Biology Underlying the Utility of Menin Inhibitors in Acute Leukemias: Use of These Agents as Monotherapy — Eunice S Wang, MD

DR WANG: Hello, thanks for coming to this session “Year in Review: Biology Underlying the Utility of Menin Inhibitors in Acute Leukemias: Use of These Agents as Monotherapy.” My name is Dr Eunice Wang from the Roswell Park Comprehensive Cancer Center Leukemia Service and I'm here today to discuss some of the most up-to-date Year in Review abstracts addressing the biology and utility of menin inhibitors as single-agent therapy for acute leukemias.

So I'd like to start with a study presented last year at EHA that outlines the real-world outcomes for a subset of acute leukemias for which menin inhibitors are now standard of care in the relapsed/refractory setting. In this real-world study, they reported the outcomes of adult patients with KMT2A, formerly known as MLL gene rearranged acute myeloid leukemia and their clinical epidemiologic registry over a number of years from 1996 to 2024.

Many of us will identify KM2 rearrangements in our patients, but don't know what the outcomes are and what we're trying to improve upon with menin inhibitor therapy. As you can see here, they examined their patients that had this KMT2A rearrangement detected by cytogenetics or fluorescence in situ hybridization.

And you can see here that there was 1 subtype of KMT2A rearranged acute leukemias with translocation between chromosomes 9 and 11q23 that had slightly improved outcomes as compared to patients that had KM2 rearrangements involving other gene fusions. In these patients, the median overall survival of all KMT2A patients was about 12.1 months.

And you can see that the outcomes in this particular subgroup of translocation (9;11) was slightly improved over those with other rearrangements with the median overall survival of 17.7 versus 14.7 with other rearrangements. If we recall from the ELN 2022 risk classification of the outcomes of intensive chemotherapy in younger patients with acute myeloid leukemia, the translocation (9;11) actually is considered intermediate risk versus other translocations, which are considered poor risk.

Now, even among these patients, the ability to transition these KM2 rearranged translocation (9;11) patients to an allogeneic stem cell transplantation in first remission was significantly associated with improved overall survival. As you can see, these patients had an overall survival that was not reached as opposed to 34.6 months in those patients who did not proceed on to an allogeneic stem cell transplantation. What are other features that can predict for improved outcomes in this subset?

Well, younger patients also had improved outcomes as opposed to older patients. You can see here on the right-hand side that younger patients, regardless of their rearrangement, had improved outcomes and the best patients were those that had both the translocation (9;11) and a younger age at diagnosis.

Moving on, what are the ways that we can detect other rearrangements or other abnormalities in the KM2 rearranged genes? There is another gene mutation, a KMT2A partial tandem duplication, which can be detected not by karyotype but also by this new technology, whole genome sequencing. In this day and era, we need to identify those subsets of patients potentially eligible for menin inhibitor therapy.

And this was an abstract presented at ASCO 2025 that looked at the ability of various technologies to detect this KMT2A partial tandem duplication, which may be something that is responsive to menin inhibitor therapy. You can see in this particular abstract, they looked at 230 clinical samples from patients with AML, MDS, CML and others, and they tried to identify different technologies to find this KM2 partial tandem duplication. As you can see here, not just karyotypic and/or fluorescence in situ hybridization can be used to detect these gene abnormalities, but whole genome sequencing can be an effective tool.

You can see here on the left-hand side that a number of patients had this detected by the Tempus array, which was potentially with a couple patients missed by conventional next-gen sequencing panel. And so this is something that we need to be considering for our patients, achieving and obtaining the appropriate diagnostic cytogenetic and mutational information to find those patients potentially eligible at the time of relapse.

So what are the results of menin inhibitor monotherapy for patients in the relapsed/refractory setting that have nucleophosmin or NPM1-mutated or KM2 rearranged leukemias? And so this was a paper that I was honored to lead describing a Phase Ib study with a Phase II expansion looking at the efficacy of one approved menin inhibitor, ziftomenib, in one particular patient population, patients with relapsed/refractory NPM1 mutant disease.

In this study, which was a compilation of Phase I dose escalation and expansion, there was a Phase II component, which was addressing for registrational intent whether ziftomenib administered at 600 mg q day achieved preliminary efficacy in a number of patients, here 92 patients, who had NPM1 mutated relapsed/refractory disease. Now we know NPM1 mutated disease is favorable risk in the absence of FLT3 at early diagnosis, but in the relapsed/refractory setting, this NPM1 favorable status is eliminated, and these patients do as poorly in the relapsed/refractory setting as any other patients with relapsed/refractory acute myeloid leukemia.

