Molecular, clinical, and therapeutic determinants of outcome in NPM1-mutated AML.

Autor:	Othman J; Department of Medical and Molecular Genetics, King's College London, London, United Kingdom.; Department of Haematology, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom.; Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia., Potter N; Department of Medical and Molecular Genetics, King's College London, London, United Kingdom., Ivey A; Alfred Hospital and Monash University, Melbourne, VIC, Australia., Tazi Y; Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY