Clonal hematopoiesis, early detection & potential therapeutics

I’m Ravi Majeti from Stanford University, and I’m here with my colleagues from the last session of the iwAL workshop. I’ll let them introduce themselves.

Courtney DiNardo, MD Anderson, Koichi Takahashi, also from MD Anderson, Uma Borate from the Ohio State University.

Our session was really focused on different aspects of clonal hematopoiesis and early detection and potential therapeutics in this space.

I’ll just give a summary of my presentation, really focused on different types of experimental models that we’ve been using, where we’ve taken the ability to use CRISPR engineering in normal human hematopoietic stem and progenitor cells to engineer the mutations of pre-leukemia and clonal hematopoiesis, and investigate their functions and potential therapeutic vulnerabilities in experimental systems, both in vitro and in vivo. And we’ve specifically been looking at IDH1 mutant cases and trying to understand the potential impact of mutant IDH1 specific inhibitor ivosidenib versus some novel therapeutic approaches in our case, oxidative phosphorylation inhibitors of complex I that seem to have a preferential effect in actually eradicating stem cells that harbor IDH1 mutations, unlike ivosidenib, which seems to promote the differentiation of those cells. And I discussed some of our ongoing work in using additional methods of sequential modeling of mutations in normal human stem and progenitor cells, and looking at both cell non-autonomous and cell autonomous effects at promoting the progression and expansion of those clones.

Those are areas of active interest to our group that are a little bit relevant to thinking about the downstream translational therapies for clonal hematopoiesis. So maybe I’ll turn to Courtney and you can give a summary of your presentation. So My presentation focused on hereditary leukemia predispositions. And what I did was kind of talk about the fact that really about five to 10% of leukemias are anticipated to have some sort of underlying predisposition component, which is really kind of a recently identified finding. We, you know, we’ve heard all about, inherited solid tumors and, and it just is, is a more recent realization. And so I talked about that and I talked about just the challenges with trying to identify patients with hereditary leukemias because typically, you know, people get genetic testing from a blood sample or, you know, a saliva sample.

And in patients with leukemia, that’s actually their tumor. So you can’t discriminate between what’s a kind of a cancer associated somatic mutation and what’s an actual inherited germline mutation. So, you know, you have to be a bit more smart and unfortunately, a bit more complicated to do genetic testing  for germline mutations in patients with leukemias. And I talked about a couple different examples. And in particular, DDX41, which is one of the probably the most common inherited leukemia predisposition about 1% or so of all MDS or AML patients will have a DDX41 mutation and almost all of them are germline. And so just tr trying to kind of raise awareness and make people realize that this is actually more prevalent than I think a lot of people appreciate.

Yeah. Fantastic. Kochi, please.

My talk was focusing on the risk stratification of clonal hematopoiesis or CHIP. I reviewed the recent studies investigating the genotype specific risk of the CHIP and, both from the case control studies and also the observational studies. And I summarized that these studies have led to the identification of certain CHIP mutations which confers highest risks, or leukemia potential, those include p53 mutations IDH1 and 2 mutations, and RUNX1 mutation as well as, splicing factor gene mutation, and also JAK2 mutations. And I also went over some of the web portal tools that enables the risk prediction for certain individuals with having CHIP. and I think the uses of these web portals will enable us to identify the CHIP patients who are at highest risk of potential for the leukemia transformation, which may lead to the targeted interventions for those. Yes.

Speaking of interventions, Please.

So, thank you. So leading off Dr Takahashi’s presentation, I discussed the challenges and the opportunities of potentially intervening in these high risk patients. As Courtney mentioned, we have, you know, we sort of haven’t really kept up with our solid tumor colleagues in terms of their strategies for early detection, early intervention, and potentially cures. It’s more complicated in blood cancer, especially leukemias to one, identify these mutations early, but even more importantly, figuring out which one of these patients are particularly high-risk that they are going to develop a full-blown blood cancer in the future. And so, you know, based off some of the talk and the studies that Dr Takahashi summarized I think we now have the opportunity to identify these high-risk individuals and then potentially design studies to intervene in this patient population so they don’t develop a blood cancer.

So I specifically discussed a study that I am leading where we target a very, I think broad but important player of inflammation called IL-1 beta And we’re doing this by using an antibody called canakinumab in half the patients in this trial. And the idea is to take the first step towards learning whether we can do this successfully, and then also understand through this trial how these patients evolve when they do or do not get the therapy. But then last but not the least, also understand what success looks like or, you know, how not being successful looks like. What are we really measuring?

Are we measuring the possibility that these patients do not progress to MDS or AML? Are we measuring a reduction in these high risk mutations? Are we looking at, we know what, what this does to inflammation in their body and, and how this impacts their disease, and so on and so forth. So I think this is a great opportunity, and I think a really expanding, exciting new area in our field. Yeah.

One thing that brings together a couple of topics, I mean, this is a question for Courtney, is that in the patients who do have germline predisposition syndromes, when they potentially develop a CHIP mutation on top of the predisposition syndrome, how that scenario plays out because now you have a somatic variant that may be interacting with the germline variant?

I know it’s early days to think about this from a data point of view, but love your perspective.

Yeah. And I, it’s unfortunately a complicated answer, but we know probably the most about germline RUNX1 as an example. It’s been, was one of the first identified, and, only 30 to 40% of people who have an inherited RUNX1 mutation will go on to develop a myeloid malignancy, an MDS or AML, so you don’t wanna transplant everyone. Right. That would be, you know, giving a lot of people a really toxic therapy that they don’t actually need. So, you know, one of the things that we’re looking at is, you know, does the acquisition of these somatic mutations, this clonal evolution, identify those patients who are more likely to develop that myeloid malignancy?

So that’s definitely, it makes sense, right? And that’s probably what the story will be, but it’s gonna be different gene by gene, for instance, DDX41, which I mentioned, you don’t really get other mutations other than typically a second hotspot mutation on the DDX, on the other allele. So, you know, it’s not so much a clonal acquisition of other things. It’s whether or not you get that second hit for that particular predisposition.

