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pleural or pericardial effusions, fever, respiratory or renal failure, arthralgias, acute leukaemia, acute leukaemias
DIFFERENTIATION SYNDROME, ADVERSE EVENT, ACUTE LEUKAEMIA, ACUTE LEUKAEMIAS, LEUKOCYTOSIS
The prognosis of acute leukaemias harbouring rearrangements of the gene lysine methyltransferase 2A (Genetic rearrangements of This phase 1 dose-escalation study was conducted across nine sites in the United States. Because revumenib is a substrate of cytochrome P450 3A4 (CYP3A4), two parallel dose-escalation cohorts, one without (Arm A) and one with (Arm B) strong CYP3A4 inhibitors, were conducted. Revumenib was administered orally every 12 h (q12h) in continuous 28-day cycles. Although all patients could enrol at study initiation regardless of cytogenetic and mutational profile, given the strong preclinical rationale demonstrating that the menin–KMT2A interaction is a targetable vulnerability in acute leukaemia with Baseline characteristics of patients are provided in Extended Data Table The dose-escalation schema is shown in Extended Data Fig. A total of 67 treated patients (99%) had an adverse event during treatment with revumenib whereas 53 patients (78%) had a treatment-related adverse event (TRAE) of any grade (Table Any-grade treatment-related and TEAEs, regardless of causalityAll AEs shown as ALT, alanine aminotransferase.A common occurrence in antileukaemia therapies that induce myeloid differentiation is the development of a clinically apparent differentiation syndrome. Differentiation syndrome is caused by cytokine alterations associated with haematopoietic differentiation, with common manifestations including fever, arthralgias, leukocytosis, pleural or pericardial effusions and respiratory or renal failure in severe casesPharmacokinetic studies showed that dose-proportional exposure was achieved in both Arm A (no strong CYP3A4 inhibitor) and Arm B (with a strong CYP3A4 inhibitor). Steady-state levels were achieved in approximately 48 h, with no evidence of drug accumulation (Extended Data Fig. Following a review of prespecified protocol criteria on safety, tolerability and pharmacokinetic data, the revumenib doses of 226 mg q12h and 276 mg q12h in Arm A and 113 mg q12h and 163 mg q12h in Arm B met the prespecified criteria for RP2D.The pharmacodynamic effects of revumenib were assessed through transcriptional changes following treatment using RNA-seq of bone marrow cells (Fig. 