iwAL 2023 | New treatments in AML: FLT3 inhibitors & novel combinations

Hello, my name is Naval Daver. I’m a faculty in the Department of Leukemia at the MD Anderson Cancer Center, Houston, Texas, we’re coming from iwAL. Had a good discussion on new treatments in acute myeloid leukemia, focusing on FLT3 inhibitors and maintenance. And I’m pleased to have with me my colleagues here, Dr Jessica Altman, Dr Gail Roboz, and Dr Harry Erba. So in this last session, maybe I’ll start with, Dr Altman, you discussed FLT3 inhibitors in relapsed/ refractory FLT3 mutated acute myeloid leukemia. We have, of course, standard approved agent gilteritinib, but moving into different combinations, sequential approaches.

So in your practice today, if you have a patient who has relapsed after frontline therapy, let’s say with standard induction midostaurin, 55-58 year-old healthy individual, and you’re thinking about potentially transplant, what are the treatment options you would think about? What molecular information would you need? How would you approach that patient?

Right, thank you, Naval, it’s nice to be with all of you today. So, for individuals with relapsed FLT3-mutated acute myeloid leukemia who’ve had prior exposure to + and midostaurin, we and others have shown that they retain the response to gilteritinib. So we did both a multicenter study where we, looked at individuals, with relapsed FLT3-mutated disease, who had prior midostaurin exposure from six centers, including your center. And we demonstrated that the response rate and duration of response was very similar to what was seen on ADMIRAL. The ADMIRAL and Phase I study Chrysalis also looked at their patient population and found again that, if there was prior midostaurin exposure, their response rate to gilteritinib was maintained. So those are individuals where I offer a FLT3 inhibitor, gilteritinib, based on work that we’ve done. And with the addition of venetoclax, and showing that that can safely be combined with gilteritinib, we do offer for those individuals particularly who are going on to stem cell transplant, we do offer the addition of venetoclax. It’s important to point out that the combination therapy is much more myelosuppressive. It is not easy to give. You can’t just give the two a prescription for the two medications and allow the patients to just kind of walk away and never to be seen again. They need frequent monitoring of the, of their blood counts, and constant check-ins. But I think you asked some other important questions within that larger question of what additional molecular information is important. I think it would come increasingly important to know the relative burden of FLT3, NPM1 and additional mutations as we look at resistance mechanisms, especially as we have the study of and hopeful eventual approval of menin inhibitors. Those are agents that may be able to be either combined replaced, sequenced, with FLT3 inhibitors in these patient populations.

One of the things I wanted to jump in, just because it’s such a, it’s such a great question and such a thorough answer. So when you’re thinking about though venetoclax and gilteritinib for these patients, which I think is often offered at this point, I mean I would say that a lot of times the gilteritinib data alone, they stand on their own better than chemo. I think people have learned to not torture patients with ongoing cycles of intensive chemotherapy. But I do think there’s a lot of adoption of the doublet, but those patients are really only expected to have an MLFS type of response, right? That’s a marrow clearance response. And I run into this a lot that sort of what what is actually happening afterwards to that patient. Because if you are trying to get into a transplant, then sitting around and waiting for count recovery is not helpful, not important. But if you’re not, does the patient have the correct expectations of what is actually what’s going to happen there because you really aren’t getting counts up? Or am I doing something wrong? Yeah, yeah, I think that’s, I mean, and in the community for good or bad, I mean we are seeing definitely a lot of people using combinations and not using it kind of optimally or the way it’s guided.

And I think that is the key message that from a lot of these meetings we’re getting is that combination is never one plus one. It should not be one plus one. You really need to look at that combo. So you’re right for the transplant patient, it doesn’t matter. One cycle, two cycles, very nice, 80% response, get your transplanters ready, move forward and, and then you can do maintenance or whatever. Post-transplant. For those who are not, we really and Jessica can speak to her experience, are starting with much less ven. We will do 14 days usually with the gilt at 80 and then we usually drop it quickly because the goal here is to allow count recovery and to give them some good quality of time without transfusions. It may not be curative, but can you get a year, year and a half? That’s kind of the idea. And also I think here to mention and Jessica mentioned in her talk that is the addition of HMA in the salvage really adding anything? I personally don’t think so. Frontline may be a different story. There’s different clones. It plays, aza-ven is standard of care. But I think here, if I had to choose, I think a doublet is sufficient, but it’s also interesting that we may also be looking at other doublets. that could be even better tolerated. So if you have an MLL-NPM a menin doublet or sequence, whatever, we have to look at the different ways we do it could give you better count recovery or an IDH combination with FLT3, So I think it’s a very cool area. But for the community doctors listening, I think the key is you need to repeat molecular sequencing because you could lose a FLT3. And then of course this whole discussion is, you know, mood or you could gain other mutations and then you could have other combinations. So I think it’s a cool discussion sometimes, or I don’t know if it’s cool or interesting or sometimes annoying with transplanters though. And I’m curious at your centers, so the quote unquote empty marrow transplant concept, right? Depending on what day of the week it is, you get a a lot of flurry of different answers.

