iwAL 2026 | Targeting FLT3-mutant AML: frontline strategy, MRD-guided transplant, and RAS-targeted approaches

Navar Daver:

Hello, my name is Navar Daver. I’m a faculty in the Department of Leukemia at the MD Anderson Cancer Center in Houston, Texas. It’s a great pleasure talking to you from iwAL 2026. We’re going to be discussing some of the updates in FLT3 that we just had a session. It’s a pleasure to introduce my colleagues and friends, Dr. Catherine Smith from UCSF, Dr Eunice Wang from the Roswell Park Comprehensive Cancer Center, and Dr Sasha Pearl from UPenn. So we had a pretty lively session, a lot of discussions, a lot of questions. We had to cut it short because of the break, but let me start with you, Sasha. You gave an overview of the frontline FLT3, and I think we were all disappointed by the data from the gilteritinib versus midostaurin 7 plus 3 PASHA study. So can you give us some updates on your thoughts on that study? What did we see? How can we use this knowledge to kind of better design studies in the future? What are your thoughts?

Alexander Perl:

First off, I think it’s a very good study in terms of it was well-designed. It was designed to answer an important question. We have multiple FLT3 inhibitors. Which one should we be using frontline? The other question I think that people want to know as they’re using these drugs is what’s the endpoint that really matters to us? Is survival the right endpoint when we have effective salvage? Should it be event-free survival so that we just pick the right drug first and patients stay with best effective therapy from day one, hopefully don’t need to go through salvage therapy. And there’s still plenty of data yet to be seen from that study that I don’t think we have yet. The MRD data are not yet public. Hopefully we’ll get an update on that at ASH. The overview of the study was that it randomized over 700 newly diagnosed patients with either a FLT3 ITD or FLT3 TKD mutation. It randomized them to what’s standard in Europe, which is a double induction, so two induction cycles, with each cycle having a FLT3 inhibitor for 14 days, consolidation, transplant if they were going to go to transplant, and maintenance thereafter for a year. And it was comparing gilteritinib to midostaurin. So midostaurin being approved, gilteritinib only being approved in relapsed/refractory. And what the study found was that gilteritinib had a small impact on early outcomes in terms of remission rate, but had a bigger impact on relapse rates, but didn’t improve overall survival. The event-free survival looked a little bit better, maybe not significantly better, 0.052 on the p-value. But is that enough for us to say that that’s better anti-leukemic therapy and enough to change our standard frontline therapy? In my mind, I still think EFS is important in AML. I want to give my best therapy first. But at present, if the question is, can you get a drug approved off of this? The answer is no. You can’t improve overall survival. It didn’t meet its primary endpoint. These are secondary analyses that show advantages of one drug over another. So I think, yeah, we were all disappointed. We thought that this would do much better. But I think one of the reasons that that happened was gilteritinib was effective as salvage. So the patients on the midostaurin arm really had a better option in salvage therapy than the patients on the gilteritinib arm. And we saw that. The outcome after relapsed or refractoriness was much better in the midostaurin arm than in the gilteritinib arm.

Naval Daver:

And I think this is a theme that I worry is going to be recurrent in the AML space because for the first time, we actually have effective drugs. So this could be very similar to what happens with intensive chemo menin, right? And then people will get a menin inhibitor or combo, menin inhibitor and salvage and maybe get responses. And I think we truly need to start thinking as the myeloma colleagues did about PFS, EFS, because OS will improve with better salvage therapy. So I think this is probably the key message that we have to take away from this as we design these next studies. Eunice, let me ask you a lot of discussion and debate about who do we transplant in the FLT3 space today. So what’s your general practice? Let’s say for younger patients below 65, how do you think about transplant for FLT3 ITD AML? What mutations impact your decision, MRD? Are you transplanting them all? Like what’s your approach? And then maintenance as well after transplant. What do you do?

Eunice Wang:

Yes. So I think that the question is now putting the question aside of how you get them to CR. When you achieve a CR in a FLT3 ITD mutant patient, what is the next step for them? As you mentioned, should we go to transplant? Should we do consolidation? So should we do maintenance chemotherapy? And I think a lot of that is patient-specific. However, the general data that we have from the few clinical trials in space suggests that it really divides up into post-chemotherapy induction consolidation. Do you do chemo or do you do transplant? And if you do transplant, do you do FLT3 after that? So the data in the post-chemo setting suggests that there’s no benefit to using midostaurin after consolidation in terms of relapse-free survival. Maybe less relapse, but no overall survival benefit. Should you use gilteritinib after consolidation? No. But the data with quizartinib from the Quantum First study, which actually also employs this highly sensitive 10 to the minus 4, 10 to the minus 6 MRD assay, suggests that that particular drug, which is a second generation FLT3 inhibitor, actually can be effective in both MRD positive and MRD negative patients that are not going to transplant. And interestingly enough, for those patients that have achieved by that highly sensitive MRD assay, a MRD negative status, primarily in those patients that have a particular genotype, NPM1, FLT3, ITD, DNMT3A, that those patients without allogeneic stem cell transplantation benefit enormously from that FLT3 because we think that there’s probably underlying residual disease that even our most sensitive assay doesn’t pick up, but that there is a three-year overall survival in those particular patients, which achieve that MRD-negative status. And therefore, when you compare that to the outcomes of allogeneic stem cell transplant in CR1 for those patients, it seems like those patients could be considered in a randomized data for a allo-free treatment, i.e. continuous quizartinib, for at least three years. Now, for the people that go to transplant, we have data from Morpho suggesting if you’re MRD-positive, again, in the pre-peritransplant setting, that gilteritinib is effective, not for MRD-negative, but again, MRD-positive is kind of like the opposite. And then there are some things that we know, again, that NPM1, DNMT3A, FLT3 ITD patient probably seems to be really of benefit. The gilteritinib in the post-transplant setting for patients that are NPM1 wild type who are MRD-positive or negative is really not effective. So I think that we are now using really the second generation FLT3 inhibitors. And we’re seeing some data emerge that the particular genotype and the sensitive MRD assay can help determine if there is a subset. So that was actually a source of great debate, as you remember from the discussion. Some of the transplanters were like, if there’s even one patient that you do that with, that it relapses, we shouldn’t be doing that. But I think that even now in our favorable risk ELN 2022 patients, even those patients that we consider favorable risk that we do not transplant as a rule, there’s going to be some people that relapse, right? There’s going to be some people. And if there’s 11% of those that relapse, we still don’t recommend transplant for the other 90%. So I think this is going to be a hot topic because on some of the studies, including those that Sasha mentioned, 30% to 55% of patients in CR1 with FLT3 ID are going to transplant. And maybe there is. That’s a lot of patients. And maybe this could be practice changing.