You can see here that the use of ziftomenib in patients which are heavily pretreated with the median of 2 prior rounds of therapy, including allogeneic stem cell transplantation, was about 33% with 22% of patients achieving a CR with and without hematologic recovery, 14% achieving full count recovery and 8% achieving CR without hematologic recovery. The median time to achieve a response on this study was less than 2 months and the median duration of this response was almost 5 months, 4.6 months and more than half of patients treated with single-agent menin inhibitor therapy in this setting achieved MRD negativity.

As you can see here on the right-hand side, overall this monotherapy was well tolerated. Although adverse events were seen, you can see the most common adverse events were those that we would expect in patients with relapsed/refractory AML, specifically febrile neutropenia, anemia, thrombocytopenia and nonfebrile neutropenia. There was evidence of some GI side effects, diarrhea and nausea.

Of note, the special toxicities of interest that we experienced with menin inhibitors include differentiation syndrome, which occurred here in 25% of patients, as well as QTc prolongation, which was only described in 3% of patients. Differentiation syndrome here was only Grade 3 in about 14 out of these 90 patients and did not achieve, did not result in any deaths on study. It was easily mitigated by protocol-specified steroid and other administration technologies.

Based on this data, we can see here that this drug is extremely promising for these very, very poor outcome patients. In the historical comparison, the overall response rate in this patient population, prior to the advent of menin inhibitors, would be a CR/CRh rate of 12%. You can see here overall survival of these patients treated with ziftomenib was 6.6 months, with responding patients achieving an overall response, overall survival rate of over 15 months versus 3 to 4 months in patients who did not respond to therapy.

And as previously mentioned, the duration of response on this study was 4.6 months. Based on this data, ziftomenib was approved for treatment of these patients with relapsed/refractory NPM1 mutant disease in November 2025 and is now moving forward in additional studies in the combination regimens.

What about the other menin inhibitor, revumenib? Revumenib was approved at the prior year for treatment of patients with KM2 rearranged leukemias and in November 2025 was also approved for the treatment of the same patient population NPM1 mutant relapsed/refractory disease. So what is the response rates of revumenib in these 2 particular biological subsets of acute myeloid leukemia? Well, we have the updated results of the AUGMENT-101 Phase II study of revumenib monotherapy in these 2 biological cohorts. I'd like to first present the results from Aldoss et al from EHA 2025.

Shown here are the inclusion criteria of patients with KM2 rearranged or NPM1 mutant disease. And you can see here the patients received revumenib dosed at the recommended Phase II dose, which is 163 mg twice a day in combination with a strong CYP3A4 inhibitor. Outcomes were CR/CRh and safety with overall outcomes looking again at duration of response and overall survival.

You can see here that here in KM rearranged patients, the overall response rate was 63%, but a similar CR/CRh rate about 23%, achieving either a CR or CRh, and approximately 50 to 60% of these patients achieving a response, again, achieving MRD negativity. Now, again, these were heavily pretreated patients and appeared that the number of prior regimens did not matter that much in terms of response rate.

However, patients who received prior venetoclax seemed to have a slightly decreased response rate as opposed to other patients. Again, the median duration of the CR/CRh rate was a little bit longer, 6.4 months in these KM rearranged patients. Time to first response was about 1 month to 2 months, and about one-third of these responders did proceed on to an allogeneic stem cell transplantation. This AUGMENT-101 study, primarily in KM2 rearranged patients, enrolled younger patients, including patients in the pediatric age group.

As you can see here, these are some of the side effects, very similar to what we saw with the other menin inhibitor with nausea, vomiting, diarrhea, neutropenias. We see, again, about 26% of patients having this differentiation syndrome, with about 17% of them having Grade 3 and above. One key difference between revumenib and ziftomenib was the high incidence of QTc prolongation, which, as you can see here, was reported in 29% of patients with QTc prolongation Grade 3 and above occurring in about 13% of patients. This is something that needs to be monitored closely.

Both revumenib and ziftomenib have the requirement to have baseline QTc measurements with the black box warning for revumenib stating that patients that have an elevated QTc at baseline of over 450 may not be eligible for treatment with this agent. Both agents require weekly EKG monitoring for QTc monitoring.

What are the other side effects? You can see here that in the QTc prolongation that there were patients that had dose interruptions or dose reductions due to the QTc prolongation and that these QTc prolongation effects did occur early on in the initial treatment, and you can see here most of them during cycle 1. However, there were no Grade 4 or 5 QTc prolongation effects. And again, as we saw with ziftomenib, that the protocol mitigation strategies for differentiation syndrome were largely successful in managing these patients.

