Patient Information
The clinical data presented involves a cohort of 48 patients diagnosed with relapsed or refractory (R/R) acute myeloid leukemia (AML). These patients were specifically selected based on the presence of high-risk molecular features, specifically rearrangements in the lysine methyltransferase 2A (KMT2A) gene or mutations in the nucleophosmin 1 (NPM1) gene. These genetic alterations are known to render the leukemia dependent on the menin-KMT2A interaction for the maintenance of an undifferentiated, proliferative state. The patients in this study had previously failed standard-of-care therapies, including intensive chemotherapy and/or targeted agents, leading to their enrollment in clinical trials for revumenib, a potent and selective menin inhibitor.
Diagnosis
Diagnosis was established through comprehensive bone marrow evaluation, including morphologic assessment, cytogenetics, and molecular profiling. The primary focus for monitoring treatment response was flow cytometry immunophenotyping. At baseline, the leukemia cells typically exhibited a myeloid or stem-like immunophenotype, often characterized by the expression of CD34, CD117, and immature myeloid markers. Following the initiation of revumenib, serial bone marrow specimens were collected to evaluate the persistence of the leukemic clone and any phenotypic shifts. The diagnosis of response was categorized into morphologic remission with or without measurable residual disease (MRD) as detected by flow cytometry.
Differential Diagnosis
In the context of menin inhibitor therapy, the differential diagnosis of a persistent or emerging cell population in the bone marrow is complex. Clinicians must distinguish between:
- Refractory Disease: Persistence of the original undifferentiated leukemic blast population.
- Treatment-Induced Differentiation: A shift from blasts to more mature monocytic or myelomonocytic cells, which is a pharmacodynamic effect of menin inhibition rather than treatment failure.
- Lineage Switch: A complete change in the lineage of the leukemia (e.g., from myeloid to lymphoid), which can be a mechanism of resistance.
- Regenerating Normal Hematopoiesis: Distinguishing emerging healthy precursors from low-level residual disease.
Treatment and Management
Patients were treated with revumenib (formerly SNDX-5613), an oral small-molecule inhibitor of the menin-KMT2A protein-protein interaction. Revumenib works by disrupting the transcriptional program driven by KMT2A rearrangements or NPM1 mutations, thereby inducing hematopoietic differentiation and cell cycle arrest. Management required vigilant monitoring for ‘Differentiation Syndrome,’ a clinical constellation of symptoms (fever, respiratory distress, edema) resulting from the rapid maturation of leukemic blasts. Response was monitored using serial bone marrow biopsies and aspirates. A critical component of management was the integration of flow cytometry to assess MRD status, as this study demonstrated that the quality of the response (MRD- vs. MRD+) significantly dictated the subsequent clinical course.
Outcome and Prognosis
The study observed dynamic immunophenotypic changes in 52% (16 of 31) of evaluable patients. These changes included switches from myeloid/stem-like phenotypes to monocytic/myelomonocytic patterns, or vice versa, and significant alterations in antigen expression intensity. The prognostic implications of these findings were profound:
- MRD-Negative Morphologic Remission: Patients who achieved morphologic remission with undetectable MRD by flow cytometry had a median overall survival (OS) of 23.6 months.
- MRD-Positive Morphologic Response: Patients in morphologic remission but with detectable MRD had a median OS of 20.8 months.
- Non-Responders: Patients who failed to respond to revumenib had a dismal median OS of only 3.2 months.
These results indicate that while revumenib is highly effective at inducing remission, the eradication of MRD remains the gold standard for long-term survival.
Discussion
The introduction of menin inhibitors like revumenib represents a paradigm shift in the treatment of KMT2A-rearranged and NPM1-mutated AML. This study highlights a critical challenge for pathologists and oncologists: the ‘moving target’ of the leukemic immunophenotype. Because menin inhibitors function by promoting differentiation, the leukemia cells may not immediately disappear but instead change their surface marker profile (phenotypic plasticity). Failure to recognize these changes during flow cytometry monitoring could lead to false-negative results or an underestimation of the residual leukemic burden.
The association between MRD negativity and improved OS (23.6 months) underscores the potential for revumenib to serve as a bridge to hematopoietic stem cell transplantation or as a sustained therapy. However, the 52% rate of immunophenotypic shifts suggests that standardized flow cytometry templates used for AML may need to be adjusted specifically for patients on menin inhibitors to include a broader monocytic panel and to account for lineage plasticity. Future research should focus on the molecular mechanisms driving these phenotypic switches and whether they contribute to eventual drug resistance, such as the development of mutations in the MEN1 gene.
References
- Loghavi S, Farhat A, Jamison TJ, et al. Immunophenotypic changes following menin inhibition in acute myeloid leukemia. Leukemia. 2026-03-11. PMID: 41814014.
- Issa GC, et al. The Menin-KMT2A Inhibitor Revumenib in Relapsed/Refractory AML. Nature Medicine. 2023.
