Revuforj (revumenib)

CRISPR base editor screening previously predicted several MEN1 (menin) mutations that have arisen in patients receiving SNDX-5613 and confer resistance...Co-crystal structures of menin bound to each menin inhibitor suggest resistance mechanisms related to how each inhibitor engages the KMT2A binding pocket of menin. Orthogonal in vitro and in vivo MEN1 mutation generation under therapeutic pressure suggest the MEN1 mutations identified with CRISPR base editor screening are likely to arise and impact all menin inhibitors.

P1, N=0, Withdrawn, Children's Oncology Group | N=29 --> 0 | Not yet recruiting --> Withdrawn

We evaluated RAS/MAPK targeting using the MEK1/2 inhibitor selumetinib in combination with the menin inhibitor revumenib. Our preclinical study suggests a potential targeted treatment combination for KMT2A-r and RAS pathway mutant leukemia, but one which will require further optimization. COG completed clinical trials AAML03P1, AAML0531, AAML1031 and C2961.

P1, N=24, Recruiting, St. Jude Children's Research Hospital | Trial primary completion date: Jul 2026 --> Oct 2026

P3, N=468, Recruiting, Syndax Pharmaceuticals

P2, N=144, Not yet recruiting, Center for International Blood and Marrow Transplant Research

After four cycles of neoadjuvant therapy with carboplatin, albumin-bound paclitaxel and pembrolizumab, the tumor lesion regressed markedly...The patient was treated with an optimized quadruple anti-tuberculosis regimen (HZEM), and induction chemotherapy for AML with VA regimen (venetoclax plus azacitidine) plus revumenib, and supportive therapy...The overlapping clinical manifestations of the two concurrent diseases substantially increase diagnostic difficulty. Timely and thorough bone marrow examination, lymph node pathological biopsy and tuberculosis-specific screening are the keys to early and accurate diagnosis.

He was initially treated with azacitidine and venetoclax but demonstrated disease progression. In the setting of a KMT2A::ELL fusion, therapy was transitioned to the menin inhibitor revumenib, resulting in short-term clinical stability and tolerability under continued supportive care.

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.

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

Here, we detail the current targeted therapies available for AML: specifically, those targeting the BCL2 family (venetoclax), FLT3 (midostaurin, gilteritinib, quizartinib), IDH1/2 (enasidenib, ivosidenib), and MENIN (revumenib, ziftomenib). In addition, we outline potential mechanisms of resistance against these therapies, as well as efforts being taken to prevent or bypass them.