What about patients with NPM1 mutant disease? These are the same patients that we saw treated with the ziftomenib. Just skipping ahead, the overall response rate again in these patients, 48%, but very similar CR/CRc rates, about 26%, 50 to 60% of patients having MRD negativity. A little bit longer median time to first CR/ChH about 2.8 months, but the median duration of the CR/CRh, again, very similar rates, 4.7 months, and the median overall survival in these patients only about 4.6 months with some patients able to proceed on to allogeneic stem cell transplantation.

In this mostly older patient population, we saw similar rates. Again, QTc prolongation found in over 40% of patients that's seen here, and about 20% of patients having Grade 3 and above QTc syndrome, so certainly something to keep an eye on. The other side effects, including differentiation syndrome, very similar to what we saw, again, in the KM2 rearranged population, with, again, some dose interruptions, some dose discontinuations. But increased monitoring and awareness of differentiation and QTc prolongation definitely needs to be enacted for patients treated with menin inhibitors, particularly this particular agent.

Now, we know that the biology underlying KMT2 rearranged and NPM1 mutant patients responding to menin inhibitors is very complicated, but really relies upon the ability of menin inhibitors to activate and bind to master transcriptome complexes that are underlying the basic leukemogenic mechanism in both of these disease subtypes. Now, when we block the activation ability of the menin protein to activate these transcription factors, then we get differentiation of myeloblasts into more mature differentiated agents, terminal differentiation, apoptosis and cell death.

Now could the mechanism of menin inhibition also be working in other biological subsets of acute leukemia? And this is one study that is presented at ASH that looked at 5 patients that have relapsed/refractory NUP98 rearranged leukemias. Now there's preclinical data suggesting that the leukemia initiating events in this NUP98 rearranged acute leukemias may have similarities to what we see with NPM1 and KM2 rearranged leukemias in terms of the transcription factors that are activated and some of the downstream pathways.

So the hypothesis was that patients that have NUP98 rearrangements, although extremely rare, could also potentially respond. And this was early data presented from EHA looking at 3 of 5 patients with relapsed/refractory 98 rearranged leukemias that actually achieved a morphological remission on single-agent revumenib therapy. You can see here that the duration of these responses were brief in a couple patients, except for the one patient who underwent allogeneic stem cell transplantation. But overall, this drug was relatively well tolerated.

And although these responses were extremely brief, this suggests that there may be a role for menin inhibition in patients that don't have the conventional KM2 rearrangements and NPM1 mutant disease. And there are now ongoing clinical trials, but with revumenib and ziftomenib, looking at other subtypes of acute leukemias, as well as other biological subtypes that lack these specific mutations, to see which particular other biological subsets of acute leukemias might respond to this therapy.

For instance, just as an aside, there was one patient in the ziftomenib dose escalation phase that did not have a KMT2A or an NPM1 mutant disease but achieved an overall remission that lasted over 30 months with ziftomenib monotherapy that, to this day, we cannot explain why that occurred.

What do we see on the horizon next for menin inhibitor monotherapy? Obviously, these agents are approved, but are there newer agents down the pike or newer approaches that we could be looking at? And I think one thing that we were very excited by at the ASH meeting was the advent of a potential newer menin inhibitor, enzomenib, which appears to have some distinct differences from the other menin inhibitors, ziftomenib and revumenib. As you can see here, menin inhibitors are not the same.

And there is, for this particular enzomenib, a different chemical structure, leading to different physiochemical properties, distinct from what we saw with ziftomenib and revumenib, as well as with another first-generation inhibitor, bleximenib. As you can see here, there is a unique amide bond found in this particular compound. And because of this reason, enzomenib was specifically selected for further clinical development based on its ability to interact with tumor cells in unique ways.

This drug goes into cells, blocks the menin inhibition and then exits the cells very rapidly. This accounts for the fact that it is a twice-a-day drug, as opposed to ziftomenib, which is a once-a-day drug. And it also allows it potentially to have biological efficacy with potential for fewer side effects, specifically differentiation and QTc prolongation as opposed to these prior agents.

And we saw here early data in both the KMT2A and in the NPM1 mutant disease that seemed to suggest that this drug was well-tolerated and seemed to have at least similar, if not maybe a little bit improved, response rates as opposed to these other agents. As you can see here in KM2 rearranged, relapsed/refractory leukemia, the overall response rate was 73%, with the CR/CRh rate of 60% and a CR/CRh rate of 40%, which seems to compare favorably to the 23% CR/CRh rate we saw with revumenib and ziftomenib.