Alexander Pearl:

It’s actually higher than that. That’s of the whole study. Not of the patients in remission. Remission rates are somewhere 70%, 80%.

Eunice Wang:

And that’s based on data with midostaurin in the RATIFY trial.

Naval Daver:

Which is 55% almost.

Eunice Wang:

Right. And that data, I have to say no, to be honest, is years old with less sensitive MRD, a much less potent inhibitor. So I think we need to reevaluate that. And no maintenance. That study had no maintenance. And the maintenance it had was only 12 months, right? So one could say that that study does not in any way represent the tools and the practices that are available.

Naval Daver:

I mean, I think that’s kind of the theme that emerged, right? So either you go with intensive chemo targeted therapy upfront, go for your deepest possible remission early on, and then maybe if you can track those patients and use maintenance, you could avoid the later big burden of the allogenic transplant, right? Or you go with the lower intensity, which is HMA, VEN, FLT3, HMA VEN, but there’s a high likelihood those patients may not be fully cured with that alone, then you’re looking at a bridge to transplant. And I think that’s kind of the crux of everything. And, you know, one can argue both ways. I think in the end, it’s probably something you want to talk to your patients and decide, you know, what they want to go with. I think the other issue with a lot of the studies that we talk about, especially the ATMAN data, is that they again focus on OS, right? So if you look at EFS, there is a big difference. And so that’s, I think, the other discussion to the patients. If you’re a 40-year-old and you want to be one and done, get three months of treatment, get the transplant, be done in six months, 90% chance of disease doesn’t come back, there may be a road for transplant. Some may say, you know, I don’t want to take all that toxicity. I’m doing well. I’m going to go back to work. If I need it down the line in three, five years, I’m okay. So there may be a real patient component here as to their stage of life, what they’re doing, what’s important to them, their philosophy, mentality, and we’ll discuss that. Yeah. So Kathy, a lot of exciting data, wonderful talk on resistance and FLT3 mutation. So what do you think are the next steps from a trial perspective based on what we’re learning? How do we bring the RAS inhibitors? How would you conceptualize these trials? Do we do it just in a post-FLT3 inhibitor relapse with RAS? Do we move quickly to adding it frontline? How do we sequence it? Like biologically, how do you think is the quickest way to get it to the best impact?

Catherine Smith:

Yeah, no, I think it’s an open question. I mean, it’s pretty clear that RAS inhibitors are going to be useful in the relapse refractory setting. I mean, I think that is the lowest hanging fruit. There are patients every week that I see that could use one. I think that’s very clear. I think long term, the ultimate best use of these inhibitors really is going to be in that front setting. I think the ability to kind of eliminate all residual clones is required for cure, right? And like, however we do that, that’s what we need to do, right? And so I think the ability to employ these inhibitors in a way that is tolerable upfront is what we really do ultimately need to explore. But as a physician, I just want to get these into the patients that need them as soon as humanly possible. And I really think the lowest hanging fruit is all these patients that are relapsed with RAS mutations. Those patients have no treatment, zero. So I think we really need to first move in. And this is the paradigm that we use for FLT3 inhibitors back in the day, right? And for menin. You know that these patients are relapsing. They need something. Just get it into them now and then figure out the best way to use this ultimately later.

Naval Daver:

Yeah. I think it’s been phenomenal. A lot of the work you’ve done hopefully will come to fruition. The clinic, RAS inhibitors, many of them. Eventually, as you said, earlier shot, because of course there are financial and pharmaceutical development considerations they want to get, and we want to get the drugs approved. So likely moving to salvage, single agent, hopefully like menin and FLT3 activity approval, but then quickly try to see how do we move them? Do you sequence with HMA, VEN, FLT3, HMA VEN, RAS? Do you do single cell or deeper, you know, DPP-CR monitoring and start with one and then bring in the other?

Catherine Smith:

I think all these techniques will emerge. And I mean, one of the things which is good or bad, depends on how you want to see it, is the treatment of AML is becoming more nuanced, more patient-specific, more molecular-driven. And I think we’re not going to get simplified, generalized answers from any of these. I think it is going to be very nuanced and complicated. But the good part of it is that the survival and outcomes seem to be hopefully getting better. So that’s a good thing. Well, thank you all for joining us, and hope you enjoy the other sessions.

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