iwAL 2025 | Is pre-transplant intervention warranted in patients with MRD-positive AML?

Eytan Stein:

Hi there, I’m Eytan Stein. I’m the chief of the leukemia service at Memorial Sloan-Kettering Cancer Center. I’m joined by my friend and colleague, Dr Max Stahl, who directs the leukemia service at the Yale Cancer Center. And we’re going to be having a friendly discussion, some might term it a debate, around the utility of pre-transplant intervention to eradicate measurable residual disease in patients with acute myeloid leukemia. Max, let me give you the first word as my younger colleague of whether you think it makes any sense to try to eradicate MRD before a transplant. 

Maximilian Stahl:

Yeah, so I would say biologically it makes a lot of sense. We measure response, we want to reduce leukemia blasts, why should we not reduce the ones that are left? And I think that’s actually the hardest argument about any of the trials we could discuss later on to convince patients not to do that. But when we go into the details, whether there’s actually good evidence showing that it benefits patients, that’s where it gets much more dicey. 

Eytan Stein:

Yeah, I mean, I always worry that… I agree with you in the sense that certainly you don’t want to… There have been multiple studies, we don’t need to go through all of them now, that have shown that going into a transplant with measurable residual disease is probably not a good thing. I think some questions are, is there a level of MRD that might be safe to go into with a transplant? I think that’s one question. Is all MRD the same? That is, when it comes to baseline genetic risk, if you’ve got an adverse risk patient going in with MRD, is it the same as a, you know, a core binding factor patient going in with MRD? And I think the biggest issue I have with trying to eradicate MRD is that we don’t really have a good strategy about how to do it. You know, how do you actually get rid of that MRD and how are you going to do it without screwing up the transplant so the transplanters don’t say, you know, you’ve messed up my business? 

Maximilian Stahl:

Right. Yeah. The transplanters, I think this is dicey, right? You know, because you could mess up their business or they ask you to get the patient better so they can do business, right? So this is the challenging part, I think. And to your point, I think definitely it’s complicated. I’m sure there is not one MRD. There’s not one kind of genetic subset that behaves exactly like the other. There might be certain levels of MRD, as we heard earlier, like with NPM1-mutated MRD, that might still be safe or where the immune system itself can play a job and can contain the disease. And there are other subsets, such as FLT3, where the kinetics are different. and the immune system might be overwhelmed much quicker. So treating MRD across the board all the same is probably not going to give you the answer. I think you’re right. 

Eytan Stein:

So I think we would both, to move on from the debate portion maybe, I think we would both agree that, you know, if you have a p53 patient who’s gotten whatever therapy, they’re about to go to transplant, that the ability to eradicate the MRD in that patient is going to be low, and whether that even makes a difference is questionable. I had a very practical question for you, because this comes up with us all the time, probably comes up with you. You have a patient who’s got an NPM1 mutation without a FLT3-ITD. They get intensive chemotherapy with seven and three and one round of HiDAC-based consolidation. They are still MRD positive after that HiDAC-based consolidation to the point where you feel like it’s real, and now you’re going to send that patient for an allogeneic stem cell transplant. Right now at the Yale Cancer Center, patient’s ready to go to transplant, what do you do? Do you give them something? 

Maximilian Stahl:

Yeah. Yeah, that was exactly actually the example that I brought up because I agree. That’s a perfect example. I do. And often they’re not ready or there’s some other thing that they could wait. And because you usually get a response so quickly, I usually give them one cycle. You know, the hard part is how many cycles? 

Eytan Stein:

What do you give them a cycle of? You give them a cycle of…

Maximilian Stahl:

A cycle of HMA-Ven. You know, not a menin inhibitor yet. But the question which comes up and which we’re maybe not as consistent as we could be is, we’re not waiting for complete MRD-negative conversion. So as some people have shown, sometimes it takes four or five cycles of HMA-Ven, and it’s not like we’re going to treat a patient for six months just chasing this elusive goal of MRD negativity. 

Eytan Stein:

Because you’re going to lose the response, right? 

Maximilian Stahl:

That’s right. We could lose the response, or they could get an infection or something else. 

Eytan Stein:

Yeah. So we actually have a trial now that’s actually doing that. So we have a trial that is just to…basically doing what we’re all doing off-label. We’re doing it in a prospective manner to look at… Now we’re only giving one cycle of AZA-VEN, and that’s been a big criticism, but it was a big criticism from the transplanters. They said, how could you give any AZA-VEN? They wanted us to say we shouldn’t do this at all. So it’s a real question. But we’re trying to accrue to it, but- 

Maximilian Stahl:

Is it randomized data? 

Eytan Stein:

Non-randomized. So we felt that what we wanted to prove first was that… so everyone assumes that giving some AZA-VEN, I think most of us will just give a cycle or two, will actually eradicate the MRD. We don’t take that as a, I mean, I assumed it also, but I’m not sure it’s true. So we want to know first, and also given that we’re resource-constrained, can we actually eliminate MRD with one cycle of AZA-VEN or one to two cycles of AZA-VEN? And if we can’t in 20, 25 patients, I forget what the stats are, it raises the question about whether anyone should be doing this or whether they should go straight to transplant or whether they should go, you know, four cycles of AZA-VEN, which I think would be a… 

Maximilian Stahl:

Or a triplet – HMA-VEN-menin inhibitor. 

