iwAL 2025 | iwAL 2025 highlights: resistance mechanisms in AML, novel targets, menin inhibitors & more

Harry Erba:
Well, we just finished up the International Workshop on Acute Leukemia 2025 in Washington, DC. It was an amazing three-day symposium where we exchanged ideas among leukemia experts, spoke with the FDA, industry partners were there. A lot got done, a lot of provocative questions were raised and we have our work cut out for us. I’m Harry Erba, Professor of Medicine, Director of the Leukemia Program at Duke University, and I’m here with my colleagues.

Thomas Cluzeau:
Hello, my name is Thomas Cluzeau from Nice University Hospital in France.

Marina Konopleva:
Hi, I’m Marina Konopleva. I’m Director of Leukemia at Montefiore Einstein Cancer Center in New York, Bronx.

Aditi Shastri:
Hi, I’m Aditi Shastri. I’m an associate professor at the Albert Einstein College of Medicine at the Montefiore Medical Center. I’m the Director of the clonal hematopoiesis and MDS clinic.

Harry Erba:
Well, thank you all for joining me for this roundtable discussion. Let me start with you, Marina. We know we have a big problem in patients with aza-venetoclax when it stops working. And, you know, unfortunately, the response rate is only about two-thirds of patients, and most patients at some point will stop responding. Okay. What are some of the mechanisms of resistance, and how might we get around that?

Marina:
Yeah, thank you, Harry. So I’ve been focusing on that ever since the first trials have been conducted, where we identified that patients will be relapsing on trials. And I think largely the mechanisms of resistance are related to two, like, large buckets. I think the most difficult one is p53 mutations that impair apoptotic response. And patients with p53 biallelic inactivation essentially are refractory to ven-based HMA combination, at least delivered in the traditional fashion. The second is activating mutations in the signaling genes, such as FLT3 and RAS. We have reported on RAS not so long ago. We think that they activate downstream antiapoptotic proteins such as MCL1 in stem cells and make the stem cells resistant to therapy. And then there is somewhat unanswered question whether differentiation states such as monostatic subsets of AML per se conveys the resistance. And I think the opinions are somewhat diverse in that set. So I think most of us think the monostatic will not respond well to the therapy. I think that is probably more in the setting of RAS mutation in monocytic disease, and we will be reporting on that shortly. With that said, I present today some data from our center using different schedule of HMA decitabine, what we call metronomic decitabine venetoclax administration, where we deliver very low doses of decitabine and venetoclax once a week only, trying to avoid cytotoxic damage and selection of p53 mutated clone. And with that approach, we can get approximately 60% response in p53 biallelic disease. The responses last about six to nine months, so with a median overall survival of about 11 months, which is numerically better than what has been reported for traditional HMA-ven or with HMA alone. But of course, we don’t have randomized study data. So I think this provides a backbone to build on and perhaps transition patients towards allogeneic sample transplantation.

Harry Erba:
You know, MCL1 has been implicated for a while in resistance, but I haven’t seen any drugs coming forward that inhibit MCL1. Is there… What’s been the problem there?

Marina:
Yeah, I think we’re all familiar with the MCL1 saga, and there are multiple inhibitors have been into clinical development. Unfortunately, all of them seem to have on-target toxicity with the cardiotoxicity, what is the qualified as troponin leak. We don’t really know if that translates in long-term cardiotoxicity, but because of this class effect, essentially all of them were unable to move forward. So to my knowledge, we don’t have any MCL1 inhibitor that right now is in clinical trial. It was presented here that there is MCL1 ADC that is ongoing. I haven’t seen the data presented, so I think the idea is to more targeted delivery of MCL1 inhibitor towards AML blasts. I think that hopefully will pan out, but the traditional inhibitors, unfortunately, probably have very narrow therapeutic window, which I think we were just lucky with venetoclax because it’s quite a safe drug except for myelosuppression. And although there were some preclinical data that MCL1 inhibition will be cardiotoxic, it was not expected until we went into clinical trials.