In NPM1-mutant disease, dose optimization is still ongoing. But at the 200 to 300 twice-a-day range, we are again seeing CR/CRh rates that approach 40 to 50%, albeit in a very small patient population, with little evidence of significant differentiation syndrome. In these patients, differentiation syndrome was about 10 to 20% and there was no evidence of QTc prolongation reported in any of these individuals.

You can see here that in addition to the initial response rates, some of these responses in the relapsed/refractory setting are very durable, and we are seeing a duration of CR/CRh rate, which in the prior agents was in the range of 4 to 6 months, now at least 5 to 7 to 6 months, and potentially in KM2 rearranged up to 12 months, with about 10 to 30% of patients being able to move on to allogeneic stem cell transplantation. So this drug is currently in dose-finding cohorts now and has been proposed for further expansion into combination regimens moving forward. So we are going to keep an eye out for this agent in the near future to see whether this might be the next best menin inhibitor for further investigation.

Lastly, we know that monotherapy for patients is limited. And so there have been prior studies with revumenib in particular looking at why the response rates to both ziftomenib and revumenib only last in the range of 4 to 6 months. And that is because we believe that these tumor cells rapidly develop resistance.

In one study by Perner and colleagues published in Nature at the same time that the revumenib Phase I results were reported, demonstrating that up to 39% of patients over the course of revumenib monotherapy were developing mutations in the menin gene, which prevented the revumenib from effectively binding and blocking the binding of the menin protein to the KMT2A transcriptome complex. Because of the menin inhibitors' inability to bind and block the menin due to these resistant mutations, these patients quickly relapsed. And this, again, may be one of the primary mechanisms for resistance to these agents.

Subsequent work being done in the laboratory has demonstrated, using CRISPR technology, that each of the current menin inhibitors may be associated with specific menin inhibitor mutations, some of which are menin inhibitor specific and some of which may be conferring resistance across all menin inhibitors currently in clinical development.

And so how are we going to detect down the line which patients are developing which resistance mutations? There is also preclinical data suggesting that for those menin resistant mutations, which are agent specific, switching menin inhibitors or doing sequential menin inhibitor therapy in patients that are potentially not eligible for allogeneic stem cell transplantation may be a valid approach down the line.

And this abstract presented at ASH described a high sensitivity research NGS assay, MSK-ACCESS-MEN1, which included probes to examining all of the known menin inhibitor exons in cell-free DNA for possible testing and use in patients treated with menin inhibitors down the line in order to better identify and potentially predict those patients that are relapsing as well as those patients that might be eligible for alternative therapies.

And you can see here that they identified as an example an emerging MEN1 M3221I mutation in cell-free DNA from a patient with KM2 rearranged acute leukemia who had received 14 cycles of revumenib therapy and had an MRD-negative bone marrow remission. However, although clinically she was transfusion independent without evidence of relapse, this cell-free assay detected at a very early time point that she had a MEN1 mutation and this was subsequently followed by clinical relapse 3 months later with overt detection of the MEN1 mutation using other technologies.

And so this is something that certainly we're going to be looking forward to is trying to determine in our patients using a very convenient assay whether our patients are developing some of these targeted mutations that are going to confer resistance. And this may be something that we're looking increasingly at being able to offer our patients as they move forward. We believe that menin inhibitor therapy is here to stay. It's now part of the standard of care for our relapsed/refractory patients.

As we move patients into these therapies, as we utilize more of these agents and as we move these therapies increasingly in clinical trial now into the up-front and combination therapy understanding the biology of the agents, understanding the mechanisms of resistance and the other biological subtypes that might benefit is going to be crucial to optimizing our use of this targeted therapeutic agents for AML and other acute leukemias in the near future.

Potential Role of Menin Inhibitors as a Component of Combination Therapy — Amir Fathi, MD 

DR FATHI: So thank you very much for having me for this program, Year in Review. I’ve been tasked with going through a series of slides that describe menin inhibitors in combination with standard therapies, many of which have been presented over the course of the last year at major meetings in the United States, as well as in Europe. My name is Amir Fathi. I’m the director of the Leukemia Program at MGB Cancer Institute. I’m also a professor of medicine at Harvard Medical School. So without further delay let me get to the slides.

So this is a slide describing the schema for the KOMET-007 study looking at the combination of ziftomenib, a menin inhibitor, with standard conventional 7+3 induction. It may be useful, before I get into the nitty gritty of this slide, to talk about the development of ziftomenib prior to the initiation of KOMET-007.

