Hi, this is Mark Levis. I’m here in Nice, France at iwAL 2022. I’m here with my colleagues Eunice Wang, Jessica Altman and Charlie Craddock. And we just finished a lively session, apparently trying to define standard of care in AML, and I don’t think we quite did. But we had a good, lively discussion trying to. And so I’ll throw out a question to the group here, and maybe I’ll pick on Eunice first, did we conclude anything this morning about what the current standard of care is? It seems to be moving in all sorts of directions.

Well, I think we had some general conclusions which I hope my colleagues will concur with. I think we all agree that potentially the first line therapy should be our best approach to get the person into a complete remission and whether that’s adding targeted therapies or adding different modalities, or potentially even on some of our AML patients now offering them non intensive back bones like ven-aza, whatever needs to be done, to be getting that patient into a CR is preferable. We talked a little bit about triplet therapies. Now with like a ven-aza backbone and a targeted therapy, whether that be IDH or FLT3, we talked about seven plus three plus targeted approaches,

And then we then learned from Dr Craddock that once we get some of our high-risk patients into a complete remission that potentially the best therapy for those individuals, even in the presence of a tp53 mutation, is going to potentially be allogeneic stem cell transplantation. And there was discussion about how to get those people there, different condition regimens, et cetera. And then there was some talk from Andrew Wei talking about maintenance and the importance of post transplant modifications and whether that arena could be a way to further improve outcomes. So I think it was a pretty detailed approach. Every step in the process of treating AML now is subject to new innovations and new additions to try to improve that outcomes for our patients.

We call it tailoring –

Tailoring, personalized therapy.

Now, I wonder, Charlie has got us. I think all of us, are transplant enthusiasts, anybody who treats the disease is and, Charlie and the transplant talks we heard. Really, we’re focusing on tailoring as much as we’ve been doing in AML. So, Charlie, where is transplant going with that regards? Focusing on AML, not all the diseases you transplant?

Yes, I think there are two fundamental questions, aren’t there, Mark, in a newly diagnosed patient or a patient who you’ve just gotten to CR? The first is what is their likely outcome if you just give them chemotherapy using whatever combination we have available? And what’s their predicted relapse risk? The second is, If we did a transplant, what would be the predicted risk to the patient?

The evidence, really, I think, is compelling that there is a powerful graft versus leukemia effect that results in a substantial reduction in risk of relapse compared with, application of intensive chemotherapy. But one, of course, has to be sure that that’s not offset by transplant toxicity. So I think there is a movement really now towards recognizing that in patients who are fit with a good donor, who have a predicted risk of relapse much north of 45% then they’re likely to benefit from, consideration of a transplant, although obviously that’s quite a nuance decision. So I was particularly interested in presentations from Eunice and colleagues where we were talking about, actually, how we move patients into a morphological remission so they can be considered for transplant, but also with minimal toxicity.

And I think the advent of drugs such as CPX-351 is very interesting, and one of the areas of discussion was whether ven-aza or even a triplet based on a ven regimen might be an effective where people getting into a CR with an allograft as your curative strategy. And it’s interesting you bring up this getting into a deeper remission and the fact that you pointed out we’ve long seen a primary refractory patient.

You give them seven and three or something, their leukemia is staring back up at you. You can take that patient directly to an allo and see some of those long-term survivors. And you don’t do that in the relapsed setting unless you fold in something targeted. We do see relapsed/refractory – chemo, relapsed/refractory patients,

Dr Altman, surviving when we introduce a targeted therapy. So there’s, clearly, even though I don’t like treating relapsed/refractory patients. But, we’re making some progress with that, and so the session, got into the end with the dreaded triplets that are coming. So, again, rehash for us. What your favorite triplet is? And are we, is that only going to be the relapsed/refractory setting or are we gonna actually work up the nerve to pull that up front?

Sure, thanks. So I think we’re waiting eagerly awaiting additional data. We have some preliminary data regarding HMA-ven, FLT3 inhibitors, really from the MD Anderson Group, in newly diagnosed and relapsed patients and

In newly diagnosed patients, and in relapsed patients, the response rate is quite high. And I think that what we need to get at is exactly what you alluded to is how to adjust the treatment so it is so it’s tolerable long-term. So I think that that’s one aspect that will be studied and studied, ideally in a randomized setting. Whether we we do triplet based therapy or doublets, and then use the third agent at the time of relapse. What ends up being a better both response rate, durability of response, quality of life and those questions and the relative value of those questions and the answers to those questions change based on the goals of the patient.

And then we also have data in the IDH mutated patients, really some nice randomized data with doublets. So, AZA and and IDH inhibitor versus AZA alone. So it’s interesting in the, on the one hand, you know, we had this debate over RIC versus MAC, and, well, is there really a difference?

And then we were talking about MRD. Now we didn’t talk about this today, but Chris Hourigan did do that analysis of the BMT CTN trial, the randomized trial of MAC versus RIC suggesting that patients with detectable MRD were the ones that could benefit from myeloablation.

We’re not sure that myeloablation is truly better, but it does speak to this. So, Charlie, first of all, I tried to hold your feet to the fire and say, what do you prefer, RIC or MAC? Or is there a difference, how about a relapsed, refractory patient that Jessica has managed to get into remission, with our whatever targeted agents we’ve used and they’re MRD positive, we’re going to use a myeloablative or non-myeloablative..

Yeah, I think we actually make this discussion a little bit more complex than it has to be. So well, one of the things that Alessandro Rambaldi talked about was advances in myeloablative conditioning regimens. So the FLU/BU4 regimen is now really quite well tolerated, and it has a day 100 treatment related mortality of about 7%. So if you have a fit patient and you’ve got a good donor and that may be under the age of 50 or 55 why would you not choose to prefer a myeloablative regimen, whether they’re MRD positive or negative? –

Because, I’ll interrupt them, because I want to introduce a targeted agent as soon as I can.

