Introduction: Overview — Biopharmacologic Considerations

DR LOVE: Good afternoon, everyone. I'm Neil Love from Research To Practice and welcome back to Year in Review, as today we talk about acute myeloid leukemia and specifically the rapidly evolving role of menin inhibitors in AML. We have a great faculty today: Dr Amir Fathi from the Massachusetts General Hospital in Boston and Dr Eunice Wang from the Roswell Park Comprehensive Cancer Center in Buffalo, New York.

Today we're here to talk about, I think, one of the most exciting developments in oncology, including in AML, a really fascinating form of therapy of menin inhibitors. You should know, too, that as in all of our work, we will be discussing the use of unapproved agents and regimens. So please check out the various package inserts for more information.

As we do in all of our Year in Review series, I met individually with each one of our faculty where we recorded their presentation, about a half an hour presentation, reviewing some of the important papers of past year, including at the ASH meeting. These are in the chat room if you want to check them out. And then we'll be sending out links again to these really great talks.

Here are some of the papers that Eunice went through and also Amir. We're going to really take it to the next level today and talk about what the implications of these data are and also take the opportunity to update you on what's going on in general with AML and where menin inhibitors are fitting in and maybe are going to fit in in the future.

Here's where we're heading today. We're going to start out just talking about some basic biopharmacology and some major issues related to decision-making in the up-front and relapsed setting for AML. Then we'll get into menin inhibitors first, single-agent menin inhibitors. This is what Eunice covered in her talk. We're going to actually take our time and go through differentiation syndrome, which is a big issue with menin inhibitors. And, of course, we've already been dealing with that, going back to APL with ATRA and arsenic, IDH, et cetera. So we'll get more depth into that.

And then we'll get into a topic that Amir covered in his talk, really the future, I think, for these menin inhibitors as we've seen with other targeted therapies, combination approaches. We'll talk about some of the ongoing trials, particularly really exciting Phase III triplet trials up-front.

And finally, if we have time, which I think we will and I hope we will, we want to talk about the PARADIGM trial that Amir presented as a plenary talk at the ASH meeting in December, looking at aza/ven in patients eligible for intensive chemotherapy who are heading towards transplant. One of the most important presentations and datasets I think we've seen in the field of AML and a lot of implications in terms of how people interpret this and how that's going to fit into where menin inhibitors fit in in the up-front situation. So I'm really looking forward to having our faculty discuss this really groundbreaking study.

So I want to just start at a very basic level. I'll start with you, Eunice, and talk about how you think through up-front therapy nowadays in AML. As we talked about, our focus is the general medical oncologist. You see all the cancers we're covering in our weekend and every single one of them it seems like nowadays there's so much going on it's hard to see the forest for the trees.

But maybe we can talk a little bit about how you — you know you're going to see a patient with newly diagnosed AML, how you're thinking about what you're going to do and how you're going to decide on initial therapy, particularly what biomarkers you're going to be looking at, what kind of assay specifically you're going to send and how that's going to fit into your treatment plan. So, Eunice, let's start out with a pretty big topic and we can maybe cut to the basics.

DR WANG: Alright, great. Thanks, Neil. I really appreciate the opportunity. So when I am faced with a new patient with suspected acute myeloid leukemia, the first thing I'm going to do is assess the patient and the disease.

So in terms of the patient, if this person has AML, are they fit for intensive chemotherapy? Now we used to use an age cutoff, but I feel like in this day and age it's a lot of just clinical judgment and shared decision-making. Is this a person that you're going to give intensive 7+3-based therapy for? Are they fit for an intensive regimen? Are they fit for transplant? Or are they older, unfit with comorbidities, not necessarily age-related, that are going to make them not a transplant candidate and not an intensive chemotherapy candidate? And what are their goals in life?

The second thing I'm going to look at is I'm going to look at the disease. I'm going to confirm the diagnosis of acute myeloid leukemia, which is 20% blasts, myeloid lineage by flow or by morphology. And then I'm going to perform what I think is really key in this era is the precision medicine approach, which is looking at the cytogenetics and performing a next-gen sequencing or other myeloid panel to look for mutations. There are a number of mutations which are what we call actionable in this day and age, and they include nucleophosmin 1, NPM1, IDH1, IDH2, FLT3, and for cytogenetic abnormalities, rearrangements in that KMT2A gene.

There are a number of other mutations, what we call secondary mutations or maybe germline predisposition mutations, that are not necessarily the things I get immediately, but are things that likely are included in that panel when I'm making future decisions. So in summary, looking at the patient, what is the patient able to tolerate, intensive, non-intensive, what are their goals of care, transplant, no transplant, supportive care and then doing that complete cytogenetic, morphological, mutational workup to select for some of those targetable options.

DR LOVE: So Amir, with that as a background, obviously now we're looking at a couple of new alterations, KMT2A and NPM1, which, of course, I think everybody's already heard about. Can you talk a little bit about before menin inhibitors came out, how you looked at patients with these 2 genomic abnormalities, both in the up-front and relapsed setting?

DR FATHI: Well, I think NPM1- and KMT2A-rearranged AML are 2 quite different subsets of AML. NPM1-mutated AML in younger patients is generally associated with a more favorable disease trajectory, reason being that these patients in general are quite responsive to chemotherapy and can, in theory, in most circumstances, be cured without transplant, meaning with cycles of high- dose cytarabine chemotherapy, just because of the responsiveness of the disease. Of course, there are variations to that. Sometimes concurrent mutations can affect outcomes in these patients and certain forms of secondary AML or MDS-related AML can also have NPM1 mutations.