Great. And, Kochi, one of the things that interests me is, of course, we can start risk stratifying patients with CH but what’s the magnitude of risk? Like how much worse off are the highest risk patients in their potential for progression versus the lowest risk patients?

Yeah. That’s an absolutely great question. I think we need to also separate the relative increased risk versus absolute, risk. And I think if we look at the relatively increased risk, it looks very impressive. Like these high-risk population have like a 90 times higher risk compared to the low-risk patients who do not have a CHIP. But when you look at the absolute risk for the transformation, yes, it looks like even in the high-risk population, maybe the 10-year cumulative incidence risk is anywhere around 40% ish. But still it’s an impressive risk. And on top of it, if you also have, I think a CCUS, you know not only have a CHIP, but also with the cytopenia, I think the previous study also found that the risk of transformation is very, very high, like 80% or close to like even a hundred percent. So I think if you truly identify a high-risk population combining the mutation data plus the clinical variables, I think you can identify patients who really have a high-risk potential to transformation.

Yeah. Wow. I didn’t realize that the absolute risk could be that high 40% to me seems pretty high.

Right? Right. I mean, those are really at a selected high-risk population, but yes. Yeah. Yeah.

And Uma, I think with the early days of clinical trials, I think what really sticks out to me is the endpoints issue. Like you were just alluding to, what are the endpoints? What are we really monitoring? What means clinical benefit to the patient? And as we think about therapeutic development, what means clinical benefit in a regulatory setting, in terms of a new drug or a new indication or an FDA approval? just your thoughts on that space.

And I think this is where the very hard conversations need to happen because, you know, data that all of you presented was if you do have that IDH-mutated high risk patient with cytopenias, with the clone, you treat them with an IDH inhibitor, their cytopenias get better, you know, the clone sort of gets really low where you can barely detect it, but it doesn’t go away. And so is the patient going to stay on therapy, you know, for three years, for five years? And obviously it’s great if they don’t get MDS or AML, but at the same time now they’re taking a treatment which is a pill which is used for cancer treatment for a really long time. So to me, the first question obviously is, is the risk high enough to justify treatment? Second, if you justify the treatment, the treatment really needs to be something that the risk benefit is tolerable to the patient. I mean, we have early stage breast cancer patients that could benefit from, you know, hormone blockers, but a lot of women don’t want to take them, and the side effects are terrible. They get hot flashes. And so it’s just a hard thing to discuss and offer the patient.

And then the third thing is, what does success look like? We believe that improvement of counts means that their leukemia risk is going to go down. Well, great, it’s easy to measure, but if that’s not the right thing to look at, and the right thing to look at is do bone marrow biopsies every few months and make sure they’re not progressing. And that’s our sort of golden endpoint. And I don’t think we know. And so I think that’s where the opportunity is in this field to really hone down and figure out sort of the right way to measure success.

Yeah. Maybe I’ll just piggyback on that and saying, in terms of our experimental systems, we’re really trying to understand if therapeutic manipulations in the engineered mice models, whether that actually will impact the clone size. Ultimately, I think if you eradicate the clone, we would think that would have a clinical benefit, but we don’t know if that’s the only way to have clinical benefit. So we are really trying to understand the clone size and which cellular compartment of the clone is being targeted. So a little bit more basic question, but I hope it will inform ultimately clinical strategies.

Maybe the last question I’ll ask, and you guys are all very clinically active, is, you know, you’re at amazing academic medical centers, you get referrals from your oncology colleagues or people are getting sequenced from different reasons, but the real world is out and about, not inside MD Anderson and Ohio State. And in terms of either identifying these patients or making sure that patients have access to these diagnostic tools and methodologies, maybe are you doing outreach to your referring physician groups? Or how would you recommend community oncology and hematology groups interface with this kind of cutting-edge area of our science?

So as a non-MD Anderson person I will say what you said is so critical because our sort of catchment area is a very large rural population within the state of Ohio, West Virginia, Appalachia, and so on. And it, we have a very scattered group of community oncologists that see every single cancer, you know, and this is sort of one of the rare things they see. So we do try to do a lot of outreach. We speak to sort of their tumor boards, grand rounds conferences like these, I think sort of an important purpose because if people do want to kind of look up what’s going on with these patients, hopefully they’ll find this video that we’re making right now. But I think what you just said is so critical because until the patient gets identified and sent to us, none of these things that we’re talking about can happen, right? So I really think that is a big challenge moving forward.

And maybe you can talk about your experiences at MD Anderson.

Yeah, I mean we don’t get a lot of referrals from the outside community, and we maybe should probably do a little bit more effort outreaching to the community practice. Our main referral source is actually a, a solid tumor clinic within the MD Anderson. And I think we need to also separately look into the risk of cancer patients having CHIP versus normal individual or community person having CHIP, and they do have a different implications. But I think in this world where like you can easily get, you know, order 23 and me and perform the genome sequencing, at home, I think we are, we need to be prepared to get all these, self-referrals. Or any of these things who were identified to have a CHIP, at the home kits or like a home sequencing kit. So I think that’s a very critical part. Yeah. Maybe just your experience.

I mean, we have, we certainly have a strong referral pattern for leukemia, right? For CHIP, you know, not as much, but I think more and more as, you know, as you all were saying, it’s a lot of things are becoming patient directed and family members directed where, you know, they’re looking up information about their health and they’re identifying kind of, these opportunities are available at X, Y, Z. And so kind of more and more I’m getting kind of direct  self-referrals or emails or phone calls to say, you know, Hey, I have this, you know, how do I come see you? So I think, there’s just so many different levels of, of outreach and of awareness. And I think, you know, what we’ve been doing and we’ll continue to do is try to reach the community oncologists who don’t see so much hem malignancy. And so, you know, for them trying to manage everything is just such an impossible task. I don’t know how they do it. But then also on top, another level of going directly to patients and patients’ family members to have that information available so they know how to seek additional information.

Yeah, absolutely. Well, like when I think back to the initial genomic studies, yeah, maybe almost 10 years ago now, thinking about identifying CHIP, we called it indeterminate potential. Yeah. Frankly, as I thought about it, I was like, wow, this really is a don’t ask, don’t tell kind of a scenario. but I do see the future is really all about us figuring out how to stratify the patients, how to think about their inherited predispositions and where we go with therapeutic interventions.

