KMT2A (Lysine Methyltransferase 2A)

The menin-lysine methyltransferase 2A acute leukemia (KMT2A) protein-protein interaction has emerged as a clinically validated epigenetic target in acute leukemia, following the approval of the reversible menin inhibitor Revumenib for KMT2A-rearranged and nucleophosmin 1 (NPM1)-mutant disease...Across all chemical classes, sustained target engagement-rather than equilibrium affinity alone-emerges as the dominant determinant of antileukemic efficacy. By integrating structure-activity relationship (SAR), resistance mechanisms, safety considerations, and translational scope across oncology and metabolic indications, this review provides a roadmap for the rational design of next-generation menin inhibitors and establishes menin as a model system for modern epigenetic drug discovery.

We critically evaluate the preclinical and clinical development of menin inhibitors, including revumenib, ziftomenib, bleximinib, and icovamenib, summarizing efficacy signals in relapsed/refractory disease, safety profiles, and emerging resistance mechanisms. Special attention is given to combination strategies with venetoclax, FLT3 inhibitors, chemotherapy, and epigenetic agents, which aim to enhance response durability and mitigate resistance. Finally, we discuss ongoing clinical trials, unresolved challenges in patient selection and sequencing, and future directions for integrating menin inhibition into precision-based treatment paradigms for acute leukemia.

The 11q23 rearrangement ALL with non-KMT2A::AFF1 transcript is mainly KMT2A::MLLT1, T-ALL is more common, and the rate of chromosomal karyotype detection is relatively low. Persistent positive KMT2A-r is unfavorable for patient survival, and allo-HSCT during the CR1 period may improve patient survival.

This review provides a roadmap for the targeted therapy era in ALL, defining high-risk molecular subtypes and their targeted vulnerabilities. It synthesizes advances in BH3 mimetics, menin inhibition, and immunotherapy, while addressing the critical challenges of treatment resistance and phenotypic escape that define the next frontier of research.

P1/2, N=50, Not yet recruiting, Sheba Medical Center

P=N/A, N=100, Recruiting, Peking University People's Hospital

P1, N=29, Not yet recruiting, Children's Oncology Group

The presence of KMT2A amplification is a rare event in AML and is present in ~1% of AML and MDS cases. MYC translocation, KMT2A (MLL) amplification, and 5q/20q losses suggest secondary therapy-related AML and categorize this case in the adverse risk prognosis under the ELN 2022 guidelines.

Finally, the Myeloid Program is a predictive biomarker, where high baseline activity defined a vulnerable state that could be selectively targeted by MEK, AKT, and mTOR inhibitors. Together, these findings establish a framework for identifying circuit-level epigenetic compensation and for rationally designing precision combination therapies that restore differentiation or target state-dependent vulnerabilities in acute myeloid leukemia.

P1, N=22, Recruiting, Richard Stone, MD | Trial completion date: Mar 2027 --> Mar 2028 | Trial primary completion date: Mar 2026 --> Mar 2027

P1/2, N=606, Recruiting, Sumitomo Pharma America, Inc. | N=362 --> 606