iwAL 2025 | Ask the Expert: Naval Daver answers your AML questions at iwAL 2025

Hi, I’m Naval Daver from the MD Anderson Cancer Center in Houston, Texas, speaking here from iwAL 2025. 

So the next question is from Thomas Cluzeau from the Nice University Hospital in France. Do you think we need to continue to include TP53 MDS and AML in clinical trials? Do you think we need to perform specific clinical trials for this entity or several, depending on the type of TP53 mutations? So I think this is a great question by Dr Cluzeau. In general, I would say yes, we need to continue our clinical research for TP53-mutated MDS/AML. This is at this time the biggest unmet need population in acute myelodal leukemia and myelodysplastic syndrome. I think what Dr Cluzeau is trying to get at is the challenge of having too many TP53-mutated patients enrolled on your trial, because we know that this is a very difficult outcomes are poor, and we’re worried that these patients may actually not benefit, and this could impact the overall outcome of the trial to the point where a drug that could work in the non-TP53 may eventually have a negative survival signal because of a heavy TP53 enrollment. So I do think what we should be thinking about and doing is actually enrolling those patients separately on either a cohort for TP53 within the same trial that is statistically protected and will read out independently, or if we think that the drug does have some potential, I think we should do really well-designed, dedicated phase 1-2 studies with good survival follow-up, MRD data, transplant data, post-transplant survival, and then potentially consider dedicated TP53 trials as independent trials for those patients. But I do think we have seen some of the MDS studies especially come out as negative because of inclusion of very heavy populations of TP53, for example, with the magrolimab studies, and this is something we want to avoid in the future. 

Then Dr Aditi Shastri from the Albert Einstein College of Medicine, do you recommend maintenance or MRD-directed therapy post-allotransplant? In general, the answer to this is yes, and I’m going to say this is mainly post-acute myeloid leukemia patients going to transplant. In our institution, MD Anderson, we do consider maintenance, especially with those who have intermediate or high-risk features. Now we do have a number of trials ongoing. So I think the most established area where I would recommend maintenance even to other centers who may not have a trial is for the FLT3-mutated patients. So here there’s clear data that patients who have FLT3 mutation, especially those who have a molecular NGS MRD positive, either pre- or post-transplant, will benefit from gilteritinib maintenance. This was shown in the MORPHO study by Mark Levis and colleagues, and we do routinely use gilteritinib maintenance post-transplant in our FLT3-mutated patients. For the others, it often depends on what trial they were on in front line. So if they got intensive chemo or HMA-VEN-menin and went to transplant, then we will usually continue the menin inhibitor post-transplant in maintenance. And then for the remaining ones, we have done and continue to have a trial of low-dose azacitidine-venetoclax for a mutation-agnostic broad maintenance. That is not something that is established yet. So I think among the established therapeutics that should be definitely done, I think the FLT3 inhibitor maintenance, and I do believe the menin inhibitor-based maintenance eventually is going to be very important. 

This is from Dr Fernandez, US. How do you approach sequencing of venetoclax-based regimens with emerging novel doublets and triplets to avoid resistance? So this is a great question and something we’ve discussed a tremendous amount of the iwAL meeting. In general, we believe that eradicating the maximum amount of clones and trying to debulk the leukemia very quickly, very early on, gives us the best chance of avoiding clonal resistance, clonal emergence, and eventual relapse. And this is something that has been shown as a philosophy, not just in older unfit AML. It’s something we have seen in acute lymphoblastic leukemia. We’ve seen it in younger patients with AML, where we added gemtuzumab or targeted therapies. We’ve seen it in multiple myeloma. So I think that concept is true, that if we can find ways to safely incorporate two to three effective agents up front for even two or three cycles and eradicate 99.999% of the disease, that is likely going to be the best chance of eventual long-term cure. And so that has led to this approach of what we call the triplets of HMA-VEN with targeted therapies, whether it’s FLT3 inhibitors, IDH inhibitors, menin inhibitors, antibody-drug conjugates. And these are definitely showing very high efficacy, especially the targeted therapy combos with HMA-VEN and very high rates of molecular NGS ultra-sensitive MRD clearance. Now, the challenge is that these triplets cannot be delivered for a period of time. So we usually give them for three to four cycles, achieve very deep remission, often with flow and molecular MGS MRD when available, becoming negative, and then de-escalate to either a HMA-VEN backbone or the targeted therapy eventually after six to eight months. Now there’s limited data on this, but coming trials prospectively are going to be looking at planned de-escalation of the triplet to the doublet to the single agent every four to six months to to try to avoid issues with delayed or prolonged myelosuppression. And I think will guide us, but these will take the next one and a half, two years. 

