iwAL 2025 | Approaches to managing FLT3-mutant AML

Richard Stone:

Hello. My name is Richard Stone from Dana-Farber Cancer Institute in Boston, and I’m pleased to be working with my colleagues. 

Naval Daver:

Hi, Naval Daver from MD Anderson in Houston, Texas. 

Alexander Perl:

Sasha Pearl from the University of Pennsylvania in Philadelphia. 

Amir Fathi:

And Amir Fatih from Massachusetts General Hospital in Boston. 

Richard Stone:

Well, we had a very interesting session a few minutes ago about how to manage patients with mutant FLT3 AML. Some of the world’s experts were on the panel. And so I’d like to begin with Dr Daver to speak for a few seconds or minutes about how you approach the newly diagnosed patient with mutant FLT3 AML. 

Naval Daver:

Yep. Thank you, Dr Stone. So there’s a lot of progress happening in the FLT3-mutated AML space. At this time, I think the big focus is on identifying FLT3 very quickly, ideally within three to five days, and then for those patients who are younger than 60 to 65 is kind of what we’re looking at today at MD Anderson and many other centers, we’re doing intensive chemotherapy with the FLT3 inhibitor. We are using quizartinib quite a bit for the ITD-mutated, for the TKD, usually mitostaurin. There is data hopefully coming with gilteritinib. And we do have an inclination towards considering allogeneic stem cell transplant in the first remission for those patients. That is a discussion that is evolving rapidly over the last year and this year, with new MRD data and maintenance data suggesting there may be some patients where we could avoid this, but at this point, we’re still inclined towards transplant unless there’s a hurdle such as finance, logistics, or donor search. For the older patients with FLT3, we are having trials that we’re looking at and have published combining HMA-VEN with the targeted agent, FLT3 inhibitor, either gilteritinib or quazartinib. So we’ve published this data now showing high response rates, CR/CRi, molecular clearance at deep levels, and good safety. And some patients do go to transplant, some don’t. But interestingly, we’re not seeing a big difference in the transplant, non-transplant. This is not yet a standard of care. This is being looked at in a larger multi-centered study called the Viceroy study. We will hopefully have that data at ASH this year. And then after that, I think as we review all of these data, there will be decisions that will need to be made as to how to proceed further. Do we move to this or look at more data from other studies? We also do monitor molecular NGS MRD for all these patients, usually every one to two cycles, and that is giving us a lot of information. It’s still not exactly clear what the full cutoff should be, but for FLT3, after three, four cycles of any therapy, if we see any residual FLT3, it does make me feel strongly that transplant should be done if for some reason initially we had not done it. So that’s kind of the generalized approach. 

Richard Stone:

Can you just briefly tell us what the VICEROY study was? 

Naval Daver:

Yeah. So the VICEROY study is looking at azacitidine, venetoclax, gilteritinib across multiple centers. So it’s kind of using the similar MD Anderson approach that Nick Short published in JCO, but across about 25 centers. We hope to have close to 80 to 100 patients with a lot of molecular longitudinal data collection that will hopefully guide, you know, how this regimen performed outside of our experience at MD Anderson. Do we get the same data survival output? And hopefully, we’ll present that at this year’s ASH. 

Richard Stone:

Dr Pearl, could you say a few words expanding on who should get a stem cell transplant in FLT3-mutant AML and who should get maintenance therapy? 

Alexander Perl:

I think the majority of patients should really seriously look at a transplant if they are FLT3-ITD-positive. It provides the greatest protection against relapse. It’s a tried and true therapy. And we’re still working at the kinks in terms of who we can define as a relatively lower risk population, and even for those people, there’s debate about what’s the right thing to do. So if at a minimum, everyone should be evaluated. For FLT3-TKD-positive patients, if they’re with, you know, relatively favorable risk genetics, core binding factor, NPM1, without any adverse risk features in younger patients treated intensively, I think those patients probably can hold off on, you know, emphasizing that they need a transplant unless they’re MRD-positive after a cycle or two of chemotherapy. But generally, I think everybody with FLT3-ITD should be evaluated for transplant. Now, who needs maintenance after a transplant? Best data we have on this comes from a randomized study called MORPHO, which looked at patients getting a first remission transplant for FLT3-ITD-positive disease. And on that study, patients were randomized either to two years of gilteritinib or a matching placebo. It was a double-blinded study. It didn’t meet its primary endpoint, meaning for all patients, there was a relapse-free survival benefit. But when we looked at analyzing this based on the presence of any detectable level of FLT3-ITD using a very sensitive next-generation sequencing-based MRD assay for FLT3-ITD, we could clearly see who benefited from the therapy. And it was the patients who were either MRD-positive within 30 days prior to the transplant or in the early post-transplant period, meaning in the first essentially three months after transplant. Either of those had the same impact on long-term outcome, which was a much higher risk of relapse and worse survival, and that was attenuated by the gilteritinib treatment. 

Richard Stone:

Excellent. Dr Fathi, could you say a few words about how you would manage a patient who’s not going to get a transplant? Would you use maintenance therapy? Which one would you use? And if in the unfortunate event that they relapse, how do you approach that? 