But across the board, de novo AML with an NPM1-mutated phenotype, in general, if you're a younger patient, you may be able to be cured just with consolidative chemotherapy. Once the disease comes back in the relapsed form or refractory form, it's much harder, particularly in subsequent lines of treatment. For older patients with NPM1 mutations, it's a little bit more controversial.

The majority of the data that we have with just favorable risk disease and cytarabine consolidation curing patients is with younger patients with higher doses of cytarabine, which you cannot give older patients in consolidation. As a result, many sites still transplant patients who are older but still induction eligible. How about azacitidine or decitabine and venetoclax? Generally speaking, we think that these patients who have NPM1 mutations also respond well to that regimen, but to date, that is not thought to be a curative regimen. Perhaps newer data will change that calculation.

As far as KMT2A-rearranged disease, that's a much uglier disease. I think both Eunice and I probably have had our share over the years of tough cases, patients presenting with very aggressive, hyperproliferative, high white count, extramedullary disease. Many of these patients have secondary AML, meaning therapy-related AML from prior exposure to anthracyclines. The likelihood of remission from intensive chemotherapy, such as 7 and 3 or even CPX-351, is not that low, per se, but the likelihood of relapse is quite high. So these patients have, I think, a much more challenging outcome, and therefore transplant and consolidation is oftentimes recommended.

DR LOVE: So Eunice, let's talk a little bit about menin inhibitors. Sometimes I think there are so many things going on for people to be aware of that we lose the forest for the trees. And I think the mechanism here is absolutely fascinating. This is a slide that you forwarded to us that I want you to talk a little bit about.

But just taking a step back, when we think about systemic therapy that we utilize in oncology, we obviously have cytotoxics. We have ADCs that often are similar to cytotoxics. We have immune therapy, working through immune mechanisms. We have targeted therapy in AML and other parts of oncology, including lung cancer. But we also have a number of agents that act through, actually, the major mechanism being differentiation of the cells, which I think is a fascinating anti-tumor strategy.

Can you talk a little bit about these sketches you have together in terms of how you envision menin inhibitors actually biologically having an anti-tumor effect, both in KMT2A and NPM1, Eunice?

DR WANG: Yeah, so this is a little bit tricky because I feel like we are very simplistically always thinking, okay, you have a receptor, it's mutated, we're going to block it. And that's going to be the way that targeted therapy works. We saw that initially with BCR-ABL, with imatinib. We've seen that with trastuzumab, targeting the aberrant trastuzumab. But I think that the mechanism by which menin inhibitors work is a much more basic level.

We know, for example, in KM2 rearranged, or used to be called mixed leukemia lineage gene rearrangements, that there is a translocation between the KMT2A or the chromosome 11 with another fusion partner that leads to this aberrant complex, right? And this complex encompasses that KMT2 gene or the MLL gene with another gene. And this actually creates a master transcriptome complex. This is a complex that interacts with DNA to upregulate numerous different transcriptome factors. This is at a basic DNA level. And those factors being upregulated are key to transforming a cell from just a normal hematopoietic stem cell to a leukemic stem cell. So those cells grow, they don't differentiate, they are activated, they proliferate and they actually form leukemia cells.

We've tried to target that master transcriptome complex for years by directly targeting and we've not been able to do it. But what happens is menin is a really important factor. It's involved in multiple endocrine neoplasms. So it definitely triggers cancer in solid tumors. And the menin protein interacts with that KM2 rearranged master complex to promote leukemia.

So instead of targeting the complex, we're actually targeting the interaction between menin and that complex. And that's a key interaction. If you block menin binding to that transcriptome and the DNA, then you can downregulate all of those different factors. And that leads the leukemia cells that are stuck in that immature undifferentiated state to progress into differentiation, just like we see with acute promyelocytic leukemia. And then those cells undergo terminal differentiation.

Now it turns out that NPM1 mutant AMLs have very similar transcription factor profiles as KMT2A. And it turns out that the NMP1 mutation leads to biology that is also very dependent on the same genes and transcription factors and that same binding of menin to that KMT2A induced process. So we block menin and NPM1 mutant disease. We also get differentiation. So these are differentiation agents that target the underlying DNA.

DR LOVE: And I might mention that when I meet with the faculty separately, I also spend some time just chatting with them after their talk. And it was very informative when I met with both of you to try to bring me more up to speed on this. And one of the things I realized when I was talking with Eunice, Amir, is I always kind of visualized that by causing differentiation, it was kind of making the cell normal. And correct me if I'm wrong, but what she explained to me was that, yeah, it looks normal, but it still has this genomic abnormality, and actually the cells die. So again, anything you want to add to that? And also, Amir, any thought about using these type of agents outside of AML in other cancers?

DR FATHI: Well, I can answer one of those well and perhaps the other not so well. But the first point of your question related to terminal differentiation and that being a therapeutic approach to treatment is exactly right. There are certain targeted agents that mainly work on differentiation, and these cells differentiate into some terminal form, whether it's a monocyte or a neutrophil or a histiocyte even, and after a period die off, as opposed to a pure cytotoxic effect where you impact cell cycling or other potential DNA damage mechanisms. It's quite different. And the mechanism of response, therefore, is different, and the dynamics or timing of response are different.