So, right. And I think the great part about these large observational studies that you talked about is they identified easy clinical parameters that anybody can see looking at a CBC. If you have low counts, if you have a high MCV, the size of your red cells is large, you have a high RDW, just a lot of different sizes. This is something anybody can do. And if they identify that and they see this picture, I think that is a simple educational message to send to people saying, these are the patients you should be worried about and get them to us sooner rather than later, and we can do the rest of the testing and maybe some counseling and risk directed therapy. So I think that’s the value of these studies that have just come out. Right. and I think that that’s gonna really distinguish from, as you said, the don’t ask, don’t tell worried, well, people versus some people that we need to be more active about. Right.

Great. Well, thank you all. It’s been a really exciting workshop.

Thank you.

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.

TP53 Mutation in AML

Hello, my name is Andrew Wei from the Peter MacCallum Cancer Centre in Melbourne, Australia. And today I have with me Dr Sanam Loghavi from MD Anderson Cancer Center. And she gave a really interesting talk today on, P53 in AML. Sanam, did you want to tell us more about what you discussed today?

Sure. Very good to be here and happy to discuss this, this perplexing topic. You know, we spoke about the significance of TP53 mutations in AML and specifically with regard to classification and prognostication. As you know, the presence of TP53 mutations in AML right now, at least in the ICC and ELN classifications is a disease-defining event. And so, you know, we know from therapies that we have currently available that this class of disease is incredibly difficult to treat. And there are a lot of subtleties and nuances in the way we identify TP53 mutations and characterize TP53 mutations and loss that could potentially impact prognostication. And I think we’re still trying to learn, what is really the best way of prognosticating and maybe pulling out the subset of disease that is not necessarily as bad as the other ones.

You know, there are studies that show that, you know, obviously having a complex karyotype in addition to a TP53 mutation that leads to loss of both copies of TP53 is just excessively detrimental. But I think, again, there’s a lot of information that we’re starting to acquire as we’re looking more into the details, including variant allele frequency, the allelic state, other chromosomal abnormalities, chromothripsis, telomere length. So these are things that I think we should be considering in our future studies when we try and prognosticate, you know, develop prognostication models for these patients.

Thanks. And Sanam, can you tell us a bit about this concept of double-hit P53. In practice, how do we define that?

So, you know, this is very interesting because I think if you think about this logically, it makes perfect sense that loss of both copies of TP53 would be much, much more detrimental because, you know, maybe going back to high school or college biology, TP53 is a tumor suppressor. When you think about malignancies, typically the way tumor suppressors, you know, invoke malignancy or are involved in the pathogenesis, is you usually have loss of both functional copies. Whereas oncogenes, like, let’s say for example, MYC, you can have one activated copy of MYC and, you know, it’ll do the magic, it’ll do the job. But for TP53, you know, for the longest time we were just looking at TP53 mutations, the presence or absence of TP53 mutations in myeloid malignancies until the landmark study that was published, by Elsa Bernard and Elli Papaemmanuil in 2021, I believe,  where they showed that in myelodysplastic syndromes, patients that had biallelic loss of TP53, and I’ll explain that in detail, were the ones that had very poor outcome. And at least in their study, patients that had just one mutation did almost similarly in terms of, you know, outcome and disease behavior to patients that had wild type TP53.

And so how do we define that in practice? You know, I’m a hematopathologist, how do I define a biallelic loss of TP53? There’s really three major scenarios. One is if you have two or more mutations. And again, realizing that, you know, the way we detect mutations right now is by bulk NGS, So we’re really not looking at individual alleles or clones, but again, by way of biology, we are imparting that when there’s two mutations, they’re probably in two alleles.

The other way is if you have mutation of one copy and deletion of the wild type copy, so that all you’re left with is the dysfunctional mutated copy.

And then the third scenario, which is a little bit more tricky, and you know, some labs don’t actually do this routinely in practice, is if you have a mutation and copy neutral loss of heterozygosity, and what that means is that the wild type allele is deleted and the mutant allele is actually duplicated. So if you FISH for TP53, you’re gonna see that there’s two copies. You’re not gonna see a loss of TP53, but functionally you don’t have a wild type TP53 copy anymore. So that is also, you know, the third scenario, and again, because I said we don’t look for that and, you know, practice at least many labs, don’t we use the variant allele frequency as a surrogate to imply that there’s copy neutral loss of heterozygosity, and, you know, a 50% variant allele frequency cut-off more or less seems to correlate with copy neutral loss of heterozygosity. So if you have a mutation with a variant allele frequency of more than 50%, you can assume that there’s probably copy neutral loss of heterozygosity.

And you mentioned that P53 mutation is a really important and poor risk entity, but that it can also overlap with other, you know, commonly occurring mutations in AML. And so if we have a patient with a P53 mutation and an, say, an NPM1 mutation  God forbid, doesn’t happen very often – how do we, you know, how do we designate that patient? Is that patient favorable or unfavorable?

So, you know, I think this is still, you know, as you said, fortunately, this does not happen very common, but again, because it doesn’t happen very common, I think our information is really limited in this scenario. But the way the risk stratification systems are designed now, at least ELN 2022, if you have an NPM1 mutation without a FLT3-ITD, obviously, that disease is considered favorable risk. Now, if you have an NPM1 mutation with an adverse-risk cytogenetics, the adverse-risk cytogenetics trump NPM1, and that patient is considered to have adverse risk disease. And we know that the majority of TP53-mutated AMLs at least for the most part, tend to have complex karyotypes. So those would be considered high-risk disease. But in terms of designation of the, you know, your top line on the report that is still by ICC and by WHO fifth edition, that is still considered an NPM1-mutated AML, because NPM1 is a class-defining alteration that is above TP53 in classification.

Conversely, I think are the myelodysplasia-related mutations, where if they occur with NPM1, at least in our current stratification- risk stratification systems, they do not alter the risk of disease. So if you have an NPM1 mutation together with an SRSF2 mutation without a FLT3-ITD, that patient is still considered favorable risk.

