ASH 2025 | AML highlights from ASH 2025: menin inhibitor combinations, MRD, and real-world data

There is a tremendous amount of excitement about AML in general at this ASH meeting because AML has made it to the plenary session. That is not with an investigational agent. That is about the comparison of standard therapy with seven and three versus azacitidine and venetoclax, or low-intensity regimens, have they finally dethroned our standard of care? But the other area of true excitement at the ASH meeting is the menin inhibitors. And I have the pleasure of presenting on the upfront use of ziftomenib with a combination of azacitidine and venetoclax. And I think there is a tremendous excitement about what we are calling triplet therapies. So azacitidine and venetoclax has become the worldwide standard of care for AML, initially in older and less fit patients, but now actually increasingly, and that’s part of the reason I mentioned the plenary, we are expanding and hoping to expand the utility of the less intensive backbone for many more patients with AML, perhaps even in combination with an intensive post-remission type of therapy like transplant. So triplet therapies, taking azacitidine and venetoclax and making it even better is very much on the forefront. And the menin inhibitors are in a bit of an arms race at the moment for several that are currently in very active development. The one I’ll be talking about is ziftomenib, which is a very well-tolerated daily drug that we think has quite impressive rates of MRD-negative complete remission in the frontline setting in combination with azacitidine and venetoclax for patients with an NPM1 mutation. Menin, of course, as a target is key in leukemogenesis for NPM1 mutated and for KMT2A rearranged AML. NPM1 mutations are common in AML, lots of patients with those, and we have seen single agent activity resulting in the recent FDA approval of ziftomenib, leading then naturally to combinations both in the relapsed/refractory and in the upfront setting. And there will be presentations on both of those. I’m leading the one for the newly diagnosed patients. So very excited about this. Have a couple of other things that I’m interested in at ASH. So of our own work, very happy to see publication of the MRD or measurable residual disease data related to the Polish acute leukemia randomized study of intensified daunorubicin plus cytarabine versus a triplet, different from what I’ve been talking about, but a triplet of cladribine combined with daunorubicin and cytarabine. The top line results were presented last year. And these two regimens intensified daunorubicin at 90 milligrams per meter squared in a doublet versus the triplet with cladribine are about the same, but yielding very, very high rates of flow MRD negativity, and those are going to be presented also at this meeting. One of the things that we learned a lot about, which will come up both in the presentation and in a poster, is the difficulty in using flow-based measurable residual disease in multicenter studies. And actually, there are multiple presentations at this meeting about that very difficult topic because depending on which lab you go to, you might as a patient literally be called MRD positive or MRD negative with the same sample in two different labs. So there is a real work effort going on to try to continue the optimization and standardization of flow-based monitoring. If I return to the topic of menin, that’s where we’re in a much richer land because the MRD monitoring using molecular MRD, using high-sensitivity NGS-PCR-based monitoring for something like NPM1 mutations is a very, very hot topic, not only for menin, but for all AML patients with, for example, NPM1 mutations. So we sort of have the haves and the have-nots, the molecular subtypes getting targeted therapies with very specific MRD monitoring, but the majority of AML patients still reliant on flow cytometry, which is glitchy to say the least. And one other thing to call attention to a poster that I’m interested in, we put together some real-world data from the ELN, from the European Leukemia Net, trying to look and see what happens outside of clinical trials in patients being treated with AML regimens. And I think this is one effort, but it’s part of a worldwide push to try to understand with all of these new now 13 AML drug approvals since 2017, how are they actually being applied in real-world settings? And are the outcomes the same as in clinical trials? So I think it’s a very interesting space that’s represented throughout the meeting.

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