So, I mean, we all know of cases where people in the midst of differentiation syndrome, you get a rash, and it's a neutrophilic infiltrate, and all the neutrophils have, let's say, FLT3 mutations or NPM1 mutations, or lung infiltrates have been also assessed and looked at in terms of more mature cells finding FLT3-mutated neutrophils following use of FLT3 inhibitors. So, that's quite intriguing and true. So terminal differentiation as a mechanism of cell death is definitely a part of it.

As far as other diseases, my knowledge, I have to say, is quite limited, but I do know that there are other cancers that are also impacted by this specific overexpression of MEIS1 and HOXA9. And in certain solid tumors, there is interest in potentially looking at menin inhibitors as a therapeutic approach, either as a single agent or in combination. Beyond that, you're going to have to speak to a solid tumor specialist.

DR WANG: Yeah, I think there's data in colorectal cancers, I think in GI cancers.

DR LOVE: Really?

DR WANG: Yeah, they're looking at —

DR FATHI: Or Eunice.

DR WANG: I'm sorry. Sorry, I just wanted to jump in that I have heard that there are menin inhibitor studies being done in GI cancers and there actually is menin inhibitors being studied in diabetes.

DR LOVE: Wow, interesting. So we talked about these 2 alterations, KMT2A and NPM1, but it reminds me a little bit of what we see with PARP inhibitors in solid tumors, where we know patients with BRCA1 and 2 respond, but then there's these LOH scores, where they get a score that seems like it predicts some benefit to treatment. And it looks like maybe these menin inhibitors, Eunice, are actually going to have activity beyond these 2 alterations.

I think this is from an EHA paper looking at NUP98r. And we know for FLT3, there's a lot of interest looking at crizotinib in people actually without FLT3 but a FLT3 signature. So, again, Eunice, can you talk a little bit about how far you think menin might go? Do you think there might be some type of score that we might be looking up someday to try to predict benefit?

DR WANG: Yeah, Neil, that's actually incredibly important. So, yes, we think that these mechanisms are not restricted to just KMT2A or NPM1 mutant, but it may just be the tip of the iceberg. And even in early Phase I studies of ziftomenib, there were a couple patients, I think Dr Fathi had one, of patients who did not have NMP1 or did not have KMT2A, but achieved CR oftentimes for — I think 1 patient had like 30 cycles of therapy.

And when we examine the biology and we look at, just like you said, the transcriptome and the transcription factors or the biology, we found that patients with NUP98 rearrangements, which is a rare entity, again, extremely rare in AML patients, actually in the laboratory responds similarly to KMT2A and NPM1 mutant patients. And here's some data from EHA last year where MD Anderson investigators treated 5 patients with relapsed/refractory NUP98-rearranged leukemias. And 3 of the 5 patients had achieved morphological remission on revumenib monotherapy. And these are patients that had previously been heavily pretreated on other agents.

So the fact that they went on to achieve a response in 3 out of 5 patients’ short duration as monotherapy was proving the principle that other patients with acute leukemias may respond in the laboratory and in the clinic. There's a variety of subtypes that seem to respond to this, even MDS patients and ALL patients, T-ALL patients. There's some preclinical data with that. So there are ongoing clinical trials where there is enrollment of patients that have this MEIS or HOXA9 transcriptome signature on 2 menin inhibitors to see which patients, again, similarly to, like you said, PARP inhibitor therapy or some of these other trials, whether that predicts for sensitivity to this mechanism of action.

DR LOVE: So Amir, anything you want to add to that? And also we're starting to see data now. Here's a paper from ASH just this last December looking at mechanisms of resistance. Can you talk a little bit about your vision of how resistance does develop in the face of a very unusual MOA?

DR FATHI: Yeah, I mean, I think this is an area that's increasingly being explored. The first mechanism of resistance with menin inhibitors that has been best characterized are these MEN1 resistance mutations, sort of mutations, point mutations, impacting the menin protein, altering it so that binding to menin inhibitors can be impacted and therefore the therapeutic effect of the drug is aborted.

And as a result, you have what's a development of secondary resistance. And we have seen, though, that across menin inhibitors, the emergence of MEN1 resistance patterns doesn't appear to be uniform. For example, in our presentations on ziftomenib, there doesn't seem to be the same rate or proportion of patients developing MEN1 resistance alterations, although plenty of patients develop clinical resistance and the duration of response is similarly brief.

So what that ultimately means is that there are likely other, and almost certainly other, mechanisms of resistance. Some of them may be related to KAT6A overexpression, another protein involved in leukemogenesis in these patients. It could be related to other groups of mutations or clones emerging, such as RTK mutations like RAS or even FLT3 mutations, although that is currently still being explored.

And finally, epigenetic and genetic reprogramming, so that the leukemic cell learns to bypass completely the interaction between menin and KMT2A and therefore its disruption with menin inhibitors. So I think it's a field that is very active to try and figure out why exactly the durability of response to menin inhibitors as a monotherapy is so brief and resistance in the clinical setting is so common. And so that's still being explored. So I think it's, hopefully we'll learn more in the coming years.

Menin Inhibitor Monotherapy

DR LOVE: Okay, well, I guess you can say that's a little bit of background. Now we're going to dive into the agents. So we have 2 approved agents here to deal with. So this is not theoretical. There are agents available and ready for use. And so we want to get into that. We'll talk about the 2 that are approved, revumenib and ziftomenib, but 2 others, bleximenib and enzomenib. And we'll talk a little bit about toxicity. We'll get to differentiation syndrome later, but we'll talk a little bit about QTc prolongation.

