MRD-Guided Risk Stratification Refines Transplant Decisions in Patients With Acute Myeloid Leukemia

Clinical Summary: 

• Pinkal Desai, MD, examines post-remission treatment strategies in acute myeloid leukemia (AML), focusing on how molecular risk classification, measurable residual disease (MRD) assessment, and patient-specific transplant risks inform decisions regarding allogenic stem cell transplantation. 
• ELN 2022 risk classification and MRD monitoring help identify patients who may benefit from transplantation, including those with persistent or rising MRD, while favorable-risk patients achieving deep molecular responses may avoid transplant in first remission. 
• These approaches support individualized transplant decisions that balance relapse risk, molecular response, age, and comorbidities, as advances in reduced-intensity conditioning and supportive care expand transplantation eligibility. 

Pinkal Desai, MD, Weill Cornell Medicine, New York, New York, discusses the evolving role of allogeneic stem cell transplantation in post-remission acute myeloid leukemia (AML), highlighting how emphasizing molecular risk stratification and measurable residual disease (MRD) assessment guide transplant eligibility and timing. 

Dr Desai reviews ELN risk categories and MRD-guided transplant decisions across favorable-, intermediate-, and adverse-risk AML, including considerations for patients with NPM1, FLT3-ITD, and TP53 alterations. She also discusses post-transplant FLT3 inhibitor maintenance, the expanding role of  reduced-intensity transplantation in older patients, and the importance of balancing relapse risk with transplant-related morality to maximize the potential for cure.

Transcript: 

Hi, I'm Dr. Pinkal Desai. I'm a leukemia physician at Weill Cornell Medicine, New York. Today I'm going to talk about an important concept that we all talk about with our patients with leukemia: post-remission acute myeloid leukemia (AML), who to transplant, and when.

There are a few things that we have to understand and establish. One is the decision to transplant or not after remission is based on two basic concepts: what is the relapse risk for the patient, number one, and what is the transplant risk for that patient at that age with all the comorbidities? And both are important in making that decision.

Let's focus on the first part. What is the relapse risk? In other words, is the leukemia good risk, intermediate risk, or high risk? We follow the ELN classification. The ELN 2022 classification puts people into favorable-, intermediate-, and adverse-risk. This is mostly for people who are treated with intensive chemotherapy-based regimens. I'll get to the non-intensive part later. But within intensively treated patients, favorable patients, which includes core-binding factor patients, people with NPM1 mutations without FLT3, and CBPA, within this category, the general trend is not to transplant.

Who do we transplant then? For core-binding factor patients, it's the ones that don't respond well to the treatment. How do we define that? It is based on MRD assessment. If we are following patients' MRD from baseline and follow-up, two cycles of chemotherapy, and if the patients do not achieve a more than 3-log reduction of their pCR transcripts for the core-binding factor leukemia, these are the people who are not going to do well, and they should be transplanted.

The second category are the people who've achieved this response, you're tracking them, and then their MRD starts rising from undetectable to some value or a more than 1-log increase. These are the people who should be transplanted as well. Generally, CBPA patients do very well, they should not be transplanted. 

NPM1, again, the same thing. You're following the pCR-based MRD, and here there are actual cutoffs rather than the log reduction. So, after two cycles of therapy, again, if you've had an optimal response, which is a value of less than .001, these people are going to do well, and you do not need to transplant. But if you don't achieve that cutoff, these are the patients who should be transplanted. And again, in the same vein, rising MRD, that's also a harbinger of relapse. These are the people who should be transplanted.

There is a caveat here that people who have some other co-mutations like DNMT3A and WT1, they may be the people who are harder to get into this MRD-negative state. If you have them at baseline, you're going to really be watching these patients very carefully and not telling them that this is very, very favorable. And there is a need that these are the people who might need a transplant later on.

Focusing on the adverse risk, everybody should be transplanted. The only one subset is biallelic TP53 mutation. Either you have a high VAF, more than 40%, or there are two mutations, or in concomitance with the 17p deletion. These people do, it's not that we don't want to transplant them, but they have less benefit from transplant. If you have somebody who is very frail, who is not the very best candidate for transplant, these are the people who should probably not be transplanted. Otherwise, everybody in adverse risk should be transplanted.

Now in the middle, which is the intermediate risk, again, the plan is to transplant. If it's FLT3-ITD, you get them into remission, you transplant. There's one caveat that there's a category within the intermediate where people can have NPM1 mutations and FLT3-ITD.

You have two ways to monitor MRD here, right? You have an NPM1 and a FLT3 monitoring of the MRD. If patients are being tracked by both modalities of MRD and both modalities are showing a deep remission, meeting criteria after two cycles, FLT3 NGS is negative, NPM1 PCR is negative, you can watch these people. Although they belong to the intermediate risk, we generally tend to not transplant them. But if any one of these MRDs is not meeting individual criteria, whether it's NPM1 or FLT3, these are people destined to relapse, and they should be transplanted.

Now for the non-intensively treated patients, we have no cure. You know, the non-intensive regimens are great at inducing remissions, perhaps, but there is no curative modality here. If somebody did get treated with non-intensive therapy, by default, if they are transplantable, they should be transplanted. We should not be leaving them on eternal cycles of non-intensive therapy because there's no cure with non-intensive therapy.

In terms of talking about once you transplant these patients, what do you do post-transplant? The largest data are coming from FLT3 maintenance. FLT3 maintenance is something that has been happening for a while. There is no single agent that's approved for maintenance therapy, but there are a lot of post-transplant continuation, we call it, continuation therapies included.

But the one group of people that have the greatest benefit are those that are MRD-negative by an NGS FLT3 assay, where the depth is to the power of 10 to the minus six. It's important that the right assay is used. If you're MRD-positive prior to transplant or immediately after transplant, these are the people where there is benefit to FLT3 maintenance. Those who are MRD-negative, you could still consider FLT3 continuation, but their benefit is lower than the ones who are MRD-positive.

The last thing I would like to say is when we're talking about transplant, there is a constant change, right? The transplant-related mortality, which is the day 100 mortality, it's been going down every decade. There has been improvement. We are getting more reduced-intensity transplants. Transplants are being offered to older patients. There are novel, you know, drugs that are being used in GVHD prophylaxis, better conditioning.

As transplant becomes safer, more people are becoming eligible for transplant. That's just the discussion that has to happen even in someone who is 75, 76. Maybe they're fit, you know, age is just a number. There is always a discussion for these people that could we potentially consider these people for a reduced-intensity transplant? Because as these advances are moving forward, even these older patients that were originally considered non-transplantable are now being considered.

So, these conversations are a constant movement because every time we recommend from the leukemia side that someone should be treated with this agent versus that agent, there is always a discussion in the end for post-remission therapy: is the patient transplant-eligible or not? And that mark keeps moving as transplant becomes safer.

Our discussion will only get more complicated, but interesting and better for the patients because now they have not only the novel agents we have at this point that are being used in these frontline settings, maintenance settings, but also potentially better transplants.

This is a good time to be in this phase where we have all these good treatment options, but it all requires a very careful discussion with patients to make sure that we are maximizing cure, not just continuation or perpetual maintenance, but cure.