Menin inhibitors (MENINi) are novel targeted therapies for acute leukemias characterized by HOX gene dysregulation (e.g., KMT2A-rearranged, NPM1-mutated), and they function by disrupting the interaction between the scaffolding protein menin and MLL1 [1, 2]. The MENINi revumenib and ziftomenib are FDA-approved for relapsed or refractory (R/R) acute leukemia based on phase 1/2 data showing complete remission (CR) or CR with partial hematologic recovery (CRh) rates of approximately 20% [3,4,5]. Numerous additional MENINi studies are ongoing [6]. Despite compelling efficacy, treatment with MENINi can lead to the acquisition of resistance mutations [7, 8]. Notably, MEN1 mutations, which occur in up to 40% of patients treated with revumenib monotherapy as assessed by ultrasensitive droplet digital polymerase chain reaction (ddPCR), can impair MENINi binding and reactivate leukemogenic transcriptional programs. Outcomes following MENINi monotherapy after resistance are generally poor, with infrequent responses and limited overall survival, especially in the presence of MEN1 mutations [9, 10].
Bleximenib (JNJ-75276617) is a MENINi currently under investigation as monotherapy and in combination regimens for acute leukemias (NCT04811560, NCT05453903) [11]. In preclinical studies, bleximenib disrupts menin-MLL1 binding to restore hematopoiesis and retains binding affinity and activity in cell lines engineered to harbor MEN1M327I mutations, and, to a lesser extent, MEN1T349M [12]. These findings suggest that bleximenib may retain activity in patients with leukemia relapsed or refractory after prior MENINi treatment due to specific MEN1 resistance mutations.
Here, we report overcoming MEN1-mediated therapeutic resistance through MENINi switching from revumenib to bleximenib, highlighting the kinetics and gradual eradication of the MEN1 M327I clone. This case demonstrates the clinical importance of MEN1 mutation testing and supports the potential role of mutation-guided MENINi switching as a strategy to overcome acquired resistance.
A 38-year-old woman with a history of diabetes mellitus was diagnosed with acute myeloid leukemia harboring t(6;11) KMT2A::MLLT4. Molecular testing was negative for FLT3, IDH1, and IDH2 mutations. She was initially treated with daunorubicin and cytarabine, followed by high-dose cytarabine, achieving a CR, and proceeded to a double umbilical cord blood transplantation (duCBT). She relapsed 2 years later with persistent t(6;11) and newly detected t(17;18) on cytogenetic studies. No somatic mutations were identified by targeted next-generation sequencing (NGS) via MSK-IMPACT. She was treated with azacitidine and venetoclax, achieving a second CR, followed by a second duCBT. Despite oral azacitidine maintenance, she experienced a second relapse 1.5 years thereafter.
At the time of second relapse, bone marrow aspiration and biopsy (BMAB) demonstrated 9% blasts with reemergence of t(6;11) and t(17;18) as well as clonal evolution characterized by new cytogenetic abnormalities of t(2;7), t(2;8), add(4), and t(4;5), consistent with a complex karyotype. Concurrent MSK-IMPACT, which included assessment for MEN1 alterations, identified no somatic mutations. She was subsequently treated with revumenib monotherapy (226 mg every 12 hours), initiated approximately 6 weeks after relapse. Prior to revumenib initiation, repeat BMAB demonstrated 44% abnormal myeloblasts (Fig. 1A).
Fig. 1: Molecular and clinical characteristics before and after Revumenib and Bleximenib.
A Trends of white blood cell count (WBC), platelet count (PLT), and absolute neutrophil count (ANC) over the course of menin inhibitor treatment. B Fractional abundance of MEN1M327I measured by digital droplet polymerase chain reaction (ddPCR) over time.
After 1 cycle of revumenib, she achieved a measurable residual disease (MRD)-negative CR by multiparameter flow cytometry, with no abnormal myeloid blasts detected at a limit of quantitation of 0.05% of white blood cells based on a difference from normal approach and comparison with her previously defined leukemia-associated immunophenotype. Notably, after cycle 1, t(6;11) and t(17;18) remained detectable in 3 of 20 metaphases, and t(2;7) was present in 2 metaphases. This temporal discordance is likely due to a differentiation of leukemic blasts to more mature components, which has been well documented in differentiation-induced treatment (Fig. 2). All cytogenetic abnormalities resolved following cycle 2. She continued revumenib and remained in MRD-negative CR confirmed with BMAB at subsequent time points (cycles 3, 4, 5, 7, and 10). After 17 cycles (68 weeks) of revumenib therapy, she developed pancytopenia and increased peripheral blasts. Repeat BMAB demonstrated morphologic relapse with 30–40% blasts and reemergence of t(6;11), t(2;7), and t(17;18). Chimerism studies at the time were 52% donor. MSK-IMPACT demonstrated emergent mutations in MEN1M327I (variant allele frequency [VAF] 23.1%) and MSH3 D362H (VAF 20.3%). MEN1M327I is a canonical menin inhibitor resistance mutation, and the clinical significance of the MSH3D362H mutation in this context is uncertain [7].