And I keep hearing anecdotal snippets that, well, if you have an ANC of even or even , is it better to go into a transplant? Do they have better, and you know, fewer infectious complications. Is there some level of micromanaging sort of from your centers of what you do with that, that both subtle neutrophil counts prior to transplant? Or is that not a thing? Can I ask a question before we get into that? Because I think that’s really important. I’m just wondering if we think that this morphologic leukemia free state is different today in the setting of targeted therapies with venetoclax than it was after standard chemotherapy. Right?

Is the prognostic relevance of it different today than if you have, you know, an empty marrow after chemotherapy? And so in those instances, right, years ago when we were not giving targeted treatments and without venetoclax, we would wait for count recovery because we were concerned that if their counts didn’t recover that it represented underlying disease. But when we’re still working out, really the mechanics of giving targeted therapies with venetoclax is, is an MLFS a better not as bad as we thought it was after chemotherapy?

I have my answer. I don’t know if it’s the right answer, but jump in.

Yeah, I, I don’t know the answer either, but you know, I agree with what you do in the terms that if the patient is eligible for a stem cell transplant, I do start with gilt and venetoclax. because you get very rapid and deep responses. But I’m certain to talk to my transplanters ahead of time and say, look, my experience with this is that once you have a marrow that’s clear of disease, please take them to transplant and we can work on a maintenance post-transplant with a FLT3 inhibitor. If I’m forced to hold the ven or hold the gilt or in some cases hold both and this has happened to me, hold both, the disease comes roaring back. That’s right. And so I understand that they would love to see a durable CR, but we’re, this is a different age as, as you were saying. I mean, we’re not talking about seven and three and high DAC anymore and going to transplant. We’re talking about using these targeted therapies. And I think we have to be smarter about the way we sequence things outside of the patient going to transplant. I hear what you’re saying about a week of venetoclax. I’ve been pretty impressed with how quickly gilteritinib alone gives you cytoreduction. So I’m not convinced that even there I need to use it. But I agree with you, if I do, it’s going to be a week or two weeks and then stop the ven to allow count recovery. I think, well, at least from our experience at MD Anderson, the transplanters are actually quite comfortable. I mean, we talk a lot and they’re seeing the data to take these patients, but as Harry said, you know, discussing upfront say We’re gonna achieve remission.

We don’t want to wait for counter recovery. And they know in the salvage setting, I think really in the end, a few years from now, even hopefully earlier molecular is gonna what drive the outcome, right? If you have a patient who’s achieved MLFS, CR, CRi, think, and we put this in the paper as well, Jessica and me, what really was differentiating outcome was the depth of FLT3 clearance raised to minus three, minus four, each log made it better. So hopefully that may be something we can use in the future for transplant decisions. I do think some of what you were talking about earlier with respect to, well, didn’t we used to do things like bridge to transplant, et cetera. I mean the extramedullary toxicity of the chemotherapy regimens that was driving our quote unquote empty marrow was definitely worse than this. So that’s part of it, maybe. But I do think that you know, I think that the concept of, you know, that these patients well, all you have to do is, you know, get them into a clear marrow and they go on to transplant, the reality is that the vast majority of the patients are not in that position because first of all, most of the, many of the patients have already been transplanted. So we’re not talking about, and then you’re talking second transplant and yes, we do do second transplants. We try. Your dataset, I think is the biggest on second transplant. It certainly looked the best big surprise and that’s all. But it’s, so yes, we’ll do it. But these are still very, very, very small percentages overall of the patients who successfully go on. So we are talking then about a bunch of people with very transfusion dependent, low blood counts on a bunch of antibiotics, not super fun. I think we would all like to be able to, I mean from a quality of life perspective, it seems to me intuitive that if you have to get platelets twice a week and red cells once a week and you’re on antibiotics, I don’t – I think Captain obvious would say that that’s not as good as having normal blood counts. Yeah. And, and I think it’s just like with HMA-ven, you just really need to deescalate quickly. I mean we did this right? We were giving people 28 days of ven and everybody was getting myelosuppressed, and now sometimes if I have 85 year old, I start with 14 days of ven. So I think all of these therapies, everybody wants the cookbook formula that this is the number of days for this for all. And unfortunately, or fortunately for our patients, because we actually have good drugs, it’s not gonna be like that. Each patient has to be individualized. Each decision has to be individualized. Are they going to transplant? Are they post-transplant? Is there a role for second transplant if they’re post-transplant? You know, are they 80 years old and you know, maybe get it alone? Yeah,