Eytan Stein:

Or a triplet, correct. 

Maximilian Stahl:

Or a quadruplet. 

Eytan Stein:

Or a quadruplet. Or a quadruplet. Yeah, yeah, yeah. Yeah, so I think that, I mean, so I’ve been, and I think that Rich Stone in this meeting brought up a very good point, which is that part of the issue with eradicating our MRD is that all of our drugs kind of aren’t great. 

Maximilian Stahl:

Right, right. 

Eytan Stein:

You know, like we have blinatumomab. And what do you think about this idea that there have been a lot of companies – not a lot – there have been some companies that have, you know… these like T-cell engagers haven’t worked or bispecifics haven’t worked so well in relapsed and refractory disease. Some companies have tried to use them in this MRD-positive space. Do you think that’s something we should be doing? 

Maximilian Stahl:

Yeah, I think this is like, this was always a question, right? Because we saw that with blinatumomab that like relapsed/refractory never really worked that well. It worked, but not that great. And then MRD, it made a huge difference. I think one of the major issues is that I think that immune engagers haven’t been so successful in AML. Probably that the problem has two components to it. Number one is that we have always tried it in a lot of disease, and you’re right, that might help doing an MRD. But I think what a lot of people also have shown is that the myeloid compartment is so dysregulated in AML, you have so many myeloid suppressive cells that, I think even when you use it in the MRD setting, you might still not get a great immune response. And I think that’s what they have seen, at least when they did the early T-cell engager trials, that even in the MRD setting, there were only a couple that actually converted, while with blina, I feel like, you know, really the vast majority of patients converts quite quickly. So I think it’s those two issues. And the microenvironment is very hard to get around, although transplant does that, to a certain extent, so maybe those T-cell engager therapies might be better positioned in the post-transplant setting when you have changed the microenvironment. 

Eytan Stein:

Right. So maybe the way to do it, like you’re saying, is to give… Take your MRD-positive patient. I mean, so we’re… I’m imagining an MRD-positive patient for which there is no targeted therapy available as maintenance. Take your MRD-positive patient, transplant them with some, you know, intensive transplant as you can, and then post-transplant give them some sort of low-dose of like a bispecific T-cell engager. I don’t think anyone’s doing that. I think the companies, that’s a very long development pathway, right? There’s no quick readout and therefore quick commercialization. 

Maximilian Stahl:

Yes, and concerns about GvHD with engaging T-cells, which can kill those platforms very easily, and I think that’s one of the major concerns that people have. But biologically, it makes sense. 

Eytan Stein:

Right. And I think that we have to be a little bit bold when it comes to doing these things, or else we’re never going to make any progress. 

Maximilian Stahl:

Yeah. In particular, you could do it for patients who are extremely high-risk. I think in the session we discussed the TP53-mutated patients, doing the same thing over and over and over again, what doesn’t work. 

Eytan Stein:

That’s the definition of insanity, right? 

Maximilian Stahl:

But it’s just, you know, for those type of patients or other patients in version 3 or complex karyotype, I think for those patients the argument could be made that the extra risk of GvHD is worth it, so to speak. 

Eytan Stein:

At your center, are you transplanting patients who are high-risk, or not you, but are your transplanters, transplanting patients who are high-risk with persistent MRD, like p53-mutated, they’ll take those patients to transplant? 

Maximilian Stahl:

They do. They did the same at Dana-Farber too. I think this was also a big part of the session, right? You know, that how do you select your patients for transplant? I actually think one part of the selection that we didn’t discuss, but that is a natural selection of patients, is by asking them to become MRD-negative or at least do an attempt at MRD negativity. Because sometimes you just lose patients that way. And I think that is a selection that sometimes the transplanters kind of build in or ask for. But our center has taken all the biallelic TP53 complex karyotype, we have not selected for those patients. 

Eytan Stein:

Yeah. I was just reviewing a paper where… or there are papers that suggest that those patients have an overall survival, I was looking, I forget where the paper was, an overall survival of about 20% long-term. In your clinical experience, is that what you’ve seen also? I have not- 

Maximilian Stahl:

For biallelic TP53? 

Eytan Stein:

For biallelic TP53, or mono-allelic with complex karyotype. I have not seen… I cannot recall the last patient who’s had long-term survival. Do you have any? 

Maximilian Stahl:

No, no, I agree. I mean, the way I usually give patients an idea of what does this do for me, right? Because I’m sure they ask you, you know, like, so I undergo all this pain, what does it do for me? I usually say the most common scenario is you delay relapse by six months or so. And then they still relapse and still unfortunately die of their disease. I would say in those initial studies that looked at TP53, they never looked at allelic status. They never looked at all those different things. And I think probably those 10%, 15% long-term survivors were probably those people where they had a small TP53 clone. 

Eytan Stein:

Without a complex karyotype, without 17p loss. 

Maximilian Stahl:

Nothing bad. One TP53 at 5% VAF. And those were included in the database. And those were the long-term survivors. But that is important to tell patients, and I try to be honest with them, because I think when they look at the data, some patients can say, 30% is not that bad, you know? And I think it is worse than you think it is. 

Eytan Stein:

I agree. I completely agree. Yeah. Thanks so much for listening to our, what started as a debate, became a little bit more of a discussion about eradicating measurable residual disease in patients before an allogeneic stem cell transplant. I’m very happy that I was joined by Dr Stahl and thank you so much.

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