1. Molecular, clinical, and therapeutic determinants of outcome in NPM1-mutated AML.
- Author
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Othman J, Potter N, Ivey A, Tazi Y, Papaemmanuil E, Jovanovic J, Freeman SD, Gilkes A, Gale R, Rapoz-D'Silva T, Runglall M, Kleeman M, Dhami P, Thomas I, Johnson S, Canham J, Cavenagh J, Kottaridis P, Arnold C, Ommen HB, Overgaard UM, Dennis M, Burnett A, Wilhelm-Benartzi C, Huntly B, Russell NH, and Dillon R
- Subjects
- Humans, Middle Aged, Female, Male, Adult, Aged, Prognosis, Young Adult, Neoplasm, Residual genetics, DNA Methyltransferase 3A, Antineoplastic Combined Chemotherapy Protocols therapeutic use, WT1 Proteins genetics, DNA (Cytosine-5-)-Methyltransferases genetics, Adolescent, Treatment Outcome, Aged, 80 and over, Nucleophosmin, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute therapy, Leukemia, Myeloid, Acute mortality, Leukemia, Myeloid, Acute drug therapy, Nuclear Proteins genetics, Mutation, fms-Like Tyrosine Kinase 3 genetics
- Abstract
Abstract: Although NPM1-mutated acute myeloid leukemia (AML) carries a generally favorable prognosis, many patients still relapse and die. Previous studies identified several molecular and clinical features associated with poor outcomes; however, only FLT3-internal tandem duplication (ITD) mutation and adverse karyotype are currently used for risk stratification because of inconsistent results and uncertainty about how other factors should influence treatment, particularly given the strong prognostic effect of postinduction measurable residual disease (MRD). Here, we analyzed a large group of patients with NPM1 mutations (NPM1mut) AML enrolled in prospective trials (National Cancer Research Institute [NCRI] AML17 and AML19, n = 1357) to delineate the impact of baseline molecular and clinical features, postinduction MRD status, and treatment intensity on the outcome. FLT3-ITD (hazard ratio [HR], 1.28; 95% confidence interval [CI], 1.01-1.63), DNMT3A (HR, 1.65; 95% CI, 1.32-2.05), WT1 (HR, 1.74; 95% CI, 1.27-2.38), and non-ABD NPM1mut (HR, 1.64; 95% CI, 1.22-2.21) were independently associated with poorer overall survival (OS). These factors were also strongly associated with MRD positivity. For patients who achieved MRD negativity, these mutations (except FLT3-ITD) were associated with an increased cumulative incidence of relapse (CIR) and poorer OS. However, apart from the few patients with adverse cytogenetics, we could not identify any group of MRD-negative patients with a CIR >40% or with benefit from allograft in first remission. Intensified chemotherapy with the FLAG-Ida (fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin) regimen was associated with improved outcomes in all subgroups, with greater benefits observed in the high-risk molecular subgroups., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)
- Published
- 2024
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