I mean sure this person, let’s give them a trial. So I think there’s a lot of personalized decision making, which is kinda the big theme in this meeting. We always think that, I don’t know, I’m gonna leave this panel right now by and go to the sort of solid tumor panel down the hall kind of thing. because in my view it’s like you do six cycles of this, you’re done, you do four cycles of this. It seems more organized. Maybe it’s not. I mean maybe the reality is that there is much more, you know, cook booking and anecdotal medicine going on there too. But I have to say that for us, I think one of the central problems is the sort of shifting of the classifications and the shifting of the responses.

Every time you get used to the data of what you have just worked for five years to understand, it shifts. Now on the one hand it represents progress, but on the other hand it’s actually pretty important, the fact that our blast thresholds are now moved down. The responses are actually different. FDA has challenges on the value of transfusion independence versus not all of this makes it pretty tough, I think. I agree. But you, you know, the case that you presented today is a great example of what we’re doing on a daily basis. We don’t have a study for the patient that you presented. And for most patients we don’t have a study. And so what we’re doing is we’re using the information in front of us from the most recent bone marrow, the most recent mutational analysis and talking to the patient about what their goals are and what they can tolerate and coming up with something. And I think that’s why we’re gonna see an improvement in the survival of patients with leukemia because, not because we’re curing more, but because we have more tools in our armamentarium and we can sequence them and keep people alive.

Correct. And, and I mean I always like to, I think this is very much like multiple myeloma. If you talk to them, they are cookbook, I mean, they have the same – because we are victims of our own success in a way. We got drugs now approved in five years. There’s no way we can have a recipe. And they had the same issue. And I think over time with, you know, good trial designs, maybe, you know, optimizing different sequences, combinations and learning, we are going to get better. But it’s going to be a tough road. And especially for those who don’t breathe and live AML like many of us do, it’s really complicated. Because community doctor said, well, you know, a year ago you were saying this and now today you’re saying this. Or even a month later, you know, and we, because we’re making changes as we learn and that’s what we can do the best for our patients. I still think that the over transplants, I mean that’s a real struggle and that’s median age of AML, right? And the one who I presented, you know, plus with a FLT3, right? So, if they need FLT3 maintenance after a transplant, do they need the transplant? And

I think that’s where, what’s the answer? And that’s where Harry,

I mean – I think Harry’s point is you have to ask the patient. Because I do have , say, you know, I want to go for two decades, this is what I want. I want , you know, I understand. But Everybody says that. No, no, no, really, I have some actually, I have a lot of those at that age who go to transplant come back and say they said , 30, 40% GvHD, like you said, 40% survival at two years. I’m not sure about that. Right. So I think there is, and I think more and more we are actually able to give them statistics and decisions because in the past there was no decision. It was either – So, to Gail, to your point, I hear what you’re saying, and you said it very nicely, that’s not fair. You’re talking to them about a curative transplant and then they need maintenance. I would sell it this way to you.

You’re giving them something that they can tolerate in the post-transplant setting that may keep the disease at bay long enough for a graft versus leukemia effect to keep it gone and cure it and ultimately stop the maintenance. Very much like we might do with an ABL TKI in ALL. Do you stop your TKIs in ALL? You don’t-

That’s because your patient will not allow you to. This is the bogus part. You say that, that we’re gonna stop. You’ve got somebody feeling great in remission on you’re not stopping it.

That’s true.