And Eunice, actually, this is Amir's conclusion slide from the talk he did. And I thought it would be good to actually show it up-front here, because he kind of summarized what we're going to talk about for the rest of the webinar here. First, just some basic issues about these agents, that they're effective, that they're safe in monotherapy, that differentiation syndrome, as we talked about, is very important. But at least in the relapsed setting, as he was alluding to, limited durability response. Then we'll get into what he covered in his talk, which is combinations, whether it's with intensive chemotherapy like 7 + 3 or HMA/venetoclax.

And actually, the potential of all-oral triplet regimen. Amazing, if you think about that. Pretty different from the 7+3 experience. And then some of the new trials that are coming out. So, Eunice, you can see here, we have the 4 agents, or the 2 that are approved, and the 2 that there's a lot of data to talk about. Can you talk a little bit about and we'll use this — I think it might be even more helpful than getting in all the slides that you all covered in your talk, a more global view of what we know in terms of efficacy and tolerability, again, particularly with these 4 agents. Eunice?

DR WANG: So, just starting with revumenib and ziftomenib, these are 2 agents that are both approved menin inhibitors for treatment of relapsed and refractory patients with specific subtypes. So revumenib is approved in relapsed and refractory KMT2A and NPM1 mutant disease. So first approval in revumenib was based on the results of the AUGMENT-101 Phase II study that you're showing here, and you can see this was a heavily pretreated patient population.

Many of these patients, extending all the way down to pediatric patients, had failed all conventional therapy. Many of them had prior transplant. Many of them had up to 7 prior lines of therapy. And you can see the response rate, the CR rate for this was 23%, but about two-thirds of patients did have some clinical benefit from the combination of the drug, whether it be morphological clearing or no count recovery, but the CR/CRi rate was still about 23%, but the feeling was that many of these patients that had achieved responses, even if they didn't achieve count recovery, were MRD-negative in more than half of patients. And you can see that about a number of these patients were able to proceed on to allotransplant.

Now, what were the side effects? Well, revumenib, the dose-limiting toxicity in early phase studies, was QTc prolongation. So you can see that that was something that was definitely an issue in the Phase II study. QTc prolongation was seen in about 30 or 40% of patients, and a certain percentage of those patients had Grade 3 to even Grade 4 events, so this was being found in about 30 to 40% of patients at some level. There is a black box warning with revumenib that if you have a QTc greater than 450, you're not eligible for this trial.

They recommend patients that are on QTc prolonging medications that they can't stop taking also not be considered. Patients getting treated with revumenib have to have baseline EKG, weekly EKGs. There also was an incidence of about 20% of patients, 15, 20% or more, having that differentiation syndrome, which is congruent with what we know is the mechanism of action and an on-target effect of these drugs. Similar data seen in NPM1 mutant relapsed/refractory patients.

Ziftomenib is approved only for patients with relapsed/refractory NPM1 mutant disease. There's no approval for KMT2A. Very similar data, 20, 22, 23% overall response rates. Similar rates of differentiation syndrome occurring in about 20% of patients, many of which not Grade 3 and above. Very little QTc prolongation, probably under 10%, 7 to 8% on the product insert. And both of these drugs having median overall response, overall survivor rates in the range of 4 to 6 months.

So again, based on the fact that these relapsed and refractory patients were heavily pretreated and despite the differentiation syndrome and the QTc prolongation effects, these agents were approved. Because even a response rate of 20 to 25% and overall benefit in 40 to 60% is a vast improvement upon historical response rates of 10 to 12% and overall survival in the 2 to 3 month range. But clearly, that's a pretty low bar, I would have to say, in terms of a benefit and that's why we're looking increasingly at maybe newer generation menin inhibitors, bleximenib and enzomenib.

Enzomenib, which has a slightly different pharmacological, physiochemical structure than the other menin inhibitors that have been investigated out there, tends to be a drug which has been demonstrated to go in, bind menin quickly and then fall off. So it has a shorter half-life but potential for less toxicities.

Differentiation syndrome with enzomenib, about half what we're seeing with revumenib and ziftomenib, and in early studies suggesting and very small numbers of patients having treated with enzomenib in the same sort of situation as the ones in the zifto and the revu studies, suggestion that maybe the overall CR/CRi rates are higher, maybe in the 40%, 50% range, maybe a median overall survival in the 8 to 12-month range as opposed to 4 to 6. So really a little bit of a suggestion of about half the differentiation syndrome and really minimal QTc prolongation with enzomenib.

Bleximenib, been studied primarily in Europe, similar differentiation rate, again a suggestion of at least similar response rates. We're going to have to see as more data accumulates with that. But I would have to say that having the 2 drugs already approved, having another couple drugs, moving into advanced stage studies, we're going to have ideally 4 menin inhibitors, I think, clinically available, one hopes, for treatment of patients in the near future.

DR LOVE: So Amir, this seems to come up all the time in oncology, I guess fortunately, where you have multiple agents in the same class. Breast cancer, we have 3 CDK inhibitors, 4 selective estrogen receptor degraders, and, of course, they're never compared to each other. So we have to make indirect comparison. When you look at it from the 35,000 feet, Amir, do these agents look more similar than different? At this point, I know there's not much data with enzo, but in terms of the other 3, Eunice mentioned the QTc, but in your mind, sort of globally, how do you think through how these are looking comparatively right now?