And briefly, when I did my talk today, I was focusing on what are the possible therapeutic options for patients with adverse-risk disease, such as P53-mutant AML? And one of the areas that I discussed was the possibility of combining BH3 mimetics, targeting BCL2 and MCL1. The difficulty, of course, is that MCL1 is an important pro-survival molecule for critical organs, such as particularly the heart. And that future therapeutic modalities might need to determine ways to reduce this risk by perhaps directing the MCL1 inhibitor more directly to its target, perhaps by either PROTAC-relevant options or antibody dependent conjugates, that can direct MCL1 inhibitors to leukemic cells.

And the second possibility as a new area of potentially leveraging STING agonists, which are currently used in solid cancer circles, to activate the immune system and utilize, I guess, a less recognized possibility that activating STING with these agonists can actually drive apoptosis and drive apoptosis in a P53 independent manner. And that by combination with venetoclax, we might have a very effective combination, that can perhaps make some inroads into a really difficult disease.

So, today we’ve discussed, obviously, the therapeutic possibilities, but also the diagnostic aspects and the complex nature of P53. And hopefully all of these together will provide some diagnostic, but also some therapeutic benefits for patients in the future. Thank you for joining us today, and we’ve hope you found this session and discussion interesting and educational.

Novel Targets, Combinations & Treatments

Hello, my name is Dr Eunice Wang from the Roswell Park Comprehensive Cancer Center in Buffalo, New York. I am here at the iwAL Leukemia 2023 meeting, and I’m joined by my colleagues Dr Thomas Cluzeau, from the University Hospital in Nice, as well as Marina Konopleva from Montefiore Einstein in New York, New York.

And so we’re here to talk about our talks that we gave at the meeting. The topic of my talk was intensive chemotherapy versus HMA venetoclax for younger intermediate risk patients with AML. And this topic is one of the controversies in AML because we know very well that venetoclax-azacitidine represents the standard of care for older and or unfit AML patients, but for over 40 years, the standard of care for our younger fit patients has been cytarabine and anthracycline based therapy, i.e. seven plus three. However, given the excellent tolerability and now emerging data that patients can tolerate venetoclax azacitidine and potentially go to successful allogeneic stem cell transplantation, the question is whether younger fit patients should also be offered this less toxic regimen and whether it represents a potential new standard of care for these individuals.

So in my talk, I reviewed some of the literature. There’s retrospective data, and currently there doesn’t necessarily seem to be a clear consensus whether intensive chemotherapy versus HMA-ven it is possibly going to be what we would use for these patients in addition to just standard HMA-ven. We now have triplet therapies where a targeted therapy is being incorporated into upfront therapy. For example, FLT3 inhibitors in combination with HMA ven and comparing the results of, for example, FLT3 inhibition plus seven plus three, suggests that there actually might be an advantage to a less intensive regimen in combination with the targeted therapy. Importantly, we also need to understand that most patients treated with HMA ven are not going to be cured of their disease, and therefore, if we are going to use this regimen in younger patients, allogeneic stem cell transplantation has to be part of that equation moving forward.

There are many randomized trials that we’ll be investigating this question in the next coming years, and we look forward to those results to determine which backbone regimen and targeted therapy should be used for our patients moving forward. So I’d like to introduce my colleagues, Thomas, who gave us an excellent talk on P53 mutant disease, and he’s going to give us a summary of what his conclusions were for treatment going forward for this disease.

So, thank you. Yes, yesterday I talked about the TP53, therapeutic strategy in acute myeloid leukemia. As you know, TP53 is a very poor disease and today the usual treatment failed to improve the outcome of this disease for patients eligible to intensive chemo, but also for patients not eligible for intensive chemo. The complete remission rate, CR/CRI rate, is around 30 to 40% and the median overall survival is around 5 to 6 months for patients eligible for intensive chemo using three plus seven or CPX-351, or also for patients not eligible for intensive chemo using HMA and HMA plus azacitidine and independently, if you use azacitidine or decitabine.

We observe an increase of CR rates, with the HMA plus venetoclax, but it failed to improve the median overall survival. So, I discussed during my talk, what could be, maybe the next step, in this setting in patients TP53 mutated, and we discuss about the magrolimab of course. So as you know, the magrolimab is a CD47 antibody, inhibits the ‘do not eat’ signal, and today there is two Phase III clinical trials in this setting. So the ENHANCE-2 study evaluating in TP53 AML, azacitidine plus magrolimab versus intensive chemo in patients eligible to intensive chemo and versus Azacitidine plus Venetoclax in patients not eligible to intensive chemo. This clinical trial is ongoing. there is a partial hold now, but we hope we could continue this clinical trial until the end and we hope to obtain  good results based on the results of the Phase I. And there is also another clinical trial. It was the ENHANCE-3, clinical trial evaluating a triplet azacitidine venetoclax plus magrolimab, versus azacitidine venetoclax plus placebo. It was more for patients not eligible for intensive chemo. But this clinical trial is also in partial hold, and we hope we could go to the end, maybe to improve, of course the outcome of these patients.

And in the second part of my talk, I discussed about if this disease could be cured, because today we have a good, we have discussion about if the treatment is just to prolong the survival or if it’s possible to cure, and using the data we presented, David Sallman and me, about azacitidine plus eprenetapopt, we could identify a subgroup of patients obtaining deep CR after this combination, and could undergo to allo-stem cell transplantation. And we observe a plateau around 50% in this patient, So maybe, if with the new drug, magrolimab or other drug, if we could obtain a deep CR and if we could undergo to allo stem cell transplantation, maybe we could cure these patients. It was my conclusion, it’s a hypothesis of course, but there is a lot of drugs, a lot of reconforming agent for TP53 and maybe we could find the, the good strategy for these patients.

Well, that’s great. That’s very helpful for us moving forward.

And Marina Konopleva gave us an excellent talk on one of the hottest issues in the current clinical practice of patients with AML, how to overcome or potentially address venetoclax resistance.

