Phase 1 Clinical Trial Achieves Leukemia Remission in 18 Patients

In a study published in Nature on March 15, 2023, researchers achieved complete or nearly complete remission in 18 patients with KMT2A-rearranged or NPMI-mutant leukemia. The phase 1 clinical trial recruited 68 patients and dosed them with revumenib (SNDX-5613), an inhibitor of the menin-KM2A interaction.

KMT2A, also called lysine methyltransferase 2A, and NPM1, also called nucleophosmin 1, are critical genetic components linked to leukemia. According to the Nature study, 80% of acute lymphoblastic leukemia (ALL) cases are associated with a rearrangement of KMT2A. Beyond that, up to 15% of all acute leukemias exhibit this rearrangement. The five-year survival rate of leukemia with KMT2A is less than 25%.

In addition to KMT2A rearrangements, mutations in NPM1 occur in nearly 30% of patients with acute myeloid leukemia (AML), making it the most common genetic mutation associated with AML. Despite high rates of KMT2A rearrangement and NPM1 mutations, no leukemia treatments target these genetic anomalies.

Researchers note that the interaction between menin, a human protein, and these genetic anomalies is common in leukemia cases. With that in mind, researchers focused on revumenib (SNDX-5613), an inhibitor of these interactions.

Using data from preclinical research, clinicians in this study dosed patients between November 5, 2019, and March 31, 2022, in the first-in-human clinical trial focused on these interactions. Approximately 88% of the patient population had a KMT2A rearrangement or NPMI mutation.

Most patients were over 18, accounting for 60 of the 68 participants; however, 8 pediatric patients were also enrolled in the trial.

At the close of the study, 18 patients had complete remission or complete remission with partial hematologic recovery, a rate of roughly 30%. Most of the participants in remission, 78%, had an undetectable measurable residual disease (MRD) when assessed with multiparameter flow cytometry. Beyond remission and residual disease, clinicians observed notable bone marrow responses for patients with imaging.

“In conclusion, in children and adults with highly refractory acute leukemia with KMT2Ar or NPM1 mutation, menin inhibition with revumenib monotherapy was associated with promising antileukemic activity leading to deep and sustained remission,” concluded researchers in the publication.

Although this clinical trial is still in its infancy, a new targeted leukemia treatment may be on the horizon.