DR FATHI: Thank you for providing that context, Neil, it helps me out because in truth, it is difficult when you don't have head-to-head data. I will tell you that I have had personal experience with all of these drugs. Ziftomenib, both Eunice and I were on the clinical trials that have developed that drug. We have the bleximenib studies, we've had the bleximenib studies open at my site, as well as the enzomenib studies, and more recently, have used in the last year a decent amount of revumenib in our relapsed/refractory NPM1 and KMT2A-rearranged patients. If I'm being, personally, if I'm, and you'll get a varying opinion from different folks, but if I'm, I think, being honest with myself and being objective, I don't see currently a lot of evidence suggesting that there is a substantial difference in activity across these menin inhibitors.

And certainly in terms of the 2 approved drugs, revumenib and ziftomenib. Ziftomenib didn't really have an opportunity to really fully study, be studied in KMT2A rearranged, but in NPM1-mutated disease, there does not seem to be a significant difference. The signal for QT prolongation is there for revumenib. The issue of drug interactions is there for revumenib. The potential multi-dose, multi-day, multiple times a day dosing as opposed to once-a-day dosing is also a challenge between different menin inhibitors, but those are relatively minor.

I honestly, I think over the course of the last year, I've had maybe 1 patient in whom I've had difficulty giving revumenib because of QT prolongation. Generally, it's a fairly well tolerated drug and it hasn't become, hasn't been an issue. So I think time will tell as these agents will move into the front-line where they will have, in my opinion, the biggest impact, which ones will become the most prominent in use. And I think that will determine it.

DR LOVE: And what we often see in oncology is somebody comes up with a trial that's a combination that hasn't been looked at with another one, even though you think — PD-1 is a good example. Wherever the data is, is what people do. Lung cancer and non-resectable Stage III, the trial with durvalumab looked better than pembro and people use durvalumab. So I would imagine as the trials develop, people will go with what the trials are reporting.

One other thing before you get more into toxicity, Eunice, just a global view. When I was looking at the up-front trials, both originally with, I mean, now with the crizotinib and prior trials with FLT3 midostaurin, I was actually, didn't realize how much, how effective they are in the up-front setting, particularly compared to the relapsed setting. I mean, the hazard rates for FLT3 are pretty impressive. I'm not sure people, or at least I wasn't as aware of it. Do you see that here too? How would you indirectly compare the efficacy that you expect to see with these agents? And we are seeing now, for example, 2 other targeted approaches in AML like FLT3 or IDH, Eunice?

DR WANG: I mean, I think those are very apt comparisons. You remember we have 2 agents approved in the up-front setting, midostaurin and crizotinib. And you remember midostaurin was a complete failure in the relapsed/refractory setting. It led to no CRs. It cleared peripheral blasts. It was a lot of toxicity and yet added to up-front 7 and 3 that is the gold standard for FLT3 inhibitors for years. It was the first new drug approved in 2017 for AML based on that up-front efficacy.

So I think that when you look in the relapsed/refractory setting, gilteritinib, FLT3 inhibitor is approved based on a 30% CR rate and a median survival of 9 versus 4 months. That's not too much different from the response rates with menin inhibitors in the relapsed/refractory setting. And so I would expect, given the success of FLT3 inhibitors in the up-front setting, that we're going to see similar increases.

We've already started to see, as discussed by Amir in his portion of the talk, significant improvements, probably 20 to 30% improvement in overall response rates when adding the drugs to, in the relapsed/refractory setting and a newly diagnosed setting to both ven/aza and 7 + 3. I mean, we're starting to see overall response rates of 80, 90% in the newly diagnosed setting, which is impressive. At least, I think the Beat AML study looking at revumenib, ven and aza initially reported an overall response rate of 100% in KMT2A and NMP1 newly diagnosed older unfit patients.

So I think that, I mean, I think you're right. I think I agree with Dr Fathi as well as many of my colleagues that the money is really going to be in the up-front setting. And like you said, there may not be that much differentiation between the agents because when you block menin, you only get so much activity. Whether you use this drug, that drug, or another drug, you may only max out a monotherapy, a certain efficacy.

Those patients are heavily pretreated. They have different resistance mechanisms. But when you move into the up-front setting, that's really, really going to move the bar in terms of changing the outcomes of AML patients.

DR LOVE: Yeah, I mean, reflecting back when initially the big Phase III trial with midostaurin was reported, and then a year later, I sat down with your colleague, Dan Pollyea from University of Colorado, and he presented a patient who had gotten aza/ven, and that was the first I heard of it. It was like 2018, I think, and then boy, it was on. And I think one of the things was all of a sudden, the general medical oncologist was right in the middle of AML, whereas before, I think it was like, okay, send the patient to a tertiary center for 7 + 3. Otherwise, I mean, really almost palliative care. So it has quickly become an important topic for the general medical oncologist.

Differentiation Syndrome

DR LOVE: And that leads into another thing I wanted to get into, which is differentiation syndrome. It's been out there for a while with APL. But Amir, can you contrast a little bit about the type of differentiation syndrome you see with menin inhibitors in terms of the clinical presentation, how it compares to differentiation syndromes that you see with APL, IDH therapy, even FLT3, I guess, to some extent. What do we see with menin inhibitors comparatively, Amir?

DR FATHI: Well, the differentiation syndrome with menin inhibitors can be quite heterogeneous. It can sometimes mimic what we've seen with ATRA and ATO and APL or IDH inhibitors in IDH-mutated disease, sort of the classic differentiation syndrome of weight gain, dyspnea, hypoxia, unexplained fevers, maybe some adenopathy. That's what we've seen. And although the timing between APL agents and IDH inhibitors may be a little bit different, they look very similar to one another. And they were very responsive to steroids.