Thank you, Eunice. So I presented the laboratory data trying to understand the mechanism of venetoclax resistance in acute myeloid leukemia and potential novel ways to overcome that. So we all know that, HMA venetoclax has been a changing paradigm regimen for all the unfit for chemotherapy patients with acute myeloid leukemia. But the long-term results now show that perhaps the cure rate is somewhere in the range of 20% only long-term results. So majority of the patients are relapsing, and then there’s a fraction that are primary refractory. So, our lab and also other labs have been working for years now trying to understand the mechanism of resistance to venetoclax.

So I presented several potential mechanisms of resistance. One of them was newly discovered role of mitochondria as resistance, with a novel process called mitophagy of clearance of mitochondria, and also change in the mitochondria structure. Unfortunately, we don’t have yet clinical drugs that can affect these processes, but they’re being developed.

Then I discussed two known mechanisms of resistance. One is emergence of signaling mutations, and second is TP53 mutation. So as far as signaling mutation, I presented our laboratory data, which correlate with the clinical findings that the RAS mutations are representing one of the several signaling mutations that confer resistance to venetoclax.  and, how to overcome that. We currently do not know, but at least combination with MCL1 inhibitors in the lab are promising. Unfortunately, these agents have difficult clinical paths because of cardiotoxicity that was encountered. So the novel NRAS inhibitors are needed, or other ways to inhibit downstream NRAS, such as perhaps PLK1 inhibitors, which was also presented at this meeting.

And then finally, we discussed the TP53 mutation as a major mechanism of resistance and how that mechanistically it’s mediated through pro-aptoptic Bax deficiency because p53 controls Bax activation. We also discussed that there is a potential of developing Bad activators that perhaps could overcome this resistance when used in combination with Venetoclax.

And finally, in the last part of my talk, I discussed the role of BCL XL inhibitors. This is a new development, we think some of the BCL XL overexpression can confer resistance to venetoclax also in the setting of P53 mutation, particularly in a subset of acute leukemia called acute erythroleukemia and we have used in the laboratory, the novel degrader of BCL XL and shown that it works in this subset of leukemia, which has really poor outcomes.

So I think a lot more needs to be learned from the studies. But we are hoping that in the next few years we’ll have a novel combination that canimprove the outcomes of patients treated with venetoclax among, like among us.

So I just wanted to thank you very much for your wonderful talks and for your summaries of your talks. I just wanted to know for you, what were the highlights of the meeting, sort of the take home points that you think we should be looking at, or you’ll be thinking about when we return from the meeting? Thomas what are, what are your thoughts about things on the meeting that were, you think are next unmet needs or things that we should be looking at moving forward with acute leukemia?

So, thank you for the question. I think TP53 stays an unmet need for the moment. So we have clinical trials, we have to wait of course, the, clinical trial, as you know, there is a lot of clinical trials in acute myeloid leukemia fail to improve the outcome for the TP53. So, yeah of course the TP53 mutated patient is an unmet need today. And of course the resistance to AZA-ven is a big challenge. But you find some way to bypass the resistance.  So it’s good to know that maybe we will find something to bypass the azacitidine venetoclax.

Maybe one question for you. Do you think we could be able to maybe to have a BH3 profiling, maybe before azacitidine plus venetoclax, and maybe at relapse to decide when we will have BCL XL inhibitor, vaccine, inhibitor, maybe to define which inhibitor we have to use in the future?

Yeah, I think that’s a great question. So the biomarkers of resistance and response have been challenging in the clinical setting. So there are two potential assays. One is to do BH3 profiling, which is a functional assay. And it is challenging because of the combination that we are using. So it’s a perfect predictor of dependency, but then in the setting of frontline therapy, when you combine the two drugs is difficult. But then I think at the time of progression, it’s actually feasible to understand if, what is the switch and the dependency, as you said, to BCL XL or MCL1, so we collected samples in the lab and hopefully we can do it in the next year or so. Actually, it’s on my list to do. The other essay is to do the BCL2 family expression. And there was a very nice paper came out from Andreas Trumpp Group in the Cancer Discovery that showed that expression of BCL XL and MCL1 like in a ratio of, of fashion on the stem cells, specifically correlates very well with the responses in the HMA-ven in two different clinical trials that they performed in Germany. So we are collaborating with Andreas and getting this assay in our lab and hoping to reproduce that in our work as well.

So I think these two assays hopefully will help us to figure out the dependency. And then we need drugs, of course, which is a separate discussion.

Now, there was a case presentation on a patient that had a Bad mutation and have some of these other mechanisms. So do you recommend that we should be looking for anything other than P53 in terms of predicting response? Because as we know, when patients become resistant or they’re resistant upfront to Venetoclax azacitidine, we already know that they have a poor prognosis and the treatment options are limited. Do you recommend any mutation testing prior to starting Venetoclax therapy as a, to try to anticipate who’s not going to respond?

Yeah, I think, I personally think that the mutations and signaling pathways and P53 are much more common mechanisms of resistance to venetoclax, but certainly Bax mutations exist. And we’re looking at that in our own studies. I think we have to confirm. And, so large series that Bax mutations and which ones of them really confer resistance, I think there is one specific mutation that can in fact be selected for. And I think we have to be probably test for that mutation going forward. But I assume the mutation pretreatment is at very low levels, so it unlikely that we are able to detect that at the time of diagnosis. But again, the time of progression, I think it’s worth looking into that.

And then the question is, what are we gonna do about that if we define that mutation? Because, but at at least based on Andrew Wei’s data, these mutants were remaining sensitive to chemotherapy. So I think if we detect the mutation, we probably should not be using venetoclax based regimens, but some sort of chemotherapy perhaps could be useful in the salvage setting. Yeah. So, and then, the recent unpublished at work suggests that BCL2 mutation can actually happen in AML, although very rare. Again, they have been described in CLL as mechanisms of resistance, there’s some data from Sasha Perl and Andrew Wei who identify a patient who actually developed BCL2 mutation as well. Yes. So, I think that’s also, you know, we should probably include to our panel, this mutation so that we at least understand at the time of progression that this drug should not be used.

