27 March 2023

Scientists have hailed ‘encouraging results’ for treatment of acute leukaemias that have KMT2A rearrangements or NPM1 mutations.

A phase 1 trial of the drug revumenib has showed, among 60 patients with advanced acute leukaemias with KMT2A rearrangements or mutant NPM1, the overall response rate was 53%.

The rate of complete remission or complete remission with partial hematologic recovery was 30%, while 78% of patients achieved clearance of measurable residual disease.

The study, called AUGMENT-101, was led by a team at The University of Texas MD Anderson Cancer Center, Texas, USA. Results were published in Nature.

Study lead Dr Ghayas Issa, assistant professor of leukaemia, said: “Acute leukaemias with KMT2A rearrangements are difficult to treat and NPM1 mutations are the most common genetic alteration in acute myeloid leukaemia.

“These subsets have no specifically approved targeted therapies. I am encouraged by these results, which suggest that revumenib may be an effective oral targeted therapy for patients with an acute leukaemia caused by these genetic alterations.

“These response rates, especially rates of residual disease clearance, are the highest we have seen with any monotherapy used for these resistant leukaemia subsets.”

In KMT2A-rearranged or NPM1-mutant acute leukaemias, the interaction of the menin protein with KMT2A (previously known as MLL) is critical in driving expression of leukaemia-promoting genes.

Preclinical studies suggested targeting the interaction between menin and KMT2A may be an effective strategy for treating cancers with these mutations. Dr Issa said targeting menin disrupts the gene transcription machinery and shifts gene expression in cancer cells from a leukaemia pattern to a normal pattern.

The AUGMENT-101 study is a first-in-human, open-label, dose-escalation, and dose-expansion study to evaluate the safety and anti-tumour activity of revumenib in children and adults with advanced KMT2A-rearranged or NPM1-mutant acute leukaemias.

The trial enrolled 68 patients with a median age of 43, with youngest participants being 10 months. Out of the cohort, 82% had acute myeloid leukaemia, 16% acute lymphocytic leukaemia and 2% had mixed phenotype acute leukaemia.

Among these patients, 67.6% had KMT2A rearrangements, 20.6% had NPM1 mutations and 11.8% had other genotypes. Patients were heavily pre-treated, with a median of four prior lines of therapy and 46% had a prior allogeneic stem cell transplant.

The median duration of response was 9.1 months and median overall survival was seven months. Twelve patients went on to allogeneic stem cell transplant following a response to revumenib.

Differentiation syndrome was reported in 11 patients, while manifestations of differentiation syndrome in all patients resolved with steroids and/or hydroxyurea, and all were grade 2 or below.

Dr Issa said: “The responses in this trial show that menin inhibitors may be a promising treatment option that is well tolerated by patients and could be the newest addition to successful targeted therapies for acute leukaemia.

“I look forward to additional data from this and future trials to inform the potential opportunity to offer this targeted treatment to more patients.”

Researchers are now enrolling for phase II of the trial.


Issa GC, Aldoss I, DiPersio J, Cuglievan B, Stone R, Arellano M, Thirman MJ, Patel MR, Dickens DS, Shenoy S, Shukla N, Kantarjian H, Armstrong SA, Perner F, Perry JA, Rosen G, Bagley RG, Meyers ML, Ordentlich P, Gu Y, Kumar V, Smith S, McGeehan GM, Stein EM.  (2023) “The menin inhibitor revumenib in KMT2A-rearranged or NPM1-mutant leukaemia.” Nature, doi: 10.1038/s41586-023-05812-3

Link: https://www.nature.com/articles/s41586-023-05812-3

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