And oftentimes, you didn't have to stop the offending agent. You could treat with steroids through it, and the patient would do fine, would do well. That same paradigm doesn't really apply, in my view, to menin inhibitors. Because in some instances, the differentiation syndrome that you see with menin inhibitors, which occur more, in my view, in a quicker timeframe, oftentimes within the first 7 to 10 days, can be much more exciting in a bad way. It can lead to clinical instability. It can lead to coagulation problems, a DIC. It can lead to heart failure.

I've seen heart attacks on certain scenarios. I've seen rapid rise in white count that cannot be controlled with hydroxyurea and sometimes requires chemotherapy or leukapheresis. I've seen rampant rises in platelets that are difficult to control. And simply using steroids sometimes is not enough, but it's an important adjunct still to the treatment. So if you don't recognize differentiation syndrome quickly, and if you don't pause the menin inhibitor, initiate steroids, and do all these additional steps like cytoreduce, manage TLS, manage DIC, the likelihood of a bad outcome, in my view, is much higher than the traditional form of differentiation syndrome.

I am sometimes calling it a differentiation crisis. The other aspect is it can manifest in different ways. It can be a traditional form of DS, as I mentioned, a more oligoproliferative type of DS. But both Eunice and I, I think, were witness to a couple of presentations at a recent meeting. I myself have seen it of HLH with the histiocytes actually showing the KMT2A rearrangements within the bone marrow. How does this happen?

Probably related to either the way that monocytic AML looks with a lot of extramedullary disease and differentiating these cells may lead to worse DS, or it may be related to the endpoint differentiation, what we talked about earlier. Maybe the form of differentiation triggered by menin inhibitors in these diseases is different causing more aggressive manifestation of DS, but quite different and should definitely be monitored very closely for.

DR LOVE: Yeah, I checked out that conference you told me about on differentiation, 2 days of just differentiation syndrome. So here we're talking about it for just a few minutes. Eunice, what about the issue of preventive corticosteroids? Any situation where you would use that? And what do we know in terms of correlation with tumor burden? Do you see less of it if you do a combination, say with 7 + 3 and patient gets, has less tumor bulk?

DR WANG: Yeah, so I think across the board when we look at menin inhibitor monotherapy, the overall percentage of patients that develop some clinical evidence of differentiation syndrome is in the range of 20%, 15 to 20%, maybe 10% with enzomenib. And I think the recognition of the rapidity and the risk factors for menin inhibitor differentiation system is really important.

Tumor burden is extremely important to be cognizant of for, and the rises that we're seeing and the differentiation syndrome we're seeing can start during cycle 1 after only a few days and last all the way into cycle 2. So for patients with white count above 20,000, we really recommend not starting menin inhibitor monotherapy, giving them hydroxyurea, even doses of cytarabine to cytoreduce them.

In patients that have a high proliferative rate or have a high disease burden, I think prophylactic steroids as we do with APL is essential. And then I think the other thing is the recognition of the rapidity of this syndrome. There have been patients that can develop differentiation effects, meaning they can develop a rash or they develop elevated white blood cell count without necessarily developing the actual clinical syndrome.

But the patients that develop the clinical syndrome, as Amir said, can present from anywhere from shortness of breath, DIC, kidney failure to congestive heart failure, pericardial effusions, pleural effusions, heart attacks. So sometimes patients with rapidly rising white blood cell counts on menin inhibitor therapy, some of them need to be hospitalized for closer observation. And if they start to develop more clinical symptoms, they may need intensive care unit monitoring.

Again, it's generally within the first 1 to 2 weeks. I would be very prone if I suspect differentiation syndrome in somebody whose white count is doubling to maybe if they're not on steroids starting steroids, and if they're not improved within 24 hours considering giving some cytotoxic reduction and holding drug.

So there has been a lot of evidence that mitigating the syndrome is really important. Early introduction of steroids or prophylactic steroids can be key. And it typically only occurs with cycle 1 and cycle 2. So I agree with you, prevention, recognition. I think as the trials went on and we all became super hypervigilant for differentiation syndrome, I think it's something that can be easily managed in our groups.

I think that community physicians, can manage this as long as they have some guidelines and recognition is on.

DR LOVE: Yeah, I was just going to say you had sent me this slide here of a case of a patient who got revumenib who had relapsed disease who had differentiation syndrome. Anything you want to say about it? I noticed this patient had a pericardial effusion, but anything you want to say about this case?

DR WANG: Yeah, so I think, again, this highlights a couple of things, just the timeframe, the first cycle, first 10 to 14 days, the rapid rise in white count, the need for steroids as well as cytoreduction to control it. And then you can see less common in cycle 2. And in many of the differentiation in the patients that get treated with menin inhibitors I'm saying, you actually need to wait 2 cycles or longer for there to be achievement of CR.

So I think it's very important that when, particularly when we first started treating patients, we were looking for the bone marrow to be cleared of the blast within 1 cycle as we do in a conventional cytotoxic therapy. But you have to remember that with revumenib and ziftomenib, it could be 2 cycles or longer before you're clearing the blasts because of the differentiation mechanism of action. So that's something else to keep in mind, that not to stop therapy because you develop DS, but to stop therapy if you need to, but to restart the drug and continue it on for the clinical benefit.

DR LOVE: So, Amir, anything else you want to add to this? We'll note too that both of the approved agents do have information in the package insert about differentiations of revumenib. It's a black box warning. But also there's information, a black box warning as well with ziftomenib. Anything you want to add to this, Amir? Is there any correlation between the development of DS and treatment benefit?

