ISAL 2023 | Novel transplant strategies in AML and the importance of reducing the risk of relapse in patients

We are at a time, I think, where it’s recognized that an increasing number of adults with acute myeloid leukemia in remission in CR one will benefit from transplant and should be considered as allo-mandatory. And the question therefore becomes how do we improve outcomes for these patients? And we need to be thoughtful that there are two causes of treatment failure: the first is transplant-related death and the second of course is relapse. Interestingly, in the last 10 or 15 years there has been substantial reductions in the risk of transplant-related mortality, partly because of better graft-versus-host disease prophylaxis, partly because of better tissue typing and better selection of unrelated donors and of course more broadly better supportive care, particularly the advent of letermovir. But we have really not made much progress in terms of reducing the risk of disease relapse, which is our main focus, but just to deal with reducing transplant-related mortality. So I think it’s very important that one is mindful when you’re having a transplant discussion with a patient to try and determine their fitness, particularly relating to comorbidity, but also just thoughtful about the complex social circumstances that particularly older patients sometimes have their carers, they may have to travel a long way and there are certain patients who should not proceed to transplant on the basis of high predicted transplant-related mortality because they have so many comorbidities. We really don’t transplant people over 60 who are not really fit. And also there are some patients for whom social circumstances are complex and the transplant is just not a good fit. So if we think about how we might reduce the risk of relapse, I think the data that has been presented from the US CTN 0901 study, although there are some limitations, some challenges interpreting that data set, I think it’s perfectly reasonable to say if you’re fit you should go for a myeloablative transplant, probably using a Flu/Bu4 regimen, possibly…

We’re examining in the COSI trial whether the TBF regimen is a benefit and we’ll hopefully see some data there. If you’re older, then really operationally you can only deliver safely a RIC and we don’t have any evidence of a superior regimen yet. The FLAMSA-Bu regimen, we know there’s no survival benefit from that, Flu/Bu2, Flu/Mel both look quite good. So that’s it: get them into transplant. If you want my opinion as to whether we’re going to dramatically reduce the risk of relapse by manipulating either a myeloablative or reduced intensity regimen, it’s probably a short conversation, I don’t think we are. So the question then is how can we modify or manipulate the post-transplant graft-versus-leukemia effect? And there are a number of strategies there, potentially the withdrawal of immunosuppression much quicker in patients at high risk of disease. I think importantly, using regular MRD monitoring post-transplant in patients at high risk of relapse, there’s data that we hope will emerge from Victoria Potter’s PRO-DLI trial randomizing patients with mixed T-cell chimerism in remission to receive DLI or not. It’s a very important study.

And then alternatively, of course there’s maintenance strategies. We have heard that the top line results of the MORPHO trial are negative, but I, like many other people think there will be a subgroup of patients who benefit from gilteritinib maintenance. And we’re conscious that sorafenib maintenance is two positive studies there. Our group has just completed the IMPACT Transplant Trial Network in the UK has just completed a randomized study looking at post-transplant CC-486 maintenance, 326 patients and we hope to have results from that in a couple of years. So that’s interesting. And then finally, I think there is also this pressing opportunity to think about whether you might minimize the amount of disease in patients going into transplant. At the moment there’s no evidence that in patients who are MRD positive you should delay transplant. But it is intriguing to wonder whether you could do a randomized study of some sort of targeted therapy that might have a benefit there with modest toxicity. So it’s a really exciting area. We’re now getting randomized trials that are informing our practice. At long last, we need to be accelerating recruitment to trials and looking how these new therapies can transform outcomes.