Harry Erba:
Great. Thomas, many of our patients are now getting HMA with venetoclax, the older unfit. There’s a lot of interest in thinking about moving that regimen forward into younger patients, especially patients who have adverse risk genomics. And so a lot of our patients are going to have seen azacitidine or decitabine with venetoclax, and then relapse. And we’ve seen a number of studies where other drugs, ADCs, targeted therapies, have been added on. I’d like you to comment on whether you think these drugs should be added on, or do you think they should be used in combination or be used alone at the time of relapse?

Thomas Cluzeau:
So this is a great question. So today, I guess, yeah, we could stratify the patient, patient receiving intensive chemo in first line and patient receiving azacitidine plus venetoclax. And I totally agree with you. A lot of patient receiving azacitidine plus venetoclax and outside of the approval. So younger patient, adverse AML. And at the time of relapse, the patient had already receiving Azacitidine plus Venetoclax. So today there is two strategies at relapse. So if the patient did not receive Azacitidine plus Venetoclax, of course, maybe we could propose a combination with Azacitidine plus Venetoclax plus another drug depending on the genotype of the patient. So IDH1 inhibitor, IDH2 inhibitor, FLT3 inhibitor or ADC. But for the patients relapsing after azacitidine plus Venetoclax, this is something to explore. But we could maybe add a new drug because as we know, Venetoclax could be… add something. Venetoclax had a synergistic effect with a lot of drugs. So maybe we could have an impact even if the patient receiving B4 has acitidine plus venetoclax. But to analyze the data, we need to very well stratify the patients, depending on the first treatment the patient receives, to be sure we could very well analyze the data. And the second point is when we add a new treatment in combination with azacitidine plus venetoclax, we could have a limit of toxicity very quick because as we know, there is a lot of hematological toxicity with azacitidine plus venetoclax. And when we add some drug, of course, we could increase the impact of hematological toxicity. And maybe there is also something to think about the reduction of the venetoclax at the time of the relapse when we try to combine in the triplets.

Harry Erba:
Okay. Thank you. Dr. Shastri, as was pointed out in the session, I’ve been around for a while. That was Andrew Wei saying I’ve been around for a while. And, you know, we’ve known about the leukemic stem cell, and there have been attempts at targeting the leukemic stem cell by finding some antigen that’s specific for the leukemic stem cell and then targeting that with an antibody or what have you. Is there some other pathway in the leukemic stem cell that might be more amenable to targeting?

Aditi Shastri:
Yes, I think that’s a great question, Dr. Erba, and you’re absolutely right. You know, I think over the decades, we’ve seen descriptions of multiple different antigens that could be more selectively overexpressed in leukemic stem cells. But unfortunately, a lot of development of some of these agents have been hampered by the fact that there could be, yes, some selectively increased expression in leukemic stem cells, but normal stem cells express these antigens as well. And so if we were to imagine a therapy that is knocking them out, you know, say targeting CD123, you know, some of these other targets, we do expect some toxicity towards normal hematopoietic stem cells as well, which unless we build in some kind of mitigation strategy for that, it becomes difficult to take these treatments further into clinic. I think with the advent of the fact that, you know, we’re doing more sequencing now, we understand fusions and other things, we understand downstream, you know, transcription factors and things better, I think this gives us more opportunity to also target intracellular factors, like transcription factors in the cells that could be more specifically overexpressed in leukemic stem cells. There are better drug delivery, you know, to the stem cells that can be, you know, taken in intracellularly as well and applied. So I think that this is definitely an advance, like having better drug delivery to intracellular targets in leukemic stem cells. The other thing that I think really was my takeaway from iwAL is, you know, we always talk about early stage disease or precursor disease having increased inflammation, you know, like inflammation being a marker or a target that could potentially be targeted. But from some of the data that was presented here, you know, throughout the meeting, what I can see is inflammation is a viable target even later in the disease state, you know? And so these anti-inflammatory therapies in combination with say, aza-ven or other backbones, you know, definitely have a future in really targeting leukemic stem cells. Sequencing some of these therapies, you know, post-chemotherapy as more targeting MRD, you know, could also be a very interesting strategy that we could take forward into the clinic.