DR FATHI: If you ask me to just theorize about it, I would imagine there is because the underlying mechanism of both response and syndrome is differentiation. The challenge is oftentimes the syndrome can be severe, and as a result, it can lead to a pause in treatment, therefore decreasing the likelihood of response or potentially causing the death of the patient in a minority of cases, also obviously impacting the response rate. But if all else is equal and every patient gets through the particular case of DS, I think it is more likely that they will have also a clinical response.

Menin Inhibitor Combination Approaches

DR LOVE: So let's talk a little bit about combination approaches. I think that's where a lot of the excitement is, and I think we've heard a little bit about why. So we're talking about combinations with intensive chemotherapy, but also HMA venetoclax. And we're going to go through a bunch of initial data. Now there's some Phase III trials looking at this important question.

But, Eunice, just a word about the potential for all-oral treatment of AML. We have the oral decitabine out there. I think we saw a paper at ASH looking at that that was pretty convincing. And now we have another oral agent, so you may have an all-oral triplet coming up. Any thoughts about that? Are you using oral decitabine right now outside of clinical trial with venetoclax as up-front treatment of AML, Eunice?

DR WANG: So we haven't outside of a clinical trial. I think most of the insurance companies in our area are not necessarily paying for oral decitabine in place of systemic HMA, but obviously it is something that our patients are increasingly asking for, particularly because those patients getting HMA/ven based therapies are older, unfit, they have difficulty transporting themselves, and they have a, back and forth, and that they think that moving forward, when and if we are able to, I think that that is probably going to be the standard of care. I would like to, however, caution.

So in our area, because of the need for frequent transfusions and tumor lysis and profound cytopenias with cycle 1, we typically give cycle 1 of HMA/ven in the hospital and then follow up with it in the outpatient setting. I think targeted therapies that are also oral offer the opportunity for patients to have increased quality of life, but they still require frequent monitoring and visits to just ensure that they are not developing further infections or cytopenia associated adverse events.

DR LOVE: So Amir, in your talk, you go through now the initial data that we're seeing in combination and now ongoing trials, can you just provide an overview of what some of the issues are? Here we see the KOMET-007  trial that looked at ziftomenib plus 7 + 3. Can you talk about this and some of the other ongoing trials and data that we have right now?

DR FATHI: Sure. I think pretty much all of the menin inhibitors that we have talked about today are undergoing 2 types of combination therapy investigations. One is the combination of the menin inhibitor with a 7 and 3 backbone, which is generally in the newly diagnosed setting, as you can see here in this slide. Most of these in the up-front setting show a very similar rate of composite remission, that top line there of around 90%. Now, whether this is substantially different than what you would see with NPM1, which again is very responsive to treatment, we will have to see from Phase III studies.

But certainly this is quite promising with KMT2A-rearranged patients in whom also you have this very high composite remission rate. In general, I have not personally seen this high a rate of composite remission for KMT2A-rearranged patients, so that is quite promising.

The next combination approach is with azacitidine and venetoclax or HMA and venetoclax currently approved for 75 years or older patients or those with substantial comorbidity preventing intensive chemotherapy. These HMA/ven patients in combination again with menin inhibitors have shown a lot of promise. There have been patients studied in the relapsed/refractory setting initially and now more recently in the newly diagnosed setting. Here is the data you just showed with revumenib that was published in JCO. Here we actually have ziftomenib presented by Gail Roboz at this year's ASH meeting. This was relapsed/refractory data. So in relapsed/refractory patients, there is a range of composite remission rates all the way from 40% to 60%, but in newly diagnosed patients, they again start to hover in that 80% to 90% range.

The other thing I would mention is that when you combine, particularly in a newly diagnosed setting, menin inhibitors with a backbone of either induction or aza/ven in the newly diagnosed setting where you expect responsiveness to treatment, the likelihood of DS goes way down. We have not seen substantial degree of DS. In a relapsed/refractory combination setting, we've seen a few.

Again, not as much as the monotherapy setting. So certainly concurrent treatment seems to decrease the burden of disease that would then be differentiated leading to the syndrome.

Future Directions

DR LOVE: So Eunice, any comment about these Phase III trials that are all getting ramped up? Again, Amir went through these. You have the KOMET-017 trial looking at zifto with aza/ven. We have the EVOLVE trial looking at revumenib with aza/ven. And also an NPM1 Phase III trial with revumenib. And also the cAMeLot study, a Phase III trial as well with bleximenib, again with aza/ven. Any thoughts about these? Are you putting patients on these trials right now, Eunice? Any thoughts about — also we have the HOVON study, also looking at blexi now with intensive chemo. Any comment about these ongoing studies?

DR WANG: Well, they're all very similar, as you can see, going through all these different designs and schemas. They're all essentially combining their menin inhibitor with either cytarabine anthracycline-based therapy. Both the HOVON study and the KOMET-017 study have an additional arm looking at the importance of maintenance therapy with the menin inhibitor on that backbone. And the ven/aza studies are almost identical, which is substitution of different menin inhibitors. I think we all are accruing. I think the question is going to be, are we going to have enough patients for all of these studies?

