Few targeted therapies are available for the treatment of acute myeloid leukemia (AML). Menin inhibitors constitute a new class of agents that target the underlying biology of NPM1-mutant and KMT2A-rearranged acute leukemia by disrupting the interactions between the KMT2A and menin proteins, which forces leukemia cells to differentiate into normal cells. Preclinical studies and early clinical trials of menin inhibitors in the treatment of AML have shown strong results.
This edition of “Drawing First Blood” highlights a recent ASH Clinical News webinar moderated by Mikkael Sekeres, MD, MS, chief of the Division of Hematology at the Sylvester Cancer Center at the University of Miami, on the use of menin inhibitors in the treatment of AML.
During the webinar, Eytan Stein, MD, chief of Leukemia Service for Memorial Sloan Kettering Cancer Center in New York, and Laura Michaelis, MD, division chief of hematology and oncology at the Medical College of Wisconsin, discussed some of the questions surrounding the development and use of menin inhibitors and what questions remain to be answered.
Mikkael Sekeres, MD, MS Eytan Stein, MD Laura Michaelis, MD
Mikkael Sekeres, MD, MS: What are menin inhibitors, and how do they work?
Eytan Stein, MD: That is an easy question with a tough explanation. We have known for some time now that AML is one phenotype but with many different molecular and genetic alterations. For example, there are targeted therapies for AML with IDH or FLT3 mutations that are already available in clinical practice.
Menin inhibitors block that interaction between a protein called menin and the KMT2A complex — previously known as the MLL complex. Two subtypes of AML seem to be particularly dependent on the interaction between menin and the KMT2A complex: AML with KMT2A rearrangements, which occur in 5% to 10% of patients with AML, and AML with NPM1 mutations, which occur in about 30% of patients with AML.
Laura Michaelis, MD: One thing that is important to remember is that we think this scaffold protein is part of a differentiation block. Preclinically, one of the bigger concerns with menin inhibitors was differentiation syndrome. This has prompted most of the clinical trials to provide guidance and preventive interventions for potential differentiation syndrome.
Dr. Sekeres: What types of patients are more likely to have NPM1-mutant and KMT2A-rearranged AML?
Dr. Michaelis: The block of patients with KMT2A rearrangements is one that has historically been a high-risk group. High-risk groups often achieve remission but have a high risk for relapse, and depending on which rearrangements we are looking at, there is a hierarchy of likelihood of relapse.
NPM1 mutation is something we see more of with normal karyotype. If your patient has a normal karyotype, then the likelihood of NPM1-mutant AML goes up. If you are looking at all-comers with AML, 25% to 30% might be NPM1-mutated. If you look at subtypes of normal karyotype, the likelihood may be higher.
Dr. Stein: I am suspicious of KMT2A if a patient has received prior cytotoxic chemotherapy for some other tumors, usually breast cancer or lymphoma … especially if that patient has monocytic leukemia. There are also patients who develop de novo KMT2A mutations. NPM1 is harder. It tends to occur in younger patients, but white count is variable depending on concurrent FLT3 mutations.
Dr. Sekeres: Can you walk us through a bit of the history of the development of menin inhibitors?
Dr. Stein: The excitement related to menin inhibitors started almost two decades ago. Scientists were trying to solve how to improve outcomes of all patients with KMT2A rearrangements. This was especially true for pediatricians who treated a specific subtype of acute lymphoblastic leukemia (ALL) that occurs in infants who have very poor outcomes. This led to elegant basic research to discover the components of KMT2A complex that were required for leukemogenesis.
Early research showed that menin was somehow involved with promoting leukemia in KMT2A-rearranged disease, but researchers didn’t yet understand how that worked. Using a variety of genetic methods, they were able to disrupt this menin-KMT2A interaction in mice, and their survival was much better than what you would normally see. The mice appeared to be cured.
Dr. Michaelis: The first phase I study of a menin inhibitor was presented at the [American Society of Hematology (ASH)] meeting in 2023.1 It was a first-in-human study with the agent initially studied for safety and efficacy with dose ramp-up. From there it is now in phase II expansion, and a number of other menin inhibitors are being studied in clinical trials.