And then, Thomas, you talked about a lot of treatment options for P53. So looking towards the future, what are you most optimistic about? Do you think we should continue to pursue immunotherapy for P53 mutant disease? Because obviously venetoclax doesn’t work. I know you talked about magrolimab, which we’re kind of waiting with bated breath. I mean, what do you think is going to be sort of the most promising or possibly potential therapies in clinical development for p53 mutant disease?

So I, I guess the the reconforming agent could be really interesting for TP53. So we try with eprenetapopt, unfortunately the Phase III in MDS was negative, so we can’t continue for the moment the development in the acute myeloid leukemia. But there is a lot of reconforming agent, so for the moment, it’s not in development, but it’s our job to do that. So, but we identified a big list of drugs, could reconform TP53 to change the mutated TP53 in the wildtype TP53, and reactivate the function of the TP53 pathway. So if I want to do a hypothesis, I would like to go on the maybe a little bit more in a reconfirming agent and to find the good one, to improve the outcome of this setting.

Now, in the discussion part of your talk, there is some controversy because some people believe that patients with P53 mutant disease should not undergo allogeneic stem cell transplantation because the outcomes are so poor. Now, you presented data that patients can actually get upfront therapy and successfully, I think the cure rate or the survival rate was up to like 45%. Can you discuss that controversy, because I think we’re a little torn in the field. We wanna do something for P53 mutant patients, but is transplant the right way to go? Or maybe just, you know, clinical trial? What, what are your thoughts?

I totally agree about the two parts because, today the allo stem cell transplantation do not work in TP53. There are some patients alive after allo stem cell transplantation, but it’s not too much. We stay around 10 to 15%. It’s not good, but it’s not good maybe because  before stem cell transplantation, we have not the good strategy, today, azacitidine alone, maybe azacitidine venetoclax, is a little bit better because we could, we could put more patients to allo stem cell transplantation. But the results after azacitidine plus venetoclax is not good also, after intensive chemo, the results are not too good. So it’s why there is a discussion about is it really necessary to do an allo stem cell transplantation after this treatment? But I hope in the future with the new combinations, if we could obtain  deep CR as we know in the other AML patients. I think it’s the same in the TP53 mutated patients. MRD is a good surrogate marker for allo stem cell transplantation. So if we could obtain maybe more negative MRD using new combination therapy, maybe allo stem cell transplantation could be a good option. But today it’s not a good option because we have no good treatment before.

Okay.

And your opinions about the drugs targeting the SIRP-alpha, CD 47 axis, what are your thoughts, negative data with magrolimab, and AZA waiting for the results? I mean, do you think that that pathway, maybe not that drug, but targeting that pathway, still has legs for P53 mutant disease?

So I think the magrolimab is, it’s still, as I said during my talk, it’s still on the game. For me it’s a good drug, it’s a good drug it’s a safe drug if we manage well the drug using the guidelines. So I hope we could, finish the two Phase III clinical trials ongoing have the results and maybe for the first time a big improvement for the TP53 patients. So I think the magrolimab is, we still have hope. Yeah, so I hope, yeah, I hope of course, okay, we need to hope.

Maybe I can add that I do think that SIRP alpha antagonists do have a hope as well. At least, you know, preclinical data initially was developed by John Dick’s group, in fact, and their preclinical data similar to magrolimab, show efficacy in patients with complex karyotype P53 mutated disease. We don’t really understand the mechanism why this was, show efficacy in patients with complex karyotype P53 mutated disease. we just have to see which drug will be kind of making it to the finish line. But I think as a concept of inhibiting CD47, SIRP alpha interaction, I personally is a believer of that. And I hope we can find an agent that is safe and given with the appropriate backbone, also will have efficacy. Because additional discussions were of course, whether the backbone of AZA-ven with an intensive regimen is given now for 28 days of Venetoclax, whether that combination with Magrolimab would be having more side effects and whether different backbone would yield better outcomes. So that remains to be seen.

No, I agree. I mean, I think that just like the first FLT3 inhibitors that maybe we developed in, the clinic or in patients weren’t not successful potentially, maybe magrolimab isn’t necessarily gonna be the one, but there’s hope that there’s many other agents targeting that access that could work in those really dismal prognosis. So I agree that we should hang in there and be persistent. And I know that there are other drugs beyond magrolimab  that might be considered newer generation agents. and we can wait for those trials as well.

So thank you very much for taking the time to listen. I’d like to thank my esteemed colleagues, Dr Konopleva, Dr Cluzeau, for their time in discussing the key abstracts that they presented at this year’s iwAL 2023 meeting.

Transplantation & Immunotherapies

Hello, I’m Charlie Craddock from Birmingham in the UK, and it’s a real pleasure to be joined by David Sallman from Moffitt in Florida, Mark Levis from John Hopkins, and Nelli Bejanyan from Moffitt.

We’ve just had a really fantastic session covering some broad areas around how we think about improving outcomes in patients with AML through distinct and varied immunotherapeutic strategies including transplant. And David, I want to just start with you really to give us a state-of-the-art with where we are on CAR-T cell development in AML. It’s an area of active interest at the moment.

Yeah, I mean, I think at this wonderful conference, I think we’ve heard a lot about exciting breakthroughs, you know, throughout, but unfortunately a majority of patients are still ultimately relapsing and really having a novel cellular therapy like we have in other hematologic malignancies, I think is really paramount. You know, to all of us, I think we’re still in our infancy stages. I think there are, you know, several targets. The three main ones right now being CD33, CD123, CLL1, that are starting to move, you know, farther along in clinical trials. And finally, some of them are actually to expansion to where we can really see what the efficacy signal is, both with and potentially without, you know, salvage transplant, second transplant, you know, DLI.

So we are seeing responses. I think the challenge is the response rates have been low, the durability has not been great. And so the big questions is why is this? Are we treating the wrong patients at the wrong time? So are these patients that are too heavily relapsed/refractory, T-cell fitness that’s significantly impaired, or is this a target issue where we know that unfortunately there’s a ton of heterogeneity and are we really missing a majority or a significant proportion of blasts? And I think those are the big questions. I think we are seeing anecdotal great responses. I do think, you know, moving the field forward is going to be out of the box approaches. So I do think compound CARs with OR-gating strategies, where again, they will activate with seeing multiple different antigens, is probably gonna be the key going forward. I think with that consideration, there may be increased toxicity, especially myelosuppression, and so I do think thinking about that in tandem, designing early trials may in CR1, MRD-positive disease and getting them to transplant in the best optimal remission is where we’re going. But again, I think this is going to take us actually years and not months to really potentially move that field forward. But again, optimism is, is always important.