As many in the audience may be aware, the first 2 menin inhibitors that were developed and then studied in clinical trials as monotherapy in the relapsed/refractory setting were revumenib and ziftomenib. Revumenib was ultimately assessed in a dose-finding phase, as well as a dose-expansion and a Phase II phase looking at both NPM1 and KMT2A-rearranged AML, the 2 subsets of AML that are thought to be sensitive to menin inhibition. And similarly, ziftomenib in KOMET-001 was studied in a dose-finding, subsequently dose-escalation in Phase II with the focus of the Phase II more just on NPM1-mutated patients.

Those 2 Phase II studies of revumenib and ziftomenib respectively have led to the approval, the registrational approval in the United States, of revumenib in both NPM1-mutated and KMT2A-rearranged AML as monotherapy in the relapsed/refractory setting and for ziftomenib in relapsed/refractory NPM1-mutated AML as monotherapy. They are now standard of care in those settings, and we have them available. There are also multiple other menin inhibitors that we will get to that have also been studied as single agent, including bleximenib, as well as enzomenib. Those are also recently studied as single agents.

What I want to talk about today, starting with ziftomenib, is combination studies basically looking at these menin inhibitors in addition to the current standard of care. One of the standard of care for younger, fit patients is 7+3 induction or induction/intensive induction chemotherapy. The other one is the combination with azacitidine and venetoclax, which we mainly reserve for patients who are older and not thought to be fit for intensive induction chemotherapy. It is currently approved, aza/ven or decitabine/ven, in patients who are either over the age of 75 or otherwise have substantial comorbidity that prevents intensive induction chemotherapy.

So for patients in the United States AML really the approach in the up-front setting is either intensive chemotherapy if you’re younger and fit, in most scenarios that has been the case for decades, perhaps it’s evolving now, but that’s the current standard of care, and aza/ven in patients who are older and not fit for intensive therapy; aza/ven or decitabine/ven, the hypomethylating agents.

So back to our slide. Ziftomenib in addition to 7 + 3 was studied in the KOMET-007 study, which like the monotherapy studies had a dose escalation Phase IA portion followed by a Phase IB portion that looked at the validation of ziftomenib plus 7 + 3 in both KMT2A -rearranged and NPM1-mutated AML. Now, what are the benefits of adding menin inhibitors to intensive chemotherapy or HMA/ven combination in older patients? Well, perhaps there is some degree of synergy. Perhaps we can get higher rates of response. Perhaps we can get lower MRD levels.

And more importantly one of the known class effect adverse events, differentiation syndrome, which can be severe and potentially lethal with menin inhibitors, it’s a mechanism of action of the drug differentiation, which can cause an inflammatory reaction called differentiation syndrome, relatively common in monotherapy, may be ameliorated when added — when the menin inhibitor is added to combination therapies because those combination therapies cytoreduce/decrease the amount of malignant cells that can be differentiated. So we thought perhaps greater efficacy, great synergy and better tolerability because you have less disease and hence less risk for these challenging problems that may arise during therapy.

The primary endpoints here are pretty as expected. Adverse events, DLT designation, rates of initial response and secondary events looking at other response measures and duration of response. For this study 7 + 3 was given as is standard over the first 7 days. On day 8 ziftomenib was administered and given daily and continuously thereafter.

I have a few slides to go through the tolerability, safety and also the potential efficacy of these agents. Here is a table that was presented by Harry Erba at EHA last year looking at ziftomenib in combination with 7 + 3. These are the most common Grade 3 or higher emergent adverse events in 10% or more of all patients studied for this combination. As you can see here, the majority of the toxic events that emerged in both KMT2A-rearranged and NPM1-mutated patients are as expected. They’re predominantly cytopenias, febrile neutropenia, things you will see in general when you treat patients with intensive chemotherapy, as would be expected.

The Grade 3 or higher ziftomenib designated or related adverse events, as designated by the site investigators or the site, are also presented at the lower box here. Twenty-nine patients had Grade 3 or higher ziftomenib-related adverse events, the most common of which are presented here. Again, relatively low in number. And again, it’s sometimes hard in the middle of intensive induction chemotherapy to say this is cytarabine, idarubicin or daunorubicin, the traditional chemo of 7 + 3, or is it the drug? Is it the study drug? For a minority of patients these cytopenias were attributed to ziftomenib.

As I mentioned earlier, DS, or differentiation syndrome, is a big concern with menin inhibitors, at least with monotherapy. In the up-front setting in combination with 7 + 3 only 1 case of DS was seen in the KMT2A-rearranged patients, which goes according to our theory that getting rid of a lot of the bulk of the disease probably decreases the risk of DS.

