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ASH 2022 | Should patients with AML who are MRD-positive proceed to allogeneic stem cell transplantation?

Charles Craddock, CBE, FRCP(UK), FRCPath, DPhil, University of Birmingham, Birmingham, UK, debates whether patients with acute myeloid leukemia (AML) who are measurable residual disease (MRD)-positive should proceed to allogeneic stem cell transplantation (alloSCT) or whether they should receive further chemotherapy to reduce the MRD burden before proceeding with transplant. Prof. Craddock explains that whilst there is evidence that pre-transplant MRD positivity increases the risk of relapse, there is no prospective data from randomized trials supporting the use of further chemotherapy. Currently, it is thus recommended to proceed with alloSCT if the patient is MRD-positive. Prof. Craddock also highlights the importance of investigating strategies to improve transplant delivery to reduce the risk of relapse. This includes determining the best conditioning or maintenance strategies and monitoring MRD carefully. This interview took place at the 64th ASH Annual Meeting and Exposition congress in New Orleans, LA.

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Transcript (edited for clarity)

One of the commonest areas for discussion in our weekly MDT meeting is in patients who you believe should proceed to an allogeneic transplant for the treatment of acute myeloid leukemia in first remission, what you do if by flow technologies or by PCR, they are shown to be MRD-positive pre-transplant. And the reason that there is debate is because there’s now clear retrospective and more recently prospective evidence that the presence of pre-transplant MRD increases the risk of relapse...

One of the commonest areas for discussion in our weekly MDT meeting is in patients who you believe should proceed to an allogeneic transplant for the treatment of acute myeloid leukemia in first remission, what you do if by flow technologies or by PCR, they are shown to be MRD-positive pre-transplant. And the reason that there is debate is because there’s now clear retrospective and more recently prospective evidence that the presence of pre-transplant MRD increases the risk of relapse. And in certain population of patients, particularly patients with a FLT3 mutation, that increase can be very substantial.

And so the argument goes that one might consider giving these patients further chemotherapy so that you reduce the MRD burden, proceed to transplant, hoping that the risk of relapse is lower because you’ve eradicated the MRD. Alternatively, you make a case. While the most effective curative option is an allogeneic transplant and if you delay by giving further chemotherapy, you may compromise a safe delivery of transplant. Or in fact, a patient may not be able to go to transplant because of toxicities. And also you could point to the fact that there’s no randomized data that giving further chemotherapy to reduce the MRD levels necessarily improves outcome.

So I think it’s important for us to recognize that randomized trials are required to answer this question with good prospective data, and we don’t have those studies. There are a couple of lines of evidence that suggest that it might be useful to give further chemotherapy. These are data in first of all the Jeffrey Lancet CPX study, the pivotal licensing study where patients who got CPX as opposed to DA did better, but they did particularly well if they went to transplant. So possibility that actually what you do before transplant in terms of chemotherapy may improve outcome. And there was the same observation in the RATIFY trial where the midostaurin did better but particularly after transplant. Against that is the fact that retrospective studies show no impact of courses of intensive chemotherapy.

So our practice, and I think it’s the practice of many centers actually, is to say in the absence of good prospective data, what one needs to do is proceed to transplant as quickly as possible and to consider how you can optimize the transplant delivery so that you reduce the risk of relapse. And essentially, there’s two ways that that can be done. The first is there’s now clear evidence from the US CTN 0901 study which randomized patients in exactly the scenario of AML in first remission, that if patients were MRD-positive and they got a myeloablative conditioning regimen, their outcome was better than if you had a reduced intensity transplant. So I think if you’re under 55 and you’re fit and you can have a myeloablative regimen, particularly if you’re MRD-positive, that’s the way to go. The challenge of course is the majority of patients are older than that. They’re not fit enough to have a myeloablative regimen. So the question there is if you’re using a reduced-intensity regimen, which one to use?

So we recently delivered through the UK NCRI AML group, the FIGARO trial, which is a randomized study of an intensified sequential RIC regimen versus a standard FB2. And interestingly, that showed there was no benefit of intensifying the regimen. So I think at the moment, if you can deliver a myeloablative regimen, you should. But otherwise, proceed to a safer RIC regimen as you can.

And then the other area where there is emerging evidence that you can improve outcomes of these folks is if they’re FLT3-positive, then there’s evidence that maintenance with sorafenib improves outcome. We also know there’s a very powerful graft-versus-leukemia effect in patients that are grafted, if I might. So think about tapering immunosuppression very early. Think about possibly the use of prophylactic DLI. Certainly monitor MRD carefully in patients who deem to be at a high risk of relapse.

I think this is an area where we’re going to need really good randomized studies which integrate genomics, MRD, and treatment interventions along the lines of what’s the optimal RIC regimen, still work to be done there. But also, thinking about randomized studies of post-transplant maintenance therapy. And in that context, I’m really delighted that the AMADEUS trial, which is again run through the UK NCRI group, the IMPACT group as well, shows that it is possible to recruit rapidly to these studies. This is CC-486 maintenance, oral azacitidine from between day 14 and day 80 to a year post-transplant. And that study has now randomized 310 patients, and we hope it’s going to close next month. So hopefully that will begin to give us some answers about the maintenance question.

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Disclosures

Novartis: Consultancy; Abbvie: Consultancy,  Research Funding; Celgene: Consultancy, Research Funding; JAZZ: Consultancy, Research Funding; Daiichi-Sankyo: Consultancy.