Harry Erba:
Maybe for the last question to address to the entire panel, I’ll ask you each for maybe to point out one issue that we’re having with the following clinical trials. And I’ll try to follow up at the end with anything that I see left over from each of your comments. As we all know and heard at this meeting, there are a number of menin inhibitors that are being developed that are targeting NPM1 and KMT2A rearrangements. Let me focus on the NPM1. And as you know, these drugs have been tested in the relapsed/refractory setting as single agents. They have some modest activity as single agents. And they all have different pharmacokinetic profiles, dosing strategies, drug-drug interactions. But at the end of the day, we’re going to have a number of them. And to move these forward, they are going to be combined with 7 and 3 in randomized clinical trials. And so just with that as an introduction, I’d like each of you to comment on what you see as some of the challenges in developing a menin inhibitor in combination with 7 and 3 in these randomized trials. And I’ll start at the end and we’ll come back this way. Dr. Shastri?

Aditi Shastri:
Yes, thank you, Dr. Erba. That’s actually a very relevant question, especially in this time when we’re launching into so many combination studies of menin inhibitors with chemotherapies up front in the relapsed setting. The one thing that was my big takeaway from the discussion with our leukemia colleagues is that although there is a differentiation syndrome, which is kind of described well on paper, managing it in reality can be quite challenging. There are differences from a lot of the ideas of how we manage this differentiation syndrome is extrapolated from our experience with other drugs, like, for example, drugs like arsenic, Atra. And this may not exactly be the same with our menin inhibitors. So now that some of this is teased out, though, I think we’ll have to see how this plays out when we combine it with chemotherapy. And especially if we’re looking to really use these treatments outside of large academic centers, you know, then side effect profile needs to be very well teased out.

Harry Erba:
So I love that comment. The handling of differentiation syndrome is really important. Recognizing it can be challenging in the relapsed/refractory setting, since most patients will not have a response. When you see a leukocytosis and fevers and pulmonary infiltrates and hypoxia, it could be differentiation syndrome or it could be progression. Here, where we’re giving it with intensive chemotherapy, at least we’re doing something to control the disease. So far in those phase one studies, we’ve seen less differentiation syndrome. But as one of the investigators, I’ve also seen what I would call form frust of the differentiation syndrome, where a patient may have just a low-grade fever and none of the other features. And it’s clear by looking at the peripheral blood, ultimately, that that’s due to differentiation. But handling differentiation syndrome as these drugs are put out there into the community, I think is something that’s going to require some education. Marina?

Marina Konopleva:
I think the major issue with the front-line chemotherapy plus menin in NPM1 specifically, is that NPM1 in general is chemo-sensitive disease. We have so many already clinical options to control that. obviously… has been shown to be highly efficacious in British studies. But also when you look at the data of 7 plus 3 plus venetoclax, the responses in NPM1 mutated AML are amazing. And these are the patients who don’t even need to undergo stem cell transplantation. So the challenge I see that with the design of 7 plus 3 plus main trials is that the control arm is 7 plus 3, which of course is a standard of care right now in the US. And by the time of the trial, we’ll probably show that 7 plus 3 plus menin will be perhaps superior to 7 plus 3. With that said, in parallel, we have trials ongoing 7 plus 3 plus ven versus 7 plus 3. And so, like, how do we decide at the end of that? And I’m confident that that will show that because we have already data from a single-center trial that NPM1 mutated will be long-living patients and who don’t need even further transplantation. So how would we decide based on the separate trials that actually Menin plus chemo will be superior to ve n plus chemo? And I frankly don’t know the answer to that. Perhaps there are some subsets of NPM1 co-mutated disease that could be more sensitive to Menin versus Venetoclax alone. Hopefully we’ll be able to tease it out based on the post-trial analysis of subsets. But I think that will be kind of our major challenge thinking forward. With that said, I think having multiple options is not a bad thing, and hopefully we’ll find the answer, you know, a few years from now.