Mark, some general observations maybe about the patient population that we should be thinking of most eligible for this approach?

Well, again, I’ve harped on perhaps not using the TP53 complex karyotype crowd or carving that out distinctly. because I think we lose a lot of therapies when we, I think they’re two different diseases and often our benefits are on the margins and the addition of a population that is so dramatically different.  So if we have to think differently about the disease, but then, I think it becomes easier if we get an agreement to do that. this is my – I’m convinced this is what’s weighing down a lot of trials right now, is that population as as sorry as we are for them, we’ve got to carve them out of the field. I think, I think relevant to that, the challenge biologically, they’re a hyper proliferative, non increased blast patient that you have potentially time, but then a lot of these patients are getting into the early, you know, CAR-T studies and is that negatively impacting? So that, I think that’s a huge, important consideration.

So, David, you published on the immunosuppressive, bone marrow microenvironment in P53 mutated. I mean to what extent do you think there are host issues here, either around T-cell numbers or fitness, or possibly an immunosuppressive microenvironment that might abrogate an effective a CAR-T?

Yeah, I mean, I think that it speaks, again to Mark’s point and then, you know, why are these patients not responding? And I’m not aware of any P53 mutant patient that has responded to any cellular therapy, again, outside of something that was, you know, immediately to transplant. So we do know the immune microenvironment is dramatically different. It’s a very exhausted anergic phenotype, potentially inflammatory, at the same time. And the scary part and this is some data out of, of MD Anderson where they did single cell cytokine profiling, looking at poly functionality of T-cells, and even in P53 patients before they ever got therapy, there’s really this profound dysfunction. So I do think for P53, I’d be much more thinking about an allogeneic type product because of this impaired T-cell, but then even with that, I think we need to think about, you know, potentially some of the direct immunosuppressive mechanisms of the malignant stem cells in that population.

So it’s gonna have to be an out of the box approach, probably an allogeneic approach. But again, I think carving it out and thinking about a very specific platform for that group. And again, the bar is low, so I think if we had a signal there and we could see deepening of remission, which again, several of us have shown, you know, translating to ultimately improved outcomes of transplant, maybe a key consideration. And I think FDA was open to potentially carving it out.

And then just switching gears, Mark, you, you, your work’s been pivotal in establishing pre-transplant MRD as a prognostic indicator when patients have proceeded to transplant. And I think it was identified at the meeting, you know, that one of the really hot questions that is out there at the moment is, is it possible to ask a question as to whether targeting pre-transplant MRD might be a route to reducing relapse post-transplant, improving transplant outcome?

It’s quite a challenging area to develop clinical trials, and I think there aren’t any at the moment. So some general comments. So First, there’s sort of two sides of the MRD issue, the regulators brought up, no, we want this thing standardized in all our minds, we believe it. Okay. We believe we’ve designed an assay that easily can be standardized. So we actually have two, we have NPM1 and FLT3 that are kits that are reproducible. They’re gonna get the same result anywhere in the world with basically following the recipe. That’s a huge tool. We want to validate the, we validated NPM1. We’re probably going to succeed in validating FLT3-ITD. But as you say, what do we do with that now? Can we eradicate it? And, and how so and so that elicited as you know, quite a lot of passion and ideas being flung out.

I still do like the concepts that were brought up, focusing on the less intensively treated patients. Those are the patients that are gonna have higher levels of MRD. NPM1 mutant patients do really well regardless. And so that’s a tough population to improve upon. But the older patient, not so much. We know this, we’re using aza-ven, we’re very pleased with ourselves, but still not, we have far to go. And that’s the population, I think, we should be saying you’re MRD positive with either NPM1 or FLT3, we’re going to use a FLT3 inhibitor or a menin inhibitor or something else randomized at the start. Because those patients going to transplant, if you do intention to treat at randomization, you will lose some of those patients. I think that has the potential to get us an answer and maybe use MRD to benefit patients, come up with a new therapy.

And Nelli, you’re a coalface transplanter. Any comments about how you might design such a study? Or what do you think might be targets?

Some of the studies can be designed actually to use intervention in a context of allogeneic transplantation. Either that would be optimizing further the conditioning regimen, and that can be additional drugs or cellular therapy approaches incorporated there. Or doing something consolidative after allogeneic transplantation. I believe more in cellular therapy, I’m a transplanter, but, because I know that AML most of the time can be cured with cellular therapy and standard being allogeneic transplantation, if we can learn more about subset of cells that can benefit patients in terms of enhancing further the GvL effect without compromising, their outcomes in terms of increasing GvHD that would be type of a strategy I personally would look for in the context of allogeneic transplantation.

So let’s just talk a little bit more then about DLI, because you know, we know this is a really, it is pretty well tolerated if you get your dosing schedule right and it, we all know that it can be highly effective in patients who are MRD positive or cytogenetic relapse. And before I came, David, we had a lady with cytogenetic relapse, P53 mutated MDS, who just has had the most fantastic response to DLI. And then of course we have other people stacking up who don’t. So the challenge, I guess, Nelli, and perhaps you could give some thoughts on this, is how do we optimally employ cellular therapy post-transplant? What are the exciting areas?

I’m more than happy to comment on that. In regards to a conventional donor lymphocyte infusion, obviously there’ve been concerns there in terms of increasing risk of graft versus host disease. In some studies, it’s up to 40% or 50% of the patients developing acute or chronic graft versus host disease. That definitely increases the morbidity and affects quality of life of the patients as well.

However, though, in the high-risk setting, not only in prophylactic, but also preemptive, at least retrospective number of studies from different institutions and registry data are supporting the use of donor lymphocyte infusion post-transplant. We need to still learn more about the dosing schedule and the frequency of that. And who are the patients who benefit more with that strategy, is that the patients who are intermediate risk disease patients or these adverse risk disease patients benefit as well? We don’t know the answer for that because of the limitation of heterogeneity of what is being reported so far.