Dr. Stein: There were two compounds neck and neck to get into clinic. One is a compound now known as ziftomenib, and the other is revumenib. The revumenib study, AUGMENT-101, was published in 2023 and included two cohorts of patients: those patients who did and did not receive CYP3A4 inhibitors.2 Revumenib is a substrate of CYP3A4. Initial results were reported in 2022, with a dose found for both cohorts. It then moved into a phase II pivotal study and is now sitting in front of the [U.S. Food and Drug Administration] and undergoing review.
Dr. Michaelis: AUGMENT-101 included patients with relapsed or refractory (R/R) acute leukemias, including a cohort with KMT2A-rearranged AML. Patients could have had up to three lines of prior therapy. The complete remission (CR) + CR with partial hematologic recovery (CR/CRh) rate was about 25%, and toxicities were considered manageable.2
Dr. Stein: Data on a few other menin inhibitors were also presented at the 2024 [meeting of the European Hematology Association]. What is interesting about all the drugs is that the overall response rate seems to be about the same, about 60%, while the rate of CR/CRh is around 25%. The difference between the drugs seems to primarily be with toxicity. For example, revumenib can cause QT prolongation.
Dr. Sekeres: Which patients are eligible for menin inhibitors based on the clinical trial criteria?
Dr. Stein: If a patient has primary refractory AML with two rounds of induction without response, then they would be eligible for a menin inhibitor.
Dr. Sekeres: If you were talking to a patient, how would you explain the likelihood of response to a menin inhibitor?
Dr. Stein: For a patient eligible for allogeneic stem cell transplant (alloSCT), I tell them that we are trying to clear the blasts from their bone marrow. What typically happens with this class of drugs is that the blasts go away first, and then, ever so slowly, the blood counts improve. However, because the durability of response (DOR) is relatively short, once we get that blast clearance and no evidence of measurable disease, we want to get to transplant as soon as possible.
I also explain that CR/CRh is 25%. If they’re not eligible for transplant, we are really trying to get them to CR/CRh because those patients seem to have longer DOR than those with a lesser category of response.
Dr. Michaelis: I agree with Dr. Stein here. I also see this as a way to get to transplant with either blast clearance or, even better, getting them to CR/CRh. For those who did get a response, it wasn’t long, maybe six-and-a-half months. In the AUGMENT-101 trial, it did allow people to get to transplant. The lack of DOR speaks to the fact that in monotherapy arms we have seen resistance develop, and those resistance mechanisms may speak to the fact that menin inhibitors are not best used as a monotherapy. That is why the drug is being tested in combinations as well.
Dr. Sekeres: Are you alluding to a future where menin inhibitors are not given as a monotherapy but in combination?
Dr. Michaelis: There are a lot of combination trials open or in the works right now looking at menin inhibitors.3,4 For example, menin inhibitors in combination with cytotoxic induction therapy like the traditional 7+3 or in combination with the BCL2 inhibitor venetoclax either alone or plus hypomethylating agents. There are also studies looking at these combinations with traditional salvage cytotoxic therapy.
It’s also interesting to think about the potential for the investigation of these agents when disease burden is low. For example, there’s evidence that some of the resistance to BCL2 inhibitors might be through alterations in the KMT2A scaffold, so something like this could be used as a chaser for the BCL2-type backbone to get rid of potential resistance. Another possible avenue of investigation is to study whether menin inhibitors could be effective as remission maintenance after alloSCT.
Dr. Stein: I should warn people not to get too caught up in the hype. In the future, we could see data presented at ASH or at corporate presentations combining a menin inhibitor with 7+3, and it will look like response rates are 100%. We need to understand which specific patients are on each study and what genetic abnormalities are there. There are subtypes of KMT2A that often go into remissions. In addition to CR/CRh, we also need to look at longer-term endpoints like relapse rates, DOR, and, ultimately, overall survival.
