iwAL 2025 | Ask the Expert: Charles Craddock answers your transplantation questions at iwAL 2025

Greetings from a fantastic iwAL meeting in Washington, DC. And I’ve been given some questions to respond to. 

The next question has come from Andrius Žučenka from the Vilnius Vilnius University Hospital Santaros Klinikos. Do you expect menin inhibitors to be potentially safe and effective as post-allotransplant maintenance therapy? I think it’s a fantastic question, Andrius. And the long and the short of it is yes, but I think we’ll have to use them carefully. The reason I’m so enthusiastic about the use of menin inhibitors is that despite the fact that we anticipate that menin will be getting worldwide approval for the treatment of relapsed disease, many of the patients who with relapsed AML, either NPM1 or KMT2A mutated, who go into remission do need a transplant and their risk of relapse is high. So, the setting in which menin inhibitors will be transformative is in the management of either relapsed NPM1 or KMT2A-mutated AML, or increasingly, I think, up front in patients transplanted for NPM1-mutated AML with evidence of MRD that makes them allomandatory, or KMT2A mutations. The risk of relapse in this patient population is substantial. It’s in the region of 40%. And there’s really good evidence from the MORPHO study in which gilteritinib was looked at as maintenance therapy in patients allografted for FLT3-mutated disease, a benefit from maintenance therapy, particularly in the population of patients who were pre-transplant MRD positive. So I think the patients who are going to be transplanted for NPM1 disease have positive MRD pre-transplant. That’s the reason they’re going to transplant. And so I think it’s a perfect setting in which to be demonstrating that maintenance with a menin inhibitor improves outcomes. Now the only caveat is, of course, in all maintenance studies you have to be confident that the therapy you use is well-tolerated post-transplant. As Mary Horowitz wisely says, there are three considerations in the choice of an optimal maintenance therapy, and these are tolerability, tolerability and tolerability. So we will have to dose menin inhibitors post-transplant carefully, looking out particularly for cytopenias. But I think this is a very exciting setting and in fact the UK is launching a study using enzomenib maintenance in patients transplanted for MPM1 or KMT2A mutated disease next year. 

From Dr Patel in France, a question, a very important question. In routine UK practice, many patients face delays in donor identification. How do you balance moving quickly to LOSCT while waiting for the best possible donor match? So, a great question, Dr Patel, and it’s not just in routine UK practice, but it’s across the world, that we are in a significant proportion of patients who need a transplant for whom it is their best curative option, unable to identify a suitably matched sibling donor or unrelated donor. And I believe that this challenge, which of course is particularly acute in patients from ethnic minorities and really represents a completely unacceptable difference in ability to identify a donor and therefore proceed to curative therapy, is going to be transformed by the results that were published in JCO a couple of months ago of the ACCESS trial. Just to remind you, this was a single-arm, large Phase II study performed by the U.S. Clinical Trials Network, Bone Marrow Transplant Clinical Trials Network, in which they looked at patients who had post-transplant cyclophosphamide, their GVHD prophylaxis, but who were transplanted using a mismatched unrelated donor, sometimes with multiple mismatches. And the results from the ACCESS trial are remarkable. The overall survival and the GvHD rates were broadly similar using post-transplant cyclophosphamide in patients transplanted using a mismatched unrelated donor compared with those seen with matched unrelated donors. And as a result in the ACCESS trial, there was a very significant increase in the number of patients from different ethnic groups who were able to actually identify a suitable donor. So, in the UK, we are meeting, in fact, next week to revise our donor, alternative donor algorithm with the aim of implementing these practice-changing data as quickly as possible. Watch this space. There are still, of course, questions about what should the dose of post-transplant cyclophosphamide be, and we’ll have to do further studies. I think the other point to make is that use of post-transplant cyclophosphamide in patients transplanting using a matched unrelated donor also looks really exciting, although we do need to await the results of formal randomized studies, such as the MoTD study being done in the UK, comparing post-transplant cy with standard GVHD prophylaxis regimens such as ATG. 

Thomas Cluzeau from Nice, do you think we need to propose maintenance therapy post-allogeneic transplant for all MDS/AML patients? Do you prefer prophylactic, preemptive, or treatment at relapse? It was a great question, Thomas, and I think we can confidently say now on the basis of the MORPHO data, but also the SORMAIN data using sorafenib, that in patients allografted for FLT3-mutated disease, there is a good case for using post-transplant maintenance, particularly in patients who are MRD-positive pre-transplant or peri-transplant, immediately around the time of transplant. The MORPHO study was beautifully conducted. It included meticulous MRD monitoring. And the patients who benefited from post-transplant gilteritinib were very clearly those who are MRD-positive. The role of gilteritinib maintenance or alternatively, if you can’t access gilteritinib, quizartinib in patients who are MRD-negative is less clear to my mind. Sorafenib is the other agent that’s used in the FLT3-mutated population as maintenance. And it’s quite widely used in parts of Europe. But our experience is it’s very difficult to manage the toxicities of sorafenib. So we prefer, as our standard of care in the UK, would be post-transplant quizartinib. And then the question, of course, is what happens if you don’t have a FLT3 mutation and you do proceed to transplant? There’s excitement, I think, about using a number of distinct maintenance strategies. One is using drugs that are mutation agnostic such as azacitidine and we are waiting the results of the AMADEUS trial which randomized 344 patients to oral azacitidine, CC486 post-transplant. Certainly the drug is well tolerated. Whether it reduces relapse is yet to be seen and we wouldn’t say it’s standard of care. I think there are a couple of other areas of interest. One is a drug called mocravimod, which redirects T cells into the bone marrow and away from the periphery. And very exciting Phase I/II data from Robert Zeiser. The MO-TRANS study is randomizing patients allografted for AML to receive a mocravimod or not post-transplant. So that’ll be interesting. And then finally, I think there is also the potential use of cellular therapy post-transplant in patients at a high risk of relapse. And the results of the PRO-DLI study that was performed in the UK are awaited. We should really be very thoughtful in maintenance trials post-transplant, not only about, not just about tolerability, but we should also be trying to identify patients eligible for maintenance as those with a particularly high risk of relapse. And in this setting, I think early post-transplant bone marrowers to assess MRD status are going to be increasingly important in patients allografted for high-risk disease. 