Amir Fathi:

So, yes. So we have a decent number of patients who are older or because of comorbidity are not candidates for a stem cell transplant, which for many of our patients, as Dr Pearl mentioned, is the lone path for a potential cure. We have a few options, but all of those options, I would say, come with some degree of trepidation. So one option is the data from VIALE-A, where all patients on VIALE-A who were 75 and up received a combination of azacitidine and venetoclax compared to azacitidine and placebo, and azacitidine and venetoclax won with both overall survival advantage, the primary endpoint, as well as improved composite remission. So that has become the standard of care for the majority of older patients with FLT3 mutations who are not candidates for stem cell transplant. The challenge is when you go in and do subset analysis in the VIALE-A, among the patients that did not do as well were those patients with FLT3 mutations. So that’s one typical challenge. The other approach to treatment that we sometimes do off protocol is combine hypomethylating agents with a FLT3 inhibitor. That too is fraught with some degree of challenge based on clinical trial data. The Phase III LACEWING data, which looked at, wasn’t placebo-controlled, compared azacitidine with azacitidine and the very potent FLT3 inhibitor gilteritinib, did not reveal a survival advantage. It was not placebo-controlled, so there was a decent amount of crossover and subsequent FLT3 treatment on the azacitidine arm, and therefore, the data was difficult to interpret. But we do know that there was a higher rate of response and remission in patients who received the combination of azacitidine and gilteritinib. So I do not think for the patient in whom you are pursuing palliative care or trying to prolong their life, an approach with azacitidine and gilteritinib, for example, is the wrong approach. Now in the recent last couple of years, the experience of Dr Daver, Dr Short, and the MD Anderson group has increased the use of the triplets, which I think more and more people are becoming comfortable with in terms of potential for marrow suppression because we kind of know now how to go about using it. So triplets with azacitidine or decitabine plus venetoclax and gilteritinib, that particular triplet is now becoming more common among our physicians, at least where I practice, as a potential use in individuals who we think can tolerate it pretty well. Now, if I have a, I don’t know, and we get them, Rich, as you know, in Boston, a late octogenarian or a nonagenarian with a FLT3 mutation, I might think a couple of times before I make that decision. But you do have some additional options as well. Now, you asked me, I’m talking too much, but you asked me about second line and third line treatment. And there are options, but it depends on the type of relapse. If somebody… I’ll give you an example. I have a 87-year-old who I treated with HMA and gilteritinib a while ago, and she went into a nice remission, then relapsed. Now she has a FLT3 wild type, And she is now cycle 27 of azacitidine and venetoclax. So there are ways you can salvage these patients. You can try another FLT3 inhibitor. You can try other targeted therapies. You can try a clinical trial, and there are a few clinical trials that are studying novel FLT3 inhibitors, no pun intended. And they maybe, hopefully, can advance the field based on promising early data.

Richard Stone:

Excellent. Dr Pearl, do you think it’s possible that non-intensive therapies, such as with FLT3 inhibitors, azacitidine, and venetoclax, will supplant intensive chemotherapy in this disease? 

Alexander Perl:

I mean, I think this is a very interesting question. Right now, we’re using venetoclax, azacitidine-based therapy, really primarily in older patients and those, if they’re younger, that they’re not fit for intensive chemotherapy. And we’re making this fitness assessment to say how intensively should we treat the patient. And in reality, if we look at the outcomes, particularly for the triplet combination, they look very similar in terms of the likelihood of remission and the likelihood of MRD clearance using the same types of assays. And the question has come up in patients who are eligible for low-intensity therapy, should we be using a triplet? It does potentially have more toxicity. And that’s something that we should look at in a randomized study. And currently, the MyeloMATCH program has a study that Jessica Altman and I are leading together called the EA02, where we’re randomizing this question of venetoclax-azacitidine versus the triplet venetoclax-azacitidine-gilteritinib. And in patients who are not fit for intensive chemotherapy, we hope to better understand and hopefully answer that question. Now, the question you asked was actually even further than that, which is, what about people who are fit for intensive chemotherapy? Should we think about the venetoclax-azacitidine–based therapy. I would say I wouldn’t recommend that outside of clinical trial. But I think we’re at the point where there’s growing equipoise over this question of, can we use lower-intensity therapy and really answer this question if we’re looking at equivalent outcomes of, say, MRD negativity, and we’re ultimately going on to a transplant at the far end of this. I think that’s a very important and interesting question to answer, but I wouldn’t want to do outside of the study. But I think we’re ready to answer that. 

Richard Stone:

Do you want to talk about the QUIZZICAL trial that gets at this very thing? 

Naval Daver:

Exactly. So I completely agree with Dr Pearl. I think the time is now to move with the randomized data and figure this out. I think this is really a question where a randomized trial, which as you know at Anderson, we don’t normally want to do. But this question, I cannot answer. I don’t think anybody really can answer that. Could you actually do a paradigm shift, use HMA-VEN with FLT3, let’s say, quizartinib or gilteritinib, versus intensive chemo FLT3 in that 50 or some can say 40, we can figure that out later. But young, fit patients with transplant. And I think as the data initially, the thought was we’ll show equivalence. But as the data is maturing and we’re seeing the complete molecular NGS clearance of almost equal, maybe growing numbers, and less myelosuppression, mucositis, nausea, other toxicities, we actually think there may even be a superiority. So I agree. I would not do this off trial today, but there’s trials, both QUIZZICAL, and I think MyeloMATCH is planning a similar trial. So hopefully we will be able to get away without intensive chemo for our FLT3 younger patients, which would be amazing. But let’s wait and see the data in a few years. 

Richard Stone:

Well, I’d like to thank Dr Fathi, Dr Pearl, and Dr Daver for this elucidating discussion. I must say in conclusion that we’ve come a long way since the early part of the millennia when now we use routinely FLIT3 inhibitors and stem cell transplant quite frequently. We’ve made a huge difference in the natural history of this once thought to be terrible disease. Now it’s not good, but it’s a lot better than it was. So thank you for listening.

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