# Menin Inhibition in Acute Myeloid MLL Rearranged Leukemias: A New Target for Precision Care

## TL;DR

Menin inhibitors are new targeted drugs for aggressive leukemias, showing promise in treating high-risk patients, though resistance remains a challenge.

## Contribution

This paper reviews the clinical development and resistance mechanisms of menin inhibitors in KMT2A-rearranged and NPM1-mutated acute leukemias.

## Key findings

- Revumenib achieved a 23% complete remission rate in heavily pretreated patients, with 61% MRD-negative responses.
- Combining menin inhibitors with azacitidine/venetoclax or chemotherapy improves response rates in newly diagnosed patients.
- Resistance occurs in about 40% of cases, often via MEN1 gene mutations, with distinct patterns among different inhibitors.

## Abstract

Menin inhibitors are new targeted drugs for two high-risk types of acute leukemia (KMT2A-rearranged and NPM1-mutated). Revumenib was approved in 2024–2025. In heavily pretreated patients, about 23% achieved complete remission, with most of those becoming MRD-negative. Ziftomenib, bleximenib, and enzomenib show similar effectiveness but differ in side effects, particularly heart rhythm problems (QTc prolongation varies among drugs). When combined with other drugs like azacitidine/venetoclax or chemotherapy, response rates are much higher in newly diagnosed patients, suggesting these could work as initial treatment. About 40% of patients develop resistance, usually through MEN1 gene mutations. Different menin inhibitors have different resistance patterns, so switching drugs might help. About 30–40% of responders went on to stem cell transplant, which remains the best chance for cure. Menin inhibitors are the first targeted therapies for these aggressive leukemias, showing promise both alone and in combinations, though resistance remains a challenge.

Menin inhibitors are the first targeted therapies for KMT2A-rearranged and NPM1-mutated acute leukemias, addressing a significant unmet need in these high-risk subtypes. Revumenib received approval in 2024–2025 for relapsed or refractory KMT2A-rearranged acute leukemia and NPM1-mutated AML. The AUG-MENT-101 trial reported a 23% composite complete remission rate in heavily pretreated patients, with 61% of responders achieving MRD negativity. Several menin inhibitors, including ziftomenib, bleximenib, and enzomenib, are in clinical development. They demonstrate similar efficacy, but their safety profiles differ, especially regarding QTc prolongation and coverage of resistance mutations. Combination therapies with azacitidine and venetoclax or intensive chemotherapy have achieved high response rates in newly diagnosed patients, supporting their potential use in frontline treatment. Acquired resistance, often due to MEN1 mutations at the drug-binding interface, occurs in about 40% of cases. Distinct resistance patterns among menin inhibitors suggest the possibility of sequential therapy. Approximately 30–40% of responders in relapsed or refractory trials proceeded to allogeneic transplantation, which remains a key pathway to potential cure. This review examines the molecular mechanisms of the menin-KMT2A interaction, and summarizes clinical trial data on the efficacy and safety of menin inhibitors as monotherapy and in combination.