And then a really important question from Sanam Loghavi from MD Anderson Cancer Center. Given the variable dynamics of MRD clearance, at what time point do you use molecular MRD for NPM1 and FLT3 ITD to inform transplant decisions? Well, I think there’s really good data now in patients with an isolated NPM1 mutation. In other words, wild-type FLT3, that assessment of MRD reduction after two cycles of induction chemotherapy allows you to identify patients who should proceed as soon as possible to an allograft. There’s good study from the UK group and a really important randomized study from Balzat in France that shows patients with suboptimal MRD response to two cycles of induction chemotherapy do much better with a transplant. The next question is, I think, more problematic, which is, what time point do you use FLT3 ITD MRD to inform transplant decisions? I think it begs the question, should FLT3 ITD MRD inform your transplant decision at all? There is emerging data from a number of groups, but it’s retrospective. And most of these studies were performed on patients before there was the routine use of FLT3 inhibitors. So actually, how we interpret them in clinical practice in 2025 is unclear. But there is some emerging data that patients who are MRD negative after two or three cycles of intensive chemotherapy may not necessarily benefit for transplant. And certainly I think the measurement of FLT3 ITD MRD after two or three cycles of chemotherapy may help you decide not to proceed to transplant in a patient who is not particularly fit or doesn’t have a very good donor. However, our clinical practice is that unless there are compelling reasons and if there is the patient is fit and there’s good donor availability, patients who have a FLT3 mutation should still, as standard of care, proceed to transplant. Now there may be some patients who are MRD-negative pre-transplant who, when you discuss the transplant decision with them, may choose not to proceed to transplant. And that may be for personal reasons or maybe because of the toxicity of transplant. But I think there’s also concern that in patients who relapse after chemotherapy, which included the FLT3 inhibitor, they may be quite difficult to salvage and get back into a second CR. And you may lose the opportunity to deliver a curative transplant. But suffice it to say, like all transplant decisions, these are complex nuanced discussions in which it’s important to lay out for the patient and their family the benefits and potential toxicities of transplant. I would however kind of stress that for fit adults up to the age of 75 with a well-matched donor, the 100-day transplant-related mortality, certainly of a RIC allograft, is only about 2 or 3%. The toxicity is later, it’s related to chronic GvHD, but if post-transplant cyclophosphamide really does reduce the risk of chronic GvHD, then we may become rather more confident about taking these patients, all of these patients to transplant, recognizing that the alternative of not transplanting them, if they relapse, becomes a very complex decision-making process. So I think it’s a really interesting question. I think we need actually better quality data sets, data sets on patients who were treated using standard of care in 2025 rather than 10 or 15 years ago when FLT3 inhibitors weren’t used up front. 

And finally, Dr Aditi Shastri from the Albert Einstein College of Medicine, given the negative Phase III VERONA data, what is your current approach for treating high-risk MDS patients that are candidates for allogeneic transplant? Again it’s a great question and there’s a lot of different practice across the world. Our approach in the UK is to try to get these patients to demonstrate chemo, some sort of chemo-sensitive disease and try and reduce their blast percentage to ideally less than 5% before taking them to transplant. So for patients with intermediate-risk disease where intensive chemotherapy is well-tolerated and quite active, patients with intermediate-risk cytogenetics, then we would be using intensive chemotherapy, for patients who have high-risk disease where intensive chemotherapy is less impressive we’d be using azacitidine. Were we to have venetoclax available, we would actually, until we have a clear understanding of what the Phase III VERONA data shows, be thinking actually about using venetoclax and azacitidine with abbreviated doses of venetoclax. I think it increases the CR rate. I think it’s likely that we’ll find that. And that’s all we need if we’re taking a patient to transplant, whether transplant is the definitive curative therapy. 

Oh, and I have one more question, an anonymous question. In health systems with constrained resources, what’s your view on prioritizing transplant versus novel agents for older AML patients with adverse risk disease? So I think what is emerging now is if you are fit with AML in first remission, then the transplant represents your only likely curative therapy. These patients are allomandatory and they should be taken to transplant once they’ve achieved a complete remission with induction chemotherapy. That’s the standard of care. If these patients are not fit or don’t have a donor, but as I said earlier, the likelihood of finding a donor is going to increase in future years, then it’s certainly possible to consider them for trials of novel agents. Although to be absolutely honest with you, there aren’t many trials of promising agents around at the moment. So it’s really super important that we are viewing an allogeneic transplant as the core curative modality in fit adults up to the age of 75.

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