Yes, and I think that’s where the point comes in Mark. I think with the use of say regimens such as FLU/BU4 or ATG, the risk of GvHSD is not that high, and the toxicity isn’t that severe, so I think it’s your age and your fitness that determines that. But if you are young, I mean under 50, I think those patients should go to myeloablative regimens, certainly, if they’re MRD positive and if they’re MRD negative, why not? Until this randomized data that RIC is better.

Because this this debate came up with us where we were trying to introduce our FLT3 inhibitor. We had a toxic one, sorafenib wasn’t that well tolerated. And the myeloablative patients were still recovering from myeloablation, and we had trouble getting our drugs started in time. I don’t know if you’ve had that experience, Jessica.

So just let me just finish that point. And then, Jessica will, amplify on it. So that means the majority of patients actually can’t have a mile away, but the regimen, because they’re too old, all right. The majority of patients just have to have a RIC. So again, we shouldn’t agonize too much about that. And I think what you’re suggesting is there are certain settings where you may wish to intervene very early with an agent and in which younger patients may benefit from a RIC. But I think on the whole my view is, if you’re young and fit, you should go for a myeloablative. But most of our patients have a RIC, and we need to think about how to make RICs work better.

I’ve seen that in my practice as well. I’m no longer a stem cell transplanter, I work, Only, really. I know it’s okay. So but we see that in our patient population as well, that are younger patients or are going for myeloablative regimen. And then we try really hard to figure out when we can start a targeted therapy post-transplant.

I think hopefully we’ll learn from your your data Mark that it’s going to be easier to institute the use of gilteritinib post-transplant. And hopefully there will be the survival advantage compared to placebo

So that, I mean gilteritinib is more tolerated. So now I don’t have this problem of starting my drug quickly. So, in fact, yes, I’m now shifting back to saying I want to do more myeloablation. Because I could start gilt, no problem, on day 30, I couldn’t do that with sorafenib. But I that I think I’ll kind of finish up our session here with a broader question. And I had a discussion with one of our colleagues at this meeting last night about this.

Why are we transplanters or leukemia doctors only? It seems to me that, you know, we have the best approach is to do both because the transplanters are paying attention to the molecular data now, very closely. We’re focusing on getting our patients to transplant and we’re trying to do I need to give them another regimen to get them MRD negative, or is that gonna you know, just take them to transplant? What’s the data? Why are we not integrating more?

I don’t think I meant to imply that I am not a transplant physician. I am that I’m only a leukemia doctor and that my patients don’t go to transplant. Like I know you were not implying that I wasn’t but right. I think it’s I think it, I think it is, as you said, an integrative, collaborative approach. I have one of our transplant physicians meet with the patient as soon as possible. I discuss with the transplant physician what induction and then consolidative approach and post remission therapy, because post-remission therapy spans transplant and non-transplant regimens. And then we talk about how quickly I can see the patient back post-transplant to start talking about some post-transplant maintenance. So, I agree with you completely. For me. It’s a question of time, right?

So I do think it’s a continuum. I think it’s not.. as you see a patient, you have to design their entire care plan from diagnosis to ideally cure. So I think it’s very important to personalize, as we talked about, and tailor, that treatment. So obviously, for patients with favorable cytogenetics, they’re not going to need potentially a transplant. So you want to add your gemtuzumab, or your… inhibitor to potentially intensive therapy and you want to cure those individuals. Cure rates are still 40, 60, 80% into those patients and patients with intermediate and adverse risk, then we start talking about adverse risk patients, probably shouldn’t get intensive therapy. We think these days they should probably get maybe a ven-HMA based therapy, less toxicity, getting them to that transplant and then having the discussion, what type of transplant. Intermediate risk, we’re struggling with. A lot of those patients are FLT3 mutant, IDH mutant. We didn’t talk about menin inhibitors. Those patients, are there things that we can do? We can add ven, we can add a FLT3 inhibitor. We can add an IDH inhibitor to either an intensive or non-intensive backbone.

And then we need to use our MRD to help us determine again whether transplant is going to be warranted. We are now getting with our combination targeted cytotoxic HMA based therapies overall response rates in the 90 to 100% range. When we get into that range, our therapy really is going to be dependent on MRD. Because we’re not going to be able to distinguish which one of those patients getting 100% morphologic leukemic free state are going to need to go to transplant or not. So it’s a continuum and continually working. You don’t want to get to transplant and have somebody not get the ideal regimen up front. You don’t want to get the ideal regimen up front and forget that some of those patients that have morphologic leukemic free state are going to relapse.

I couldn’t agree more. And finally, Mark, we were talking broadly here about which patients in CR1 to take to transplant. And you brought out the point that there are selected patients with primary refactory AML and selected patients with very high-risk AML characterized perhaps by…abnormality or tp53. But I think it’s key that the leukemia and the transplant physicians work closely to identify which populations in those groups are likely to benefit from transplant because clearly many won’t.

And then post-transplant coordination. Again, you’re managing the transplant complications, bringing them back into the leukemia fold to manage how to optimize the antileukemic activity. And you’re going to have to learn to be a leukemia doctor, which I know you already are a pretty good one. We’d hire you any day, Charlie, but you’re going to have to be using these agents that we are using pre-transplant post-transplant more and more.

Yeah, I think the other bit is transplanters, I hope are getting a bit more sophisticated. So many people who have a transplant do fine and they have good long-term survival. I think we’re going to be using diagnostic and possibly pre-transplant genomics and also pre- and post-transplant MRD to identify a population of patients whose outcome is poor, in whom we need to take into randomized studies of novel interventions.