So this is from Andrew Brunner at the Mass General Hospital, Boston. Given the results of the VERONA trial, where should we delineate a diagnosis of MDS or AML? So this is a good question. Dr Brunner is asking, what is the cutoff for MDS versus AML? Because we have the VIALE-A study, which was positive in AML, older unfit patients with azacitine-venetoclax. Unfortunately, at the same time, we now recently have the data with the VERONA study, which was meant for intermediate high, very high IPSSR MDS. And as we know, the top line data is negative, we have not seen the full details. So if I have a patient with a 15% blasts, should I consider this patient based on the ICC classification as MDS/AML and give them azacitidine-venetoclax, or should I consider them more of an MDS, and based on VERONA, not give them venetoclax, but just do HMA alone? I think a lot of this is not simplistic, you know, one answer fits all. It’s going to be based on the biology of the disease, the type of mutations, the fitness of the patient, and the goal of treatment. So, if the patient has what we consider AML-like mutations, NPM1, IDH1, IDH2, DDX41, RUNX1, we know these are VEN-sensitive mutations. I would go for HMA-VEN. And if I’m thinking about transplant, so it’s a patient below 70 who’s fit and transplant has a curative option, again, I would think of HMA-VEN, because even though the survival may have not been improved in VERONA, we know the remission rate was, and this will give me a better possibility and path to get this patient to transplant. So we still want to use that. But if the patient is 75 years old or has a TP53 mutation and is 60 years old or has other complex cytogenetics, then I would probably avoid venetoclax because you do have cumulative myelosuppression and the benefit may be limited and this patient may actually not be able to go to transplant. So I do think it’s going to be more molecularly driven, the selection of who gets HMA-venetoclax versus single agent HMA, and not just based on a blast percentage cutoff. 

So another question here from Dr Brunner from the Mass General Hospital is, what endpoints would be meaningful for studying new targeted therapies in frontline AML? Do they need to achieve a survival benefit? Now this is a great question. we’ve discussed this extremely in detail at the iwAL meeting and really gets to the question of do we have suitable surrogates for overall survival in the frontline setting? And I will split this into intensive chemo and low-intensity therapy. So with intensive chemotherapy, especially if you’re using targeted therapies, a lot of these now have a molecular NGS MRD assay, which can go down to one million high sensitivity and has shown good survival association. So a study using a FLT3 inhibitor added to intensive chemo or a menin inhibitor added to intensive chemo, I think could leverage use of those molecular NGS MRD clearance as a good surrogate for early accelerated approval then to be followed up by OS or EFS for long-term approval. In fact, this is being done with the ziftomenib where there’s a study of 3 + 7 ziftomenib versus 3 + 7 placebo with the accelerated approval endpoint being CR, MRD negative after two cycles using NPM1 ultra-sensitive NGS MRD, not using flow cytometry. So I do think these designs could get those drugs approved earlier to our patients earlier with a pretty strong association that if you have a true strong delta for a sensitive NGS MRD, this will eventually lead to a survival benefit. Now for older unfit, I think it’s a little more challenging in that setting. The MRD clearance often takes longer, especially the NGS MRD for FLT3 and NPM1. But I think complete CR, true CR, not CRi, CR8, but full true CR may be a good surrogate. This is something that is being considered in some of the upcoming trials using AZA-VEN-Menin inhibitor and may again allow us to get the drugs out one and a half, two years before the survival endpoint. So I think to Dr Brunner’s question, the answer is yes. There is interest, there is a discussion, and there is definitely, you know, discussions going on with the FDA to consider some of these for early accelerated approvals. But at the end of the day, it boils down to a discussion for the specific drug and the specific trial that has to be done with the regulatory authorities. 

And then last question here is from Dr O’Donnell, Scotland, UK. How can community oncologists best identify which patients should be referred for triplet regimens early given the complexity of ongoing trials? So this is a very, very good question. I would say to Dr O’Donnell, really all newly diagnosed AML should make a visit to the academic center of their region just to make sure that they are not missing opportunities. There may be trials incorporating new targeted therapies, immunotherapies, antibody-drug conjugates in the frontline setting. Some of these may be showing very promising data, may be in phase two, may have 100 plus patients, but may not be available yet in the community. We saw this with the AZA-VEN. While the VIALE-A study had been ongoing, we already had data of AZA-VEN, 150 patients with extremely strong response survival, and so it was important for those patients to be referred because otherwise they would not have gotten AZA-VEN for three to five years if they did not go on the VIALE-A study and those who were able to get it probably had a much better long-term survival. So I think it’s important to always refer to the academic center. It may even be a phone call or email just to check. I have a 76-year-old. They have such and such mutations, cytogenetics. Is there anything that you have or think could be better than the standard of care that I may offer them? And many times the answer will be yes. And the patient, the referring physician, and the academic center all benefit from that approach. So that is what I would recommend. I do agree that the triplets may not yet be fully ready for prime time, especially in smaller community centers that may not have as much blood monitoring, as much bone marrow capabilities, transfusion abilities. And so those should probably be started at least in big academic centers after one, two cycles. Once we have designed and optimized the dosing regimen, maybe those patients can transition back carefully to the community. 

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