But also there we can farther look into strategies that are, not just conventional DLI with lots of various cells, including alpha-beta T-cells that are associated with higher risk of GvHD like our group specifically is exploring doing donor lymphocyte infusion focused on gamma delta T-cells. So freshly collected from the allogeneic donor, the same donor that, patients receive stem cells from. And then we are infusing for purpose of reducing the risk of relapse in adverse risk group of patients by ELN classification and hoping that strategy will be effective but yet need to be determined. We are currently looking into safety data of that and most importantly why gamma delta T-cells because they have MHC independent cytotoxic activity against AML, but more so they don’t cause graft versus host disease. So we can give more products and higher numbers as far as we can successfully expand this.

Once you’ve established safety and you’ve got your dosing schedule right, tell us what the randomized study might look like.

The randomized study should be basically exploring this approach using its consolidative, basically expanded gamma delta T-cell infusion after allogeneic transplantation. And the standard needs to be standard allogeneic transplant without planned intervention per se.

And in this context, give a shout out to my colleague in the UK, Dr Victoria Potter at Kings who has randomized, I think it’s 160 patients to a study called PRO-DLI, which is actually looking at prophylactic DLDI, patients transplanted for high risk AML in CR1. And it involves rapid taper of immunosuppression and prophylactic use of DLI against a more controlled approach. And I hope that study’s gonna be reporting next year.

And what’s the MRD monitoring in that study?

Yeah. No, meticulous MRD monitoring if there’s a molecular marker or with flow.

And then finally, perhaps Mark, if I could just turn back to you, you presented a bit of an update on some of the MORPHO data, which you showed at EHA and you reflected perhaps on two or three lessons that might have been learned or some more general observations. Perhaps you could close with those thoughts.

Sure. It always comes down to azoles. Now, in fact, it’s a very simple answer. You asked, how would we have designed the trial differently? We would’ve said, only give azoles as indicated, because this is a theme emerging with gilteritinib and quizartinib. They have azoles. Mould-active azoles have their uses. you’ve got to use them judiciously with these drugs. You will get significant myelosuppression and toxicity and completely counter any benefit if you use them indiscriminately. And so, I think the lesson from MORPHO broadly is twofold. Give post-transplant gilteritinib to patients who are MRD-positive and use azoles judiciously. And, things can work out just fine.

Great. And we are looking forward to updated data sets. Thank you. Thank you all three. That was a great discussion.

Highlights from experts

Hello, my name is Naval Daver.

I’m a faculty in the Department of Leukemia at the MD Anderson Cancer Center in Houston, Texas. And it’s a pleasure to speak with you all. I have with me Dr Aditi Shastri from the Albert Einstein in New York. And I’ll let Dr Shastri introduce herself.

Thank you, Dr Daver. Hi everyone. I’m Aditi Shastri. I’m a faculty at the Montefiore Einstein Cancer Center in the Bronx, New York. And I’m very excited to be here at the iwAL conference, where we learned many exciting things.

Yeah. So, you know, speaking about the iwAL meeting,

it’s been a very busy, but I think productive agenda and a lot of interesting talks and discussions. So let me ask you, Aditi, what were the things you found most useful or some of the key takeaway messages or points from the iwAL discussions?

Yeah, so that’s actually a great question. So I think the things that were like a big highlight personally for me was to better understand what is the large unmet need that our patients have with acute myeloid leukemia. And a couple of things really stand out. You know, one of course is that despite the fact that we have so many FDA approved novel agents now, and chiefly venetoclax, we still have a high rate of therapy resistance to all these drugs, whether they’re menin inhibitors, venetoclax, and I think as, you know, sort of scientific physician community and various stakeholders, you know, there is a large effort to develop drugs or therapeutics to overcome this sort of therapy resistance.

And then the other thing that’s really a big takeaway for me is that TP53-mutant disease, whether that’s an MDS or AML, is still a large unmet need where I think we need to work together with the various stakeholders to develop better therapeutics.

Yeah, I think that’s great point. Especially TP53, right? I mean, we’ve been trying last few years and couple of molecules that look promising, APR, magrolimab, hopefully maybe still some hope there with magrolimab AML studies reading out soon. But it’s a tough field. I think understanding the biology and the molecular,which we are doing now with a lot of intense effort, In the last four years, will eventually lead to breakthroughs. That’s what happened with FLT3 and menin. So I think, you know, it’s depressing for now, but I think in the next few years we will start making progress. So very exciting area. And then personally, for you Aditi, what are the areas that you’re interested in, your lab is focusing in and clinically that you’re looking forward to investigate?

Yeah, thank you Dr Daver. So as a physician scientist, I have a unique opportunity to develop therapeutics for unmet need and follow them all the way bench to bedside to early phase clinical trials. And we are very focused on really understanding and overcoming venetoclax resistance. As we all know there are multiple mechanisms which are sort of adaptive in a way that patients become resistant to venetoclax and it all converges on one singular mechanism, which is really overactivation of MCL1. So although direct MCL1 inhibitors have floundered in the clinic because of cardiotoxicity, we heard some exciting updates from Dr Wei about developing better MCL1-targeting agents. But personally for us, we have actually been working on targeting on oncogenic transcription factors, STAT3, which correlates with MCL1 activity and downregulation or degradation of STAT3 can also cause loss of MCL1. So we are developing STAT3 targeting drugs, repurposing various drugs, antisense STAT3 inhibitors like danvatirsen and STAT3 degraders. So this for me is a potentially exciting area where I hope we can make a contribution to the clinical need for the AML patients.

Yeah. Well, great. Thank you very much. And hopefully maybe next year we can have you come and present some of the work. And I know the trial will be starting soon, so it’ll be exciting to start generating some data. So with that, thank you very much and hope you enjoy the rest of the meeting and, hopefully we’ll have you back next year at the next iwAL.

Yeah, thank you Dr Daver. It’s always a pleasure to talk to you and it’s been wonderful to be here at this meeting and interact with all our colleagues and friends from across the world and we shared the same agenda, so thank you.

Thank you.