We’re respecting the patient’s wishes in a way. So, is the struggle financial or is it giving the patient what they want? Because I agree with Harry, my patient, the first three months is when they complain, like they don’t want do this. And if you prime them from the beginning, this is the sequence then okay, they get over it, okay, I’m gonna do this fine. But once they’re a year, and I have a lot of young patients, you know, who are like this FLT3, you tell them, look, I could stop at two years. I don’t know, is there a 3%, 2% risk? Possibly they’re like, I’m great. I’m going to school, I’m working right. Just take it, you know, people take blood pressure meds. So I think part of it is a bigger issue of financial and other issues. I think for patients, especially in a relapse setting or high risk disease, many of them, if they’re younger, will accept it. plus, I agree. It’s a tough population. And, and then yeah, But this is why I asked the, I was trying to be provocative in asking the question that do we have to actually admit that once you have AML you always need to be on therapy? Like, is that, but we all have people who [inaudible]. There are some, but I think we’re more and more going that way. I mean if menin looks as good as it’s looking, the, the KMT2As and the NPMs are going to be on that. Yeah, you’re gonna have, we got rid of maintenance in APL and they’re okay. Right. We got rid of maintenance in ALL and they’re okay. But,

Okay, so I’ll scare you with something I do with my patients because we’re driven by what the patient wants. And you’re talking about 80 year olds who don’t want to be on a pill. I don’t agree with Dr Stein what he said today. They don’t wanna be on these pills, especially pills that they have to get a prior authorization every year and there’s a break in their therapy and they’re very anxious about, they wanna come off of the treatment. And so how do you talk to them about that? Well, first you say we don’t have any real good data, but I’ll tell you the other thing I do, I’ll do a marrow and I will do next gen sequencing. I’ll do the FLT3 MRD analysis, the NPM1 MRD analysis. And if it’s negative, I’ll tell them, I still don’t know that the disease is gone. But if you want to stop therapy, I guess this is the safest port to do that.

Yeah, I think, I think we’re learning. I mean

I think –

– If they really wanna stop therapy is what I of –

Course if they wanna stop therapy, right? It’s a patient decision. You’ve educated them well, you’ve done everything you can to find evidence of any measurable residual disease and then you have, right, and that’s their, and and here’s the other thing that’s different, and I can’t remember who spoke to it, but it’s not like the old days when a patient relapsed or after seven and three they got Ida, FLAG, or MEC, and you did the best you could. We have a lot of options now for these patients and I know you have to still get them back into remission. But that’s the thing, if you’re following an NPM1 mutated, or an IDH mutated patient, you can’t see the disease anymore. If they relapse with those mutations and the NPM1s do, we’ve got plenty of options and more options coming. I mean, I think this is a question that, you know, it’s not just us uniquely, I mean CLL has the same discussion. If you give upfront combo like ibrutinib-ven or ibrutinib-ven-obin, now they’re starting to stop therapy at one year. Yeah. So the debate, and this is the same thing happening with ALL, blina, ponatinib, as we get more confident, we’re saying, okay, this is durable, this is durable maintenance going from three to two to one year. So I think that’s the next step. We don’t have that confidence yet. Hopefully you’ll get there that okay, let’s say you gave aza-ven gilt, or whatever it may be, and you achieve deep molecular rates to minus six two bone marrow six months. Can we then just say, let’s do gilt alone for a year and then stop. So I think that’s gonna be the eventual goal. But first for now we, we just wanna get these people in remission, see that we get two year survival rates of , 70, 80%. And then next is, okay, now we have the luxury of can we stop at a year, six months.

So I think those are incredible points. So we’ve talked about kind of in the course of our conversation, those that we have targeted therapies for FLT3, NPM1, IDH, we’ve talked about APL. there is a group of patients that we have yet to make progress for and it’s very discouraging. So they were mentioned in the sessions today are patients with, biallelic or high VAF TP53 and MECOM rearranged. And it is like we had the conversation, should even those with a TP53 be offered a stem cell transplant or not? is it beneficial to find those with the TP53 when they still have an MDS state, whatever our blast percentage is based on whatever criteria we’re using. And those MECOM patients, I would go further with P53 mutated the truly, you know, high VAF, biallelic TP53. So you did that marrow because they have, you know, trivial cytopenias, but not transfusion dependent yet, early versus later intervention doesn’t matter. And it is very hard to tell a patient, you’ve got cancer and we have a treatment, but we’re not going to give it to you. Or I don’t think, I’m not sure you’ll benefit from it. They’re all going to want it. Yeah, I mean I think that that, you know, the, it’s like the rich get richer and the poor poorer. So the targets we’re good at, we want to build it out because partly that makes us happy, the patients happy. But there’s a lot of research obviously going into those, the TP53. So hopefully we will get some hits there. But for today I think it’s a tough, field. I don’t have an, I mean, I would say a couple of things. I think that we’ve, you know, I think we all are sad that some of the agents that we really thought were TP53 directed and particularly promising, aren’t looking as we had hoped. It doesn’t mean that we’re not going to keep looking. We just kind of thought we had it and then we didn’t. And that hurts.

