A new drug (Revumenib) with a novel mechanism of action for the treatment of previously treated acute leukemias

Acute leukemias are rapidly progressing, aggressive forms of blood cancer that originate from immature blood cells, usually in the bone marrow, and spread quickly. They displace the healthy bone marrow, resulting in insufficient production of functional blood cells. Those affected often experience weakness, fatigue, susceptibility to infections, and, in some cases, bleeding. In acute myeloid leukemia (AML), precursor cells of the so-called myeloid cell line are altered. In acute lymphoblastic leukemia (ALL), the cancer cells develop from immature precursor cells of the lymphocytes. Standard treatments for acute leukemias include chemotherapy, radiation therapy, and stem cell transplantation; however, these are not always successful. New therapeutic approaches are needed for recurrent disease (relapse) or for patients who do not respond well to treatment (refractory). Acute leukemias are caused by various genetic alterations in blood cells, such as a KMT2A gene rearrangement and/or a mutation in the NPM1 gene. Both genetic alterations appear to be associated with the protein menin. This protein is inhibited by revumenib, which is intended to block the activity of signaling pathways responsible for the growth and proliferation of leukemia cells.

The AUGMENT-101 study is being conducted in two phases; in both phases, both the physician and the patient are aware of the respective treatment (open-label): In the first phase (Phase 1, dose escalation), the maximum tolerated dose and the dose for the subsequent phase are determined. To this end, patients receive revumenib in increasing doses. Patients are divided into 6 study arms. Some of the groups also receive prophylaxis for fungal infections or an inhibitor of the CYP3A4 enzyme, which metabolizes Revumenib. The study is investigating whether the additional administration of the CYP3A4 inhibitor could reduce the required dose. This phase will last approximately 1 year, after which the dose for Phase 2 is expected to be determined. Phase 2 (Expansion) focuses on evaluating the efficacy, safety, and tolerability of Revumenib in specific groups. To this end, patients will be divided into three study arms: Group A: patients with KMT2Ar ALL or MPAL; Group B: patients with KMT2Ar AML; Group C: patients with NPM1-mutated AML.

According to a statement from the pharmaceutical company responsible (Syndax), no new patients are currently being enrolled in the study; however, recruitment is not yet listed as closed on the official study portals, so it is possible that recruitment may resume. Patients aged one month or older who have relapsed or refractory acute leukemia with one of the specific genetic alterations listed above are eligible to participate. The follow-up period in Phase 2 lasts up to three years in total.