There are many genetic rearrangements that can be identified in patients with AML. Two common ones include KNMT2A and NPM1 mutations. KMT2A is found in 5-15% of children and adults. NPM1 is the most common of all mutations and found in 30% of leukemia cases. Previously, targeted therapies for either of these mutations have not been available. 

The menin protein is an important factor in both KMT2A and NPM1 versions of AML. It is a building protein that controls gene expression and cell signaling. It also carries an essential role in binding and preserving cell functions. “Menin acts as a tumor suppressor, which means that it keeps cells from growing and dividing too quickly or in an uncontrolled way.”

Tumor suppressor genes are normal genes that slow down cell division or tell cells to die at the right time (a process known as apoptosis or programmed cell death). When tumor suppressor genes don't work properly, cells can grow out of control, which can lead to cancer. Menin inhibitors are a new class of drugs that are being used to counteract the effects of KMT2A and NPM1 rearrangements.

Revumenib is Shown to be an Effective Menin Inhibitor

This targeted therapy comes in pill form and breaks up the effect of the gene mutations. The results of a phase 1 trial of 60 patients showed that 18 people achieved complete or near-complete remission. 

“Revumenib is a very exciting new drug. It’s a breakthrough medicine because it actually is a targeted therapy with broad downstream effects. And it is effective in large populations of people with AML. We have never been able to target this before,” said Dr. James Mangan who is a hematologist at the University of California San Diego.

Revumenib was granted Orphan Drug Designation by the FDA in 2022. It also received Fast-Track Designation by the FDA “for the treatment of adult and pediatric patients with R/R (relapsed or refractory) acute leukemias harboring a KMT2A rearrangement or NPM1 mutation.” This new drug directly targets the changes that occur in a cell with either of these gene rearrangements.

“For patients with acute leukemia who have undergone several previous treatments, this is a very encouraging result,” said Dr. Scott Armstrong, a study author and president of the Dana-Farber Cancer Institute and Boston Children’s Cancer and Blood Disorders Center. This trial evidence effectively suggests that menin is a valid target for therapy in both genetic subtypes of AML.

A Phase 2 study of revumenib will begin soon for pediatric patients diagnosed with relapsed or refractory leukemia. This study will focus on the combination of revumenib and chemotherapy and its efficacy for pediatric patients with KMT2A rearrangement.