But I kind of agree with what Charlie said during this session that there is this, it’s difficult sometimes not to offer a transplant. It’s just too hard. And we all just know that these are patients sitting in front of us. We sometimes just need to try and we do. And on the flip side of that, I think that some of the little teeny regimens that we heard about in the conference, which might be even one day of a hypomethylating agent with a few days of venetoclax, things that are maybe holding back the floodgates type of a thing. I think that gets to what you’re saying, Harry, that I think we know that we don’t need to, we don’t have a benefit for hammering somebody’s counts over and over and over again. I personally, for some of the older patients with the TP53 if they are not transfusion dependent and not having infections, I actually do wait and patients are, are okay with hearing that, believe it or not, actually we can make things worse. So let’s not do that.

But I think that that, I think that those are patients where the exploration of some of these you know, less is more therapies for right now until somebody in that room cracks the biology, which they will, which will come cell therapies, other things. Yeah. So there’s a group of mutations that have a poor prognosis. Now in ELN, the MDS-related mutations, which include RUNX because RUNX was often seen with those and it’s hard to figure out how to target them. There’s important information with an IRAK inhibitor. But something that’s come out recently from the United Kingdom data, but also the original Phase III study was that CPX for some reason seems to be a benefit versus other intensive chemotherapy. Why would that be? But it’s two studies now versus seven and three and another one versus IDA flag showing that that subset of patients seem to have the survival benefit, secondary analysis, subset analysis. But when you start getting multiple studies saying the same thing, it’s hypothesis driving and we should be figuring it out. I thought that was really interesting and I wonder if, you know, the poor risk, I don’t know how we’ve called it the poor risk myeloMATCH study in younger adults who are fit for intensive chemotherapy or will be able to address some of that because there is a CPX versus + and we will be collecting a lot of molecular information.

So unfortunately, we wrote the study with ELN and I really wanna use ELN but we have to wait until the study launches before we get the first amendment in and the other big issue. But we will do that. Another big issue is this is not true in the case of HMA-ven because RUNX1, and I think that’s the other big, which I think Eunice brought up, that the whole ELN is not gonna be applicable in HMA-ven. And I think that’s the challenge because I think we all want to know between HMA ven intensive chemo, what you can do it, but who do you, what do you even use to select what you call intermediate? Do you use the, you know, FLT3RAS? Do you use the traditional intermediate? And so that’s another chapter, But the audience needs to know that too. And this point gets lost all the time that the biological definition of the disease, the poor prognosis, good prognosis, this is therapy dependent. This is the, APL, the worst leukemia. Well now it isn’t FLT3, the worst leukemia, well now it isn’t. This is all therapy dependent. So my other point on that was kicking the can is a therapeutic strategy that is good. You can say this what you’re on right now, it’s not that great, it doesn’t work great, but a year from now we can get you to a year. Maybe there’s something better.

Like that whole concept too, I still think is a little bit more uplifting for patients to hear some of the other stories that we’ve had that if they’re doing okay this isn’t perfect, but we’re doing better at keeping people hobbling along and maybe actually there’s another trial or you’ll be eligible for a trial. Like I don’t, I don’t think that that’s sort of a random thing to say. I think we can show how quickly the evolution has been in the last several years. And Gail, I agree with you and I think there’s, and especially the interest in that with our patients, if their hobbling along involves lower intensity, we need to change our verbiage for this. But strategies that do not require them to be hospitalized for their treatment. So whether that is a targeted and oral targeted therapy or a hypomethylating agent, hypomethylating agent with venetoclax, there’s a lot more we can do to stretch out that treatment. And I think patients are more accepting of that, especially when they don’t need the toxicities that require hospitalization. It’s basically, I mean we’re in close out but we’re talking about some patients you can watch and wait, some patients HMA alone, some patients HMA-ven, some patients HMA-ven with the other and then you have of course FLAG-IDA [inaudible] ven. And I think this is really speaking to the fact that there’s a whole spectrum of therapies from nothing to the most intensive that we have to select per patient.

And I think this really highlights that more than any time in the history for AML you need to have an expert consultation. I think this is really what it boils down to, even among the experts, we consult with each other, but for sure, I think in the community setting I think you really want to talk to somebody that you’re used to in a big academic center before embarking. Because there is really no cookie cutter formula for AML at all at this point. So I think with that, we will stop and thank you all very, very much. Thank you.