Karen Titus
June 2026—In the cat-and-mouse maneuverings that often propel new cancer treatments, menin inhibitors are proving to be successful epigenetic therapies for acute leukemia. Last November brought FDA approval of revumenib for treatment of adults and children (one year and older) with relapsed or refractory acute myeloid leukemia with NPM1 gene mutations. That same month ziftomenib, another menin inhibitor, was approved for adults with relapsed/refractory AML with NPM1 mutations with no alternative treatment option. A year earlier, revumenib received approval for monotherapy of relapsed/refractory acute leukemia with KMT2A rearrangements.
“Even though there are different genotypes that drive these leukemias, they all converge on the fact that there is HOX upregulation in these leukemias, and they all could potentially respond to menin inhibitors,” says Dr. Loghavi, who is a member of the CAP Hematopathology Committee.
Menin inhibitors disrupt the KMT2A-menin interaction that drives leukemogenesis in these genotypes, Dr. Loghavi explains, effectively releasing the differentiation block and allowing malignant cells to mature rather than proliferate.
The genotypes broadly implicated and known to be sensitive to menin inhibitors, by order of frequency in AML, are NPM1 mutations (NPM1mt), KMT2A rearrangements (KMT2Ar), and NUP98 rearrangements (NUP98r). “There’s a large difference in the frequency of these,” says Dr. Loghavi. NPM1 is present in about 30 percent of AML and about 50 percent of diploid karyotype AML, she says; KMT2A is present in about five to 10 percent of cases, and NUP98 is present in two to three percent of cases.
“So these are the genotypes we’re really interested in,” she says.
At MD Anderson, Dr. Loghavi says, “Our upfront workup for the diagnosis of acute myeloid leukemia includes several complementary ways of looking for different genotypic drivers.” One is next-generation sequencing, which enables them to identify NPM1 mutations. The comprehensive workup also includes various ways of looking for chromosomal rearrangements and abnormalities (for example, KMT2A and NUP98 rearrangements), including karyotype, FISH, RNA sequencing, and optical genome mapping.
“These are all clinical tests that are actionable,” she adds.
These are also very early days.
In addition to the current approved uses for revumenib and ziftomenib, there are ongoing clinical trials to study efficacy for other genotypes, Dr. Loghavi notes; in this setting, testing is critical to screen patients for eligibility purposes. And, in the emerging research setting, correlative studies are underway to determine mechanisms of resistance and relapse.
All of which makes it crucial for laboratories to keep up.
In an Association for Molecular Pathology webinar in March on monitoring patients receiving menin inhibitors for acute leukemia, Ghayas Issa, MD, associate professor, Department of Leukemia and Department of Genomic Medicine, Division of Cancer Medicine, MD Anderson, dove right in with specific questions for molecular pathologists:
1. When is AML with NUP98 rearrangement suspected?
a. Monocytic leukemia with mutations in ASXL1 and TET2.
b. AML with a diploid karyotype on conventional cytogenetics and co-mutations in FLT3 and/or WT1.
c. AML with a complex karyotype and co-mutations with TP53.
d. AML with co-mutations in DNMT3A, and NPM1 or RAS.
2. Which genomic alteration has no clinical evidence supporting use of menin inhibitors as effective therapy?
a. KMT2A amplification.
b. KMT2A translocations.
c. NPM1 mutations.
d. NUP98 rearrangements.
3. What is the best-described mechanism of resistance to menin inhibition?
a. Amplification of KMT2A-menin target genes.
b. Mutations in the drug binding site on menin.
c. Isoform switching.
(The answers, for those playing along: 1) AML with a diploid karyotype on conventional cytogenetics with co-mutations in FLT3 and/or WT1; 2) KMT2A amplification; 3) mutations in the drug binding site on menin.)
After most in the audience responded with the correct answers, Dr. Issa, a clinical and translational researcher, joked, “Now I feel like I don’t need to give the talk.”
But it’s a complex topic, one that’s emerging and evolving, and there’s much for pathologists to keep in mind when it comes to performing testing and discussing menin inhibitors with oncologists and other clinical colleagues.
As background, Dr. Issa noted that in acute leukemias, while menin (the protein encoded by the MEN1 gene) regulates a tumor suppressor function in endocrine glands, it’s also a critical co-factor for oncogenes in certain subtypes of leukemia. “It can play this dual role because it’s an epigenetic modifier [that] is context- and tissue-dependent.” Menin is a scaffold protein and through its interaction with chromatin regulators or transcription factors could regulate gene expression, he said.
The journey from discovering menin inhibitors in the laboratory, to clinical investigation, to FDA approval of therapies, has been a long one, Dr. Issa said. Though scientists have known about KMT2A rearrangements since the 1970s, with the identification of translocation 4;11 in leukemia, “It took incremental work, a lot of detailed science, to establish that these fusions have a particular gene expression that is shared with NPM1, and that the interaction of menin and KMT2A is critical in both.”