QT prolongation, a known side effect of revumenib, one of the menin inhibitors, has also been a potential adverse event of interest. This has been relatively rare. In the other menin inhibitors 2 cases were found to be ziftomenib related among the patients.

As far as response, now this has been across the board, at least in newly diagnosed patients, in combination quite promising. As you can see here we have 3 columns, NPM1-mutated patients, KMT2A-rearranged patients and all patients. The composite remission rate, which includes CR, CRh and CRi, is pretty impressively high across the board. I would say it’s very impressively high with KMT2A-rearranged AML, which is a subset of AML in the newly diagnosed setting, which is challenging to get into remission, so an 89% composite remission, 70% — 74% CR rate in that population of patients is impressive. Ninety-three percent of NPM1-mutated patients, also impressive, but generally those patients get into a remission with induction chemotherapy in the up-front setting anyway. Regardless, across the board high rates of composite and complete remission.

And the column there — I’m sorry — the row there that’s suggest MRD negativity is also of interest. You see the majority of patients achieved MRD-negative. It’s important to mention, however, that the MRD negativity is not central. This is local MRD testing using a variety of assays, NGS, PCR, FISH, flow. But they also had some preliminary central testing that they did. Overall so far it seems to suggest concordance. We shall see going forward.

That was ziftomenib. This is data on bleximenib a menin inhibitor, developed by Johnson & Johnson, which is a little bit behind in its development in terms of timing of when all this started. Behind is probably the wrong term, but this is the third menin inhibitor off the block. They’ve done quite well, and I think in many ways they’ve caught up. Here is the interim data that was presented by Hartmut Dohner at ASH a few months ago looking at the combination of 7 + 3 plus their drug bleximenib, and this was in a fewer number of patients; 24 total, 9 with KMT2A, 15 with NPM1. And as you can see, although fewer number, the overall gestalt you get from these bar graphs in terms of overall response and CCR, which is composite complete remission, is very similar, so impressive rates of composite remission and CR. And the majority of these patients, again, being MRD-negative.

So so far it looks impressive, and there doesn’t seem to be a substantial increase in delay of count recovery. You see here 31 days from day 1 to platelet recovery of 50,000 or higher and 30 days for neutrophil count of 500 or higher. This is overall relatively aligned with what you would expect with 7 + 3, which we expect generally count recovery around day 28-30.

Alright. So we talked about induction chemotherapy plus menin inhibitors. Now I’m going to present a few slides that look specifically at menin inhibitors plus HMA hypomethylating agents and venetoclax, the current standard of care for older patients, over age 75, or those who are not thought to be eligible for intensive chemotherapy due to comorbidity or other reasons.

So this was a trial run out of a consortium and led by Josh Zeidner and colleagues looking at azacitidine/venetoclax and revumenib in newly diagnosed NPM1-mutated or KMT2A-rearranged AML. This was published in JCO last year, and this is Table 1, the famous Table 1 of all the clinical trials. It gives you the information.

I just highlight the top part of this, which looks at the age. So this is a relatively young patient population, as you can see, for individuals getting aza/ven. In fact, only 1 of the 9 KMT2A-rearranged patients was age 75 and up, and a minority of NPM1-mutated patients was 75 and up, so it goes to show you, I think in general, the age range for — of HMA and venetoclax might be creeping down, or not creeping up but creeping down, so we are potentially treating patients with HMA/venetoclax who are younger and also these triplets that are emerging in clinical trials. So it’s an interesting datapoint.

The other aspect of this that I just wanted to highlight was obviously the response rates here that we see. The drug was generally well tolerated, but there was some degree of concern, which I will highlight — which I will highlight in a second. But before I do that look at the middle boxes there. You see the composite remission is quite promising, 78% for CR for KMT2A, which is quite impressive for that subgroup of highly resistant disease, 65% for NPM1 and overall 67%. Overall response is further down below, but it’s quite high, 100%, 85%, 88%. Composite remission is 89, 79 and 81%. So looks pretty good. Again, single — this is a single-arm study, it’s not comparative, but compared to what we know for aza/ven it’s higher. And a decent number of patients, it looks like in both cohorts, KMT2A-rearranged and NPM1 at the bottom there, that red box at the bottom, went to transplant.