Fig. 2: Transient monocytic differentiation during MENINi therapy.
A Bone marrow biopsy at 1-month follow-up demonstrates numerous cells with abundant, sometimes foamy, pink cytoplasm (arrows), consistent with monocytic differentiation (H&E stain, ×200). Flow cytometry confirmed 20% monocytes. B At 2-month follow-up, bone marrow biopsy shows normal myeloid and erythroid maturation with scattered monocytic cells. Flow cytometry shows 9% monocytes.
Based on the MEN1 mutation identified, the patient was then treated with bleximenib 100 mg orally twice daily. After one cycle of bleximenib treatment, she achieved MRD-positive CR by flow cytometry, followed by MRD-negative CR after 3 cycles with low-level KMT2A::MLLT4 reads via targeted RNA-sequencing. After six cycles, the patient achieved MRD-negative CR with normal cytogenetics and then proceeded to a third allogeneic hematopoietic stem cell transplant from a first-degree haploidentical donor. MSK-IMPACT performed on her pre-transplant BMAB confirmed the eradication of the MEN1M327I mutation with no new MEN1 mutations detected.
ddPCR performed on peri-bleximenib BMAB samples demonstrated progressive decline in MEN1M327I fractional abundance: from 29.8% pre-treatment to 4.5% (cycle 1), 2.2% (cycle 2), 0.075% (cycle 3), then 0.000% after cycle 6 (0 of 1814 droplets, Fig. 1B). The patient remains in remission following her third allogeneic hematopoietic cell transplant. She continues bleximenib maintenance, which was initiated 6 months post-transplant. At last follow-up, she was 9 months post-transplant and 15 months from bleximenib initiation.
To our knowledge, this is the first report to demonstrate successful MENINi switching to overcome and eradicate newly emergent MEN1 mutations driving clinical resistance in acute leukemia. Although this approach and the specific eradication of newly emergent MEN1 mutations have not been previously described with MENINi, the paradigm of identifying specific therapy-related mutations and transitioning to alternative targeted agents in the same class is well established. For instance, mutation-guided tyrosine kinase inhibitor (TKI) selection in both Philadelphia chromosome-positive acute lymphoblastic leukemia and chronic myeloid leukemia is standard of care. BCR::ABL1 kinase domain mutation testing for key mutations such as T315I and key P-loop mutations (e.g., Y253H, E255K/V) directly informs the selection of subsequent TKIs [13, 14].
While this case demonstrates the feasibility of MENINi switching guided by MEN1M327I, important questions remain regarding the broader applicability of this approach. Preclinical data suggest that bleximenib retains activity against M327I and, to a lesser extent, T349M, but other resistance mutations may prove to be difficult to overcome due to altered menin-MLL1 dissociation kinetics. Moreover, many patients who progress on MENINi do not harbor detectable MEN1 mutations, suggesting that additional non-genetic mechanisms may drive resistance in a substantial proportion of cases for which MENINi switching alone would be insufficient. Whether sequential MENINi monotherapy or combination strategies (e.g., chemotherapy, venetoclax-based regimens, and IKAROS degraders) more effectively prevent or overcome resistance remains to be determined. Defining the optimal sequencing of MENINi across the expanding portfolio of agents in clinical development will require systematic cross-resistance profiling and prospective clinical trials.
Translating these findings into clinical practice presents additional challenges. At present, there is no guideline-supported approach to MENINi resistance mutation testing, and substantial institutional variability exists in the capability to capture these clinically relevant mutations. As additional MENINi enter clinical development and possibly gain regulatory approval, a more comprehensive understanding of resistance mutations and their differential sensitivity to individual MENINi will be essential. Early identification of these mutations may inform preemptive treatment modification prior to relapse, potentially prolonging remission and improving patient outcomes. Finally, evidence-based guidance on the long-term use of MENINi, including best practices for post-transplant maintenance, will be critical to optimizing long-term outcomes.