Harry Erba:
Yeah, I completely agree with those comments. You know, we heard from Courtney DiNardo the work done at MD Anderson with FLAG-IDA with venetoclax, and in that subset of patients with ELN 2022 favorable risk, excluding the core binding factors, very, very high response rates, deep remissions, and an 80% survival. And what’s critically important that she said in the meeting is that this is with just two cycles of chemotherapy, that regimen, and most patients don’t go on to transplant, and they’re doing so well. So the bar is set very high with venetoclax, and as you pointed out, the United Kingdom study of 7 and 3 with GO, also setting the bar. So you’re right. At the end of the day, we’ll have this phase three study, and the disclaimer would be, but maybe a different chemotherapy regimen would have done just as well. To quote Hagop Kantarjian, and I hope I do it well, Hagop, I remember saying at one of these meetings once, just get the drug approved and then give it to the investigators, and we’ll figure out how to use it. And I completely agree with that. This may be a way of getting the drug approved. Hopefully, it will show a benefit without added toxicity when given with 7 and 3. But then we could have some fun in exploring other options of how to give this drug with other regimens or in sequence with other regimens. Thomas?

Thomas Cluzeau:
So it’s difficult to add something, but I totally agree. the challenge is to improve the outcome of the NPM1 mutated AML, but today this is a very chemosensitive disease. So maybe, yes, we have to focus on the specific subgroup with maybe… Yeah, like FLT3 maybe. FLt3, DNMT2A. Maybe there is a subset. This is the subset where we need to undergo to allow stem cell transplantation for the majority of patients. So maybe this is in this specific subgroup of NPM1 we could add something. I’m not sure maybe in the NPM1 very chemo sensitive we could increase the response rate because today we are close to 90% only with the chemo but maybe we could increase the overall survival at the end because we will not transplant a specific other subgroup as the DNMT3A or maybe FLT3. I don’t know.

Harry Erba:
Well, you’ve made it very hard to find one last thing, but it has been something that I’ve been concerned about, and that is the biology of NPM1 mutated disease. It is not just one disease. It’s not like core binding factor leukemias or acute promyelocytic leukemia where you have a specific driver and you have a regimen that is very effective for that driver and the outcomes are very good. Here with NPM1, it does define leukemia. But in my practice at least, and in some of the literature, it clearly depends on what other genomic changes are there. Now we know that, for example, in ELN 2022, NPM1 is considered favorable risk unless you have adverse risk complex karyotype. And the data has been kind of mixed on those secondary MDS-type mutations and how they impact on the prognosis of MDS. And so I think unless we’re very careful about how we select these patients, okay, menin inhibitor may be the best thing you can do for a patient who does not have this MDS-related genotype. But as Marina said, we have GO, we have venetoclax, so do we really need it there? On the other hand, in this population of patients who have spliceosome mutations, chromatin modifiers, and an MDS-like phenotype, and then they pop up an NPM1-positive clone, does it really matter in the long term that we’re able to suppress that clone when you have the basic biology left behind? But it’s exciting to have these drugs. We’ll see how it all plays out. We have a lot of work ahead of us. And it’s only possible to do this by having these international discussions about, you know, how all of these agents should be tested, how they get approved, and how we interact with our transplant colleagues. We heard for a lot of our patients, and it’s an important message, outside of favorable risk AML, transplant has to be strongly considered for every patient that we get into over remission. And we debated about P53. We couldn’t come up with a clear answer for the world. Europe does it one way. The United States might do it a different way. Hopefully we can harmonize this across the globe.

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