Now, the swim plot on the right is where I have some degree of concern and a lot of other people that are in this field also have concern because when you give aza/ven or decitabine/ven, these HMA/ven combinations, right off the top you have some degree of concern because this is for older patients, 75 and up, or those with substantial comorbidity who you couldn’t get intensive chemotherapy into, but even with aza/ven you do worry about some degree of marrow suppression. I don’t know, 15 years ago when we gave HMA alone without venetoclax you could start it and have the patient come back in 2 weeks. You check a marrow in 3 months. It’d be a little bit more easy, gradual process.

Aza/ven is not like that. It’s much more marrow suppressive, and we have to be very careful because patients can drop their blood counts and get into trouble with infection and bleeding if they’re not followed closely. It is certainly better tolerated than intensive chemotherapy, but even with this generally outpatient regimen these patients need to be monitored closely in clinic for possible need of transfusions and monitoring for infections.

So when I say that, when you add something to the doublet, to the standard doublet, you always have to worry about increased marrow suppression because you only have a little reserve left. So when I see these little red stars there on that swim plot on the right those are all deaths, and a lot of those deaths are relatively early. It makes you worried about things like infectious complications, bleeding complications, and I think this is something we need to be mindful of when we develop these triplet regimens. Once you add a drug to the backbone of HMA and venetoclax you don’t have much reserve left for the third drug, and it’s ideal that that third drug doesn’t have a marrow suppressive additive or synergistic effect because then potentially patients can get into trouble.

And revumenib in general is pretty well tolerated. It doesn’t have a significant marrow suppressive effect, but all menin inhibitors do to a certain degree, so managing the dosing, managing the duration of venetoclax, which is a big challenge in general — and a lot of physicians that I know are very careful about the duration of venetoclax, they often pause venetoclax, they decrease the duration pretty conservatively over time to make sure that the patients can tolerate it. When we develop clinical trials, we also have to be mindful of this. So this is just 1 example we will go through here.

So we talked about revumenib plus aza/ven in the newly diagnosed setting. Now we’re talking about ziftomenib. Ziftomenib I already mentioned earlier in combination with 7 + 3. This was a study that myself and other colleagues have been involved with combining ziftomenib with ven/aza. This data’s from relapsed/refractory AML patients, so different from newly diagnosed.

And why is it different? Well, relapsed/refractory AML, particularly those patients who have received prior venetoclax, in general is more resistant. So what do you worry about? You worry about more marrow suppression. Patients don’t recover their counts as well. You worry that maybe they don’t get the response rate that you would with newly diagnosed AML. So tolerability and efficacy are already compromised to a certain extent in relapsed/refractory patients. And it does matter, depending on the study that you’re running, what the patient population looks like.

So studying relapsed/refractory AML patients and comparing them from 1 study to the next to the next is fraught with risk and can be highly misleading. One study can have patients with 5 prior lines of treatment median, and another can have 3 and another can have 1. those are going to have highly different responses and tolerability data. So I always caution folks when they look at relapsed/refractory AML data to actually look at the patient population to understand what exactly you’re looking at so you don’t say oh, well this ziftomenib or well this other menin inhibitor had better responses. Be thoughtful about your comparisons.

Having said that, here we have a fairly heavily treated ziftomenib plus aza/ven population of patients. Across the board the Grade 3 or higher emergent adverse events in 10% or higher of patients are provided here. Again, this constellation of adverse events is not something that is unusual in patients treated with aza/ven or HMA/ven.

On the furthest right column there you see the ziftomenib-related adverse events. In general, it looks like the proportion of these patients developing cytopenias was much lower. And again, these are assessed and signed by the investigating physician — the treating physician at the sites.

There was no QT prolongation among these patients. You start to see a little bit of a signal for DS sometimes in relapsed/refractory patients. Why? Because if they’re not responsive to therapy, such as the backbone, the disease may still linger, and as a result of that you may get a little bit of DS, particularly, in my experience, in KMT2A-rearranged patients, who tend to have more challenging differentiation syndrome, at least based on my own personal experience.

How about the responses in relapsed/refractory AML with this triplet combination of zifto and ven/aza? Well, it looks pretty decent. You have a 48% composite remission rate and a 24 for NPM1 and 28% for KMT2A-rearranged. These patients were pretty heavily pretreated, and at the bottom there you see the proportion of responses according to lines of treatment. It shouldn’t be surprising that they go down pretty precipitously in patients who have 1, then 2, then 3 prior lines of treatment. In general, it’s decreasing returns when it comes to repeating rounds of treatment for AML, as with other cancers, but patients who had achieved a response in general the rates of MRD are quite good.

