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Acute leukaemias are aggressive blood cancers characterised by the rapid proliferation of malignant myeloblastic (acute myeloid leukaemia [AML]) or lymphoblastic (acute lymphoblastic leukaemia [ALL]) cells. Around 30% of AML patients carry mutations in the nucleophosmin gene (NPM1m), and 5% to 10% of acute leukaemias (AML and ALL) harbour histone-lysine N-methyltransferase 2A gene rearrangements (KMT2Ar). These genetic alterations are associated with a high risk of relapse after chemotherapy and hematopoietic stem cell transplant (HSCT), as well as a poor prognosis. Menin is a scaffold protein that forms a complex with KMT2A. In NPM1-mutant (NPM1m) or KMT2Ar cells, this complex activates HOX\/MEIS1 gene expression, leading to the survival and proliferation of immature leukaemic blasts. <\/em>There are currently no approved therapies targeting menin-KMT2A interaction.<\/p>\n Syndax Pharmaceutical\u2019s revumenib (SNDX-5613) is a selective oral inhibitor of menin-KMT2A complex formation. <\/em>Phase I of the AUGMENT-101 (NCT04065399) clinical trial <\/em>showed that revumenib had clinically meaningful efficacy and safety in NPM1m and KMT2Ar heavily pre-treated acute leukaemic patients. The interim KMT2Ar cohort results of the pivotal Phase II AUGMENT-101 trial were presented at the 2023 American Society of Hematology (ASH) 65th Annual Meeting, held from 9 December to 12 December 2023.<\/p>\n The efficacy population included all patients with a confirmed KMT2Ar and study follow-up for at least six months (n=57). Study participants received 163mg of oral revumenib (95mg\/m\u00b2 if weighing under 40kg) and a CYP3A4 inhibitor every 12 hours in 28-day continuous cycles. In the efficacy population, 86% of patients had AML, 12% had acute ALL, and 2% had mixed-phenotype acute leukaemia or another subtype. Patients were heavily pre-treated with a median of 2 previous treatments (and a range between one and 11 lines of therapy), with 43.6% having received three or more prior therapies. 57.4% had relapsed or refractory (R\/R) disease, 72% had received prior venetoclast, and 50% had prior allogeneic HSCT. The median age in the efficacy population was 34 years (a range of 1.3 years to 75 years, 22.8% were under the age of 18, 57.9% were female and 75.4% were Caucasian. <\/p>\n The objective response rate (ORR) in the efficacy population was 63.2% (n=36). The complete response (CR) rate plus CR with partial hematologic recovery (CRh) was 22.8%, the composite CR rate was 43.9%, the median duration of CR+CRh was 6.4 months, and 70% of patients with CR response and with reported measurable residual disease (MRD) status achieved MRD negativity (7\/10). A total of 38.9% of responders (14\/36) proceeded to HSCT, with half resuming revumenib post-HSCT. <\/p>\n The safety population included all patients who received at least one dose of revumenib, regardless of their KMT2Ar confirmation or follow-up in the trial (n=94). Treatment-related adverse events (TRAEs) occurred in 81.9% of the safety population. The most common TRAEs (\u226520%) were nausea (27.7%), differentiation syndrome (26.6%), and QTc prolongation (23.4%). Overall, 6.4% of patients discontinued therapy due to TRAEs. The study has met its endpoints and the KMT2Ar cohort stopped early for efficacy, while the NMP1m cohort is ongoing.<\/p>\n