Menin Inhibition With Revumenib for KMT2A -Rearranged Relapsed or Refractory Acute Leukemia (AUGMENT-101).

Autor:	Issa GC; Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX., Aldoss I; Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA., Thirman MJ; Biological Sciences Division, The University of Chicago Medicine, Chicago, IL., DiPersio J; John T. Milliken Department of Medicine, Division of Oncology, Washington University School of Medicine, St Louis, MO., Arellano M; Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA., Blachly JS; Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University, Columbus, OH., Mannis GN; Division of Hematology, Stanford University School of Medicine, Stanford, CA., Perl A; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA., Dickens DS; University of Iowa Stead Family Children's Hospital, Iowa City, IA., McMahon CM; UCHealth Blood Disorders and Cell Therapies Center, University of Colorado School of Medicine, Aurora, CO., Traer E; Knight Cancer Institute, Oregon Health & Science University, Portland, OR., Zwaan CM; Princess Máxima Center for Pediatric Oncology, Utrecht, and Erasmus MC-Sophia Children's Hospital, Rotterdam, the Netherlands., Grove CS; Department of Haematology, Sir Charles Gairdner Hospital, Nedlands, Australia., Stone R; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA., Shami PJ; University of Utah Huntsman Cancer Institute, Salt Lake City, UT., Mantzaris I; Department of Oncology, Montefiore Einstein Comprehensive Cancer Center, Bronx, NY., Greenwood M; Department of Haematology, Royal North Shore Hospital, The University of Sydney, Sydney, New South Wales, Australia., Shukla N; Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY., Cuglievan B; Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX., Kovacsovics T; City of Hope Phoenix, Goodyear, AZ., Gu Y; Syndax Pharmaceuticals, Inc, Waltham, MA., Bagley RG; Syndax Pharmaceuticals, Inc, Waltham, MA., Madigan K; Syndax Pharmaceuticals, Inc, Waltham, MA., Chudnovsky Y; Syndax Pharmaceuticals, Inc, Waltham, MA., Nguyen HV; Syndax Pharmaceuticals, Inc, Waltham, MA., McNeer N; Syndax Pharmaceuticals, Inc, Waltham, MA., Stein EM; Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY.
Jazyk:	angličtina
Zdroj:	Journal of clinical oncology : official journal of the American Society of Clinical Oncology [J Clin Oncol] 2025 Jan; Vol. 43 (1), pp. 75-84. Date of Electronic Publication: 2024 Aug 09.
DOI:	10.1200/JCO.24.00826
Abstrakt:	Purpose: Revumenib, an oral, small molecule inhibitor of the menin-lysine methyltransferase 2A (KMT2A) interaction, showed promising efficacy and safety in a phase I study of heavily pretreated patients with KMT2A -rearranged ( KMT2Ar ) acute leukemia. Here, we evaluated the activity of revumenib in individuals with relapsed/refractory (R/R) KMT2Ar acute leukemia. Methods: AUGMENT-101 is a phase I/II, open-label, dose-escalation and expansion study of revumenib conducted across 22 clinical sites in five countries (ClinicalTrials.gov identifier: NCT04065399). We report results from the phase II, registration-enabling portion. Individuals age ≥30 days with R/R KMT2Ar acute leukemia or with AML and nucleophosmin 1 ( NPM1 ) mutation were enrolled. Revumenib was administered once every 12 hours, at 163 mg (95 mg/m 2 if weight <40 kg) with a strong cytochrome P450 inhibitor, in 28-day cycles. The primary end points were the rate of complete remission (CR) or CR with partial hematologic recovery (CR + CRh) and safety. At a prespecified interim analysis, safety was assessed in all KMT2Ar treated patients; efficacy was assessed in those with centrally confirmed KMT2Ar . The separate NPM1 cohort of the trial is ongoing. Results: From October 1, 2021, to July 24, 2023, N = 94 patients (median [range] age, 37 [1.3-75] years) were treated. Grade ≥3 adverse events included febrile neutropenia (37.2%), differentiation syndrome (16.0%), and QTc prolongation (13.8%). In the efficacy-evaluable patients (n = 57), the CR + CRh rate was 22.8% (95% CI, 12.7 to 35.8), exceeding the null hypothesis of 10% ( P = .0036). Overall response rate was 63.2% (95% CI, 49.3 to 75.6), with 15 of 22 patients (68.2%) having no detectable residual disease. Conclusion: Revumenib led to high remission rates with a predictable safety profile in R/R KMT2Ar acute leukemia. To our knowledge, this trial represents the largest evaluation of a targeted therapy for these patients.
Databáze:	MEDLINE
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