How about newly diagnosed AML? Newly diagnosed AML with ziftomenib plus aza/ven the story is a little bit different, right? So here you see the composite remission rate is 86%. These are patients who have not been previously treated. They’re getting aza/ven and ziftomenib. The complete remission rates very impressive, 73%, composite 86%.

And this is the swim plot. In general, it looks quite good. You see a few circles at the beginning there. Those are the deaths in this particular swim plot. There aren’t that many. I think the median follow up, to be fair here, is quite brief, and I think we have to wait until subsequent updates of this data are presented.

How about another menin inhibitor, bleximenib, in combination with aza/ven? This is data showing tolerability across both relapsed/refractory and newly diagnosed looking specifically at DS and QT. As I mentioned, you start to see some signals in relapsed/refractory patients even with a triplet because if the disease is resistant sometimes you can’t really get hold of the disease before the menin inhibition has an effect. And they had a few patients, one Grade 5 event for example, related to DS. QT signal was not particularly impressive.

How about responses in both newly diagnosed and relapsed/refractory with bleximenib? On the left you see relapsed/refractory. Again, the rates of composite remission are lower compared to newly diagnosed, on the right, as would be expected with prior lines of treatment. Also keep in mind the total Ns at the bottom. This is not a high number of patients. Bleximenib has presented data on fewer patients than some of the other menin inhibitors that have been out a little bit longer, but in general the trends in terms of response are quite similar over time.

They also reported that there is no acquired MEN1 resistance mutations among the relapsed/refractory patients. I would take this with some degree of caution, however, because MEN1 resistance is only 1 type of likely secondary resistance to menin inhibitors. There probably are others that we may not have fully characterized yet. There are some known non-MEN1 resistance patterns of secondary resistance with menin inhibitors that are increasingly known and highlighted.

Enzomenib, a newer kid on the block. This was the data that was presented by Justin Watts at ASH, preliminary combination with aza/ven, mainly in relapsed/refractory patients. They didn’t note any DLTs. There were no treatment-related deaths. Differentiation syndrome occurred in about 10% of these relapsed/refractory patients, none of whom were Grade 3 or higher. QT prolongation was also quite low.

And this is the data on these 26 patients across the board. They also looked at it in combination with azole because CYP3A effects can have an effect on some menin inhibitors. Overall, the response rates seem to be quite promising in terms of objective response and composite response. Similar, again, to some of the other menin inhibitors in this relapsed/refractory setting. So more to come with this menin inhibitor as well.

The last couple of slides. So the way I would like to see the field moving for all patients in general is maybe moving from more intensive, harsh, challenging inpatient intensive therapies to outpatient doublet and triplet regimens for the majority of our patients that are better tolerated, and then maybe to all-oral triplet regimens.

And this was data presented by Guss Issa and colleagues from the MD Anderson, the so-called SAVE trial, which is quite promising data looking at the all-oral combination of revumenib, the menin inhibitor, plus decitabine cedazuridine, the oral decitabine formulation, and venetoclax. They again presented, despite this being an all-oral regimen, similar data to other newly diagnosed triplet menin inhibitor trials. High rates of response, composite remission 81% all patients, NPM1 79. And very impressive KMT2A-rearranged, albeit only in 7 patients, 86%. So this may be the future. All-oral triplet regimens perhaps are here to stay.

So finally, in conclusion, menin inhibitors are emerging. They’re effective, generally safe agents with activity in multiply relapsed/refractory NPM1-mutated and KMT2A-rearranged AML. Differentiation syndrome is a class effect. It requires close vigilance, particularly as monotherapy in the relapsed/refractory setting. In combination, generally, its effects seems to be ameliorated, particularly in the newly diagnosed setting. Regardless, it’s very important to watch for and is addressed generally with steroids and pausing of the study — of the menin inhibitor so that it doesn’t become a problem. There is limited durability of response with monotherapy. I didn’t mention this earlier, but that is one of the challenges. They respond, but they don’t respond for long, often, and it’s across the board with most menin inhibitors.

The promise of combinations. Studies are revealing promise in combination with HMA/ven, as well as induction chemotherapy. High response rates and here promising durability of response. This likely, as I mentioned, mitigates the risk of DS, the combinatorial therapy, and there is this potential over time in the future of all-oral regimens.

There are multiple Phase III studies underway: the KOMET-017 study looking at both induction and aza/ven combinations with ziftomenib; the REVEAL and EVOLVE studies with revumenib, Phase III studies; as well as cAMeLOt with bleximenib as a Phase III study. So I assume a lot of these are going to be emerging with multiple menin inhibitors in years to come. I thank you for your attention.