2A fusion transcript detection in patients with KMT2A-r AML in CR1

So we’re interested to further validate the prognostic impact of KMT2A fusion MRD, particularly in the post-induction setting. So there’s decent literature on KMT2A MRD in the pre-transplant setting but not a lot post-induction. There’s a few small series and partly that’s because it’s pretty tricky to do these MRD assays because of the heterogeneity of KMT2A fusions. We managed through collaboration with a lot of colleagues around the world to collect data on 174 patients with MRD results from six laboratories and the MRD results were from after course one, course two or course three of intensive chemotherapy in patients with a variety of KMT2A fusions all treated intensively and all achieving remission without a menin inhibitor. What we found was that MRD positivity at any time point from either blood or marrow was strongly prognostic of survival and relapse but particularly the post course 2 time point was very prognostic and it didn’t matter whether positivity was in the blood or the marrow regardless survival was poor and relapse was high if MRD was detected. And indeed, if MRD was detectable at that time, pretty much every patient eventually relapsed, no matter what you did to them, sadly. We looked to see whether there was any sort of threshold or gradient effect amongst MRD-positive patients, and we couldn’t find that. So there was no safe level of MRD. Any MRD was bad. We were interested to look at the impact of MRD within disease subgroups and within treatment settings and we showed that MRD positivity is highly prognostic regardless of what type of it came to where you had, what your mutation pattern was, how high your white cell count was and also what chemotherapy you received, where you were treated, whether you were treated in or outside a trial, and importantly, which MRD laboratory the test was done in. Finally, we saw that overall in the population, allogeneic transplant in first remission was associated with improved outcomes, improved survival and decreased relapse. This was particularly so in the MRD-positive patients and less so in the MRD-negative patients. But drilling down further on the MRD-negative patients, what we saw was that patients who received chemotherapy, which was not FLAG-Ida before achieving MRD-negativity, had quite high relapse rates without transplant. And so we don’t recommend deferring transplant in those patients. We feel that they should still be taken to transplant based on the data that we have. And even in the FLAG-Ida patients, we only have very small numbers. So to summarize we showed that MRD for KMT2A transcripts is possible in many laboratories. It’s highly prognostic for all patients with these fusions and it really identifies a group of patients with poor outcomes who need different approaches and with the advent of menin inhibitors perhaps that’s the approach that should be taken in these patients.

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