The genesis of the inhibitors, Dr. Issa explained, was the discovery of the structure of menin, and the realization “that there’s a pocket that allows the interaction of menin and KMT2A to fashion small-molecule inhibitors that would disrupt binding of menin and KMT2A.” In essence, the inhibitors create a wedge that disrupts the interaction of the two proteins; in turn, this disrupts the gene expression program that’s caused by the interaction and leads to an antileukemic effect.
AML with KMT2A rearrangements (these leukemias used to be called mixed lineage leukemias, or MLL) are diagnosed most often by conventional cytogenetics, said Dr. Issa, “which is routinely done on all acute leukemia patients. You would pick up a chromosomal translocation that involves 11q23.” It provides a macroscopic view of all chromosomal abnormalities; the assay is unbiased but low resolution, he noted. “You may be missing some cryptic fusions or rearrangements, or in the context of a complex karyotype it may not be immediately evident. That’s why it should be coupled with FISH and/or RNA sequencing. FISH was used to support the approval of revumenib.”
This is the test used at MD Anderson, Dr. Issa said. “It tells you that the gene is rearranged. It doesn’t tell you the fusion partner. It has limited sensitivity, so it’s not a great test for MRD.” It’s becoming more common to see RNA-seq used for detecting these fusions, he said, “which would tell you the fusion partner gene and would allow coverage of a large number of all these fusion partners.” It’s not quantitative, however, and currently cannot be used for measurable residual disease.
Dr. Loghavi predicts that menin inhibitors and AML will, as with other leukemia testing, move toward whole genome sequencing. “So the chance of identifying other genotypes that are rare but amenable to menin inhibition, and may not routinely be picked up by our conventional testing, is becoming higher.”
A New England Journal of Medicine article (Duncavage EJ, et al. N Engl J Med. 2021;384[10]:924–935) that looked at WGS as an alternative to cytogenetic analysis in myeloid cancers suggests that “there is a relatively good amount of KMT2A fusions that are cryptic,” said Dr. Issa, which can be picked up by WGS even when undetected by cytogenetics. “Our recommendation at MD Anderson—because we have all these menin inhibitor studies—is to do FISH on anyone with newly diagnosed AML. It’s even more relevant in relapsed/refractory AML” because menin inhibitors can change management.
“There are now multiple menin inhibitors in the clinic,” Dr. Issa said. “Their structures resemble either revumenib or ziftomenib, and they’re all showing robust clinical results.” Second-generation inhibitors are now becoming available. They all share a relatively good response rate, he added.
Combination studies have begun, he continued. “And they’re looking excellent.” But since the majority of cases in these studies are NPM1 mutant leukemias, which tend to respond well to frontline chemotherapy, “we need to wait for longer follow-ups and perhaps MRD negativity by molecular sequencing, which is a better assessment of response.”
There’s much work ahead. But ultimately, Dr. Issa said, menin inhibitors represent improvement over current standard of care.
As many in the field note, targeted therapy has its own developmental path. While much of the data on menin inhibitors is based on monotherapy, it’s likely that other treatment strategies will emerge, with their own implications for clinical testing.
What is happening in AML “is very similar to any targeted therapy,” says Dr. Loghavi, typically starting with monotherapy in the setting of relapsed/refractory disease to monitor the efficacy profile of the agent as well as its toxicity profile. Depending on how well it meets the predetermined endpoint—leukemia-free survival, relapse-free survival, overall survival, or rates of remission, depending on the agent—it might move into combination and frontline therapy.
Menin inhibitors have been quite successful in monotherapy trials, so the next step is looking at them in combination with other agents, such as HMA-Ven (hypomethylating agents and venetoclax) or high-intensity chemotherapy.
Other areas already or soon to be under investigation, Dr. Loghavi says, will be determining the efficacy of using menin inhibitors as maintenance therapy in remission or in the post-transplant setting.
No discussion of these drugs is complete without mentioning resistance and the means of measuring it.
For menin inhibitors, Dr. Loghavi says, “Predicting resistance is actually very difficult. I don’t know that we can do that right now. We do know that some resistance mechanisms arise from the acquisition of MEN1 mutations after therapy with menin inhibitors,” which alter the binding site of these drugs. “But I don’t know of any testing that we have right now that upfront would say that a patient may or may not respond to menin inhibitors.
“But,” she adds, “I do know there’s much research being done on this very subject.”
Dr. Loghavi distinguishes two ways of monitoring resistance.
One is monitoring disease relapse. “It’s not necessarily the emergence of the specific mechanism of resistance,” she says. In a patient with an NPM1 mutation who achieves NPM1 negativity, for example, a molecular method might be used to monitor for early reemergence of the mutation as an indication that the disease is returning. Likewise, flow cytometry might be used to look for the return of aberrant leukemia-associated immunophenotypes.