Similarly, if these drugs are approved, there is going to be a desire to use them in non-approved settings. We have to be humble and remember that what we think is going to be the truth might not be the truth. We could do harm giving menin inhibitors in non-approved settings. We have to wait for randomized studies to provide benefit.
Dr. Michaelis: I 100% agree. It is exciting to think about new drugs, but all the data are from non-comparative studies. We need to do the randomization.
Dr. Sekeres: We tend to focus a lot on response rates, but part of the conversation has to include toxicities. How do you address these with patients?
Dr. Stein: Revumenib is the menin inhibitor currently under FDA review. If this drug is approved, I would discuss QTc prolongation with the patient because that is a real toxicity. I will also spend time on recognizing differentiation syndrome. When dealing with other drugs that cause differentiation syndrome, patients are reluctant to call me and say they are short of breath, and sometimes I don’t hear about it until it’s an emergency. They must call at the first hint of something going wrong.
Dr. Michaelis: I also ask patients to pay attention to rash. If someone is outpatient, they are taking their temperature twice a day and have calls with a nurse or nurse practitioner every other day just to check in. I also advise not to take other medicines without discussing it with me first.
Dr. Sekeres: Finally, what other developments in the treatment of AML are you most excited about?
Dr. Stein: I’m most excited about menin inhibitors! I think they are going to follow the path of FLT3 and IDH inhibitors. Hopefully they will soon have an approval in the R/R setting and get into trials with standard-of-care agents in the newly diagnosed setting. I know it’s not a popular position, but I’m also excited about [chimeric antigen receptor] T-cell therapy in AML. Newer generations seemed to do a good job of clearing blasts from patients’ marrow, and those patients subsequently underwent stem cell transplant. The technology excites me.
Dr. Michaelis: I’ve been working with MYELOMATCH, a series of studies that will randomize both younger and potentially even older patients to intensive versus non-intensive induction regimens with [measurable residual disease] outcomes. I’m excited about the potential for being able to deploy very rapid genetic and cytogenetic testing so physicians can get more answers for patients within three to four days.
I’m also hopeful that we have moved in a direction where we are working on how we deliver care, so we understand the best ways to get people through some of these induction regimens to keep them safe and keep infection risk down. I hope we can roll out some standard operating practices for these new agents in a way that makes it possible for everybody to achieve benefit, not just those patients treated where we have a lot of experience doing it.
References
- Jabbour E, Searle E, Abdu-Hay M, et al. A first-in-human phase 1 study of the menin-KMT2A (MLL1) inhibitor JNJ-75276617 in adult patients with relapsed/refractory acute leukemia harboring KMT2A or NPM1 Abstract 57. Presented at the 65th American Society of Hematology Annual Meeting & Exposition; December 9, 2023; San Diego, California.
- Aldoss I, Issa GC, Thirman M, et al. Revumenib monotherapy in patients with relapsed/refractory KMT2Ar acute leukemias: efficacy and safety results from the Augment-101 phase 1/2 study. Abstract 2907. Presented at the 65th American Society of Hematology Annual Meeting & Exposition; December 10, 2023; San Diego, California.
- Wei AH, Searle E, Aldoss I, et al. Phase 1B study of the menin-KMT2A inhibitor JNJ-75276617 in combination with venetoclax and azacitidine in relapsed/refractory acute myeloid leukemia with alterations in KMT2A or NPM1. Abstract S133. Presented at the 2024 European Hematology Association (EHA) Congress; June 14, 2024; Madrid, Spain.
- Zeidner J, Lin TL, Welkie R, et al. Phase 1b study of azacitidine, venetoclax and revumenib in newly diagnosed older adults with NPM1 mutated or KMT2A rearranged AML: interim results of dose escalation from the BEATAML consortium. Abstract S134. Presented at the 2024 European Hematology Association (EHA) Congress; June 14, 2024; Madrid, Spain.
Disclaimer: The statements made by the participants do not necessarily reflect the opinions or stance of the American Society of Hematology. This interview has been edited for length and clarity.
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