I think I envision a time coming up where every single patient presenting to an academic center with one of these genetic mutations will go on 1 or 2 of these studies. I think the NPM1 studies are a little bit harder to read out because of the general favorable outcome of NPM1 mutant patients to standard 7+3 backbones. So in order to supersede that with the addition of a menin inhibitor might require either long follow-up, lots of patients, or in one of the studies, I think the KOMET-017, the use of MRD-negative CR as an early time point, as a surrogate for outcomes for these patients. Because otherwise we're going to need to wait years, as you pointed out, for some of these results.

I think for the KMT2A-rearranged patients, we're going to have outcomes sooner, maybe within the next couple of years, showing whether that's beneficial or not. And I think that that is going to be where we stand. But I think it's going to be important as we use these menin inhibitors in the up-front setting also to think about sequencing. We know that there are certain mutations that are associated with specific inhibitors. And so are we going to be at the stage where we're going to sequence different menin inhibitors? I don't know that there's going to be a best menin inhibitor in the up-front setting. I think it's going to be whatever trial you have. But we're going to need to look at subsequent therapies down the line to see whether menin inhibitors are going to be in that setting as well.

DR LOVE: So you've heard the concept of the best option is to participate in clinical trial, but I think here it's really the best option because it's tough for, again, a general medical oncologist to navigate all this. I think it's reassuring to have the patient in a trial so you know they're being managed well.

PARADIGM — Randomized Phase II Trial

DR LOVE: I just want to finish out with a topic we probably could have spent the entire webinar on, but we just have to mention it, which is the plenary presentation that Amir did at the ASH meeting on the PARADIGM trial. We put a bunch of slides in here, both from the discussion from Dr Wei, who had some very interesting background slides, I think, that are worth taking a look at. I'm not going to ask Amir to go through all that. And then we also put a lot of the slides that Amir actually presented there. Also, we added in the classification system so we could clarify that.

But Amir, and of course, we saw the dramatic in this particular group of patients that you're going to clarify, actually better outcomes with aza/ven than intensive chemo in these younger patients. So, Amir, I know you're getting a million questions about this study, but can you capsulize your view of it and what you think a general medical oncologist needs to know about it?

DR FATHI: So this was a multi-center study led by leading academic centers in the United States. It was an investigator-initiated study where we basically sought to determine whether patients who were traditionally induction-eligible, transplant-eligible, could potentially benefit from aza/ven, get to a remission and a transplant without a lot of the challenges that emerge from intensive chemotherapy, such as marrow suppressions, infections, bleeding, long hospitalizations, all of the additional quality of life and emotional impact of the disease.

And the primary endpoint was EFS. We found that aza/ven had displayed an improved event-free survival when compared to induction chemotherapy. Probably not surprisingly, less time in the hospital, less early burden on quality of life and trauma and emotional discomfort, a higher proportion of going to transplant or being bridged to transplant with treatment with aza/ven versus intensive chemotherapy, which was quite interesting and promising, a decreased incidence in terms of number of patients having Grade 3 or higher infectious or bleeding complications.

And we're hopefully going to publish this soon with some additional data on MRD and some additional work. The overall survival wasn't different, but not being a placebo-controlled study, there was substantial crossover. So I think OS is a challenging endpoint to look at.

The important aspect of this trial, though, which I think is important to mention in the 1 minute that I have, is any study is really a description of the patients that were enrolled and eligible on the study, eligible and enrolled for the study. So patients who had FLT3 mutations, because we could not incorporate FLT3 inhibitor into the HMA/ven arm, were not included. Patients with NPM1 mutations, particularly the younger patients who would get cytarabine consolidation for cure, were not included.

Patients with core binding factor in whom gemtuzumab/ozogamicin is approved with intensive chemotherapy, but not with aza/ven we could not randomize that to aza/ven, were not included. So many favorable risk patients were excluded. FLT3-mutated patients, which are the large components of intermediate risk disease, were excluded. This data does not apply to them.

But what it does do is it does provide an entree for what I think Eunice was mentioning earlier of potentially triplet therapies, such as with FLT3 inhibitors, NPM1, I'm sorry, menin inhibitors for NPM1-mutated patients, even IDH inhibitors for IDH-mutated patients to be potentially looked at in younger patients in the future. So I was very happy to be a part of that presentation, and I hope it helps move the field along.

DR LOVE: Yeah, and I think Eunice was saying before, I don't know if you want to close out, Eunice, that docs in practice should not be interpreting that you can just use 7 + 3 in all younger patients. Anything you want to add to that? Also, I know there's some debate about intermediate risk. I don't know if you want to comment on that, Eunice.

DR WANG: Yeah, so, I mean, I think as Amir pointed out, this was not a study that's looking at long-term outcome. This is not a study that's looking at comparing endless aza/ven for older patients. This was specifically targeting younger, fit patients, three-quarters of which had adverse cytogenetic risk who were able to go to an allogeneic stem cell transplantation. The number of intermediate risks, even those that didn't meet all of those criteria that Amir listed, was maybe 13 or 15 patients in each of those different groups.

So I'm a little wary about interpreting this data for intermediate risk, but it definitely gives us now confidence that younger, fit patients with adverse cytogenetic risk or ELN2022 risk categories can safely get aza/ven as an option for up-front therapy as a way to get them to that transplant. So for that, I think that we need to build on that and build on these triplet therapies moving forward.

DR LOVE: So Eunice and Amir, thank you so much. I'm really looking forward to Year in Review: AML 2027. I can't imagine what's going to happen this year, but I know a lot. Audience, thank you for attending. Be safe, stay well and have a great night. Thanks so much, Eunice. Thanks, Amir.

DR WANG: Thank you.

DR FATHI: Thanks so much.