The other approach is monitoring for emergence of mutations associated with resistance, such as the aforementioned emergence of MEN1, which would help predict that the patient is developing resistance to therapy. “I do think that looking for resistance mechanisms beyond MEN1 mutations would be the next big step in this field,” Dr. Loghavi says.
Some studies have suggested the possibility that the mechanism of resistance could be related to additional mutations in the binding site of the menin inhibitor, changing the binding affinity of the drugs, Dr. Issa says. One study (Perner F, et al. Nature. 2023;615[7954]:913–919) validated in a CRISPR-Cas9 model showed that “the same amino acids that are critical for revumenib interaction were found as the sites of mutations in patients. We now know that these are not just mutations related to revumenib,” he said, “but there could be a difference in sensitivity to each menin inhibitor to each mutation.” He compared it to use of tyrosine kinase inhibitors in treating chronic myeloid leukemia, where a certain set of mutations might be better for, say, nilotinib versus imatinib or dasatinib. It’s likely the same will be true of menin inhibitors. “It depends on which amino acids based on the structures on menin inhibitors are important for that particular drug.”
He and others at MD Anderson, along with researchers at other major cancer centers, are doing deep dives into understanding measurable residual disease, he said, including timelines for testing for MRD; which methods are best for doing so; and the value and availability of tests: qPCR, PCR, NGS for MRD for NPM1 and KMT2A rearrangement, cell-free DNA, and DNA-based versus RNA-based assays.
In a recent article, Drs. Loghavi and Issa looked at changes on flow cytometry in AML (Loghavi S, et al. Leukemia. Published online March 11, 2026. doi:10.1038/s41375-026-02905-6). This method is used for the majority of patients for MRD monitoring, Dr. Issa noted. But? “You have to be cognizant of a possible phenotype switch that is not necessarily related to persistence of disease or resistance,” he said.
For patients who have relapsed, “There’s about 50 percent phenotype switch,” either from myeloid to monocytic, or monocytic to myeloid stem-like. Those with MRD negativity have an excellent remission, he said. But it’s important to denote that there is the possibility of a phenotype switch, especially if the leukemia-associated immunophenotype (LAIP) approach is used for MRD detection.
Says Dr. Loghavi: “One of the important things to realize and highlight in the setting of menin inhibitor therapy is that menin inhibitors are differentiation-inducing agents.”
Much of the time, therefore, when patients are treated with menin inhibitors, particularly early in the disease process, “they may not achieve MRD negativity if you’re looking by sensitive molecular methods,” she says. “Because this is very similar to the process we see in acute promyelocytic leukemia. The rearrangement of the KMT2A gene will actually still be there in the cells that are undergoing differentiation.”
The upshot: It’s important to monitor patients and keep them on therapy, Dr. Loghavi says, if they don’t immediately become molecular MRD negative. “So flow cytometry can be helpful here in assessing differentiation versus true residual leukemia.
“The flip side of this,” she continues, “is that—again, because these are differentiating agents—oftentimes, as we’ve highlighted in the Leukemia paper, you will see a change in the phenotype of the leukemic blasts. So if you’re strictly monitoring the phenotype at baseline, and you’re looking for that population that you identified at baseline, you may actually miss an aberrant population that is otherwise identified by flow cytometry.”
“This is,” she adds, “a very difficult, complicated area in terms of diagnostic testing for surveillance. There’s a lot of nuance that goes into the interpretation of the various tests in this setting.”
Though expertise varies by institution and setting, Dr. Loghavi says, “I do think there’s a need in general, in the community, to educate our clinical colleagues on the differences in methodologies: Which genotype is picked up by which method? What are the sensitivities of each of these assays? How do you monitor the patients depending on the genotype they had at baseline? How do you monitor for relapse? Which genotype has a molecular MRD test? Which genotype has a flow cytometric MRD test?”
The questions are easy to raise; the answers, less so. “This all becomes very complicated,” Dr. Loghavi concedes, adding with a laugh, “This would be a half-day lecture for each genotype.”
Nevertheless, she says, “It’s important to realize there’s no one test that fits every situation. You need a suite of tests, so to speak, to monitor for these various genetic abnormalities. And then, depending on what you identify at baseline, there’s an optimal way of surveillance for each of these genetic abnormalities.”
These are early days for menin inhibitors and associated testing, so it makes sense that the changes seem to be unfolding step by specific step. “There haven’t been any real surprises,” says Dr. Loghavi. “It’s been a great learning opportunity in terms of seeing how the various leukemias respond to these therapies, how their phenotypes change, and how we interpret the different testing results. We learn from every case.”
Karen Titus is CAP TODAY contributing editor and co-managing editor.