News release

From: Springer Nature

Cancer: Responses and resistance to a new potential drug for acute leukaemia

Anticancer effects and possible signatures of treatment resistance are reported in a phase 1 human clinical trial of a new drug known as revumenib for the treatment of patients with advanced or treatment-resistant acute myeloid leukaemia. The findings are presented in two papers published in Nature this week.

Acute leukaemia is commonly characterized by the mutation of the nucleophosmin 1 (NPM1) gene or rearrangement of the mixed lineage leukaemia 1 gene (KMT2Ar), both of which have been shown to contribute to cancer progression. Overall survival rates are poor and there are currently no approved treatments that specifically target these gene alterations. Preclinical studies have demonstrated that a protein known as menin facilitates the progression of KMT2Ar or NPM1-mutated acute leukaemia, indicating that menin inhibition may reverse cancer progression in this subset of leukaemia.

Ghayas Issa and colleagues report the outcomes of treatment with revumenib, a selective inhibitor of menin, in 60 patients between 2019 and 2022. They report an overall response rate (some degree of remission) of 53%, with a 30% rate (18 out of 60 patients) of complete remission or complete remission with partial haematologic recovery. Of these 18 patients, 78% had undetectable measurable residual disease after nearly two months of remission These results provide evidence of the potential of menin-inhibitor treatments for acute leukaemia.

In a second study, Scott Armstrong and colleagues investigated the occurrence of selective resistance to menin inhibition. They identified specific mutations in the MEN1 gene (which encodes menin) that can result in resistance to revumenib treatment through alteration of the drug-binding site. These mutations were detected in several patients who initially responded to treatment with revumenib but failed to sustain clinical responses. Identification of these treatment-escape routes provides valuable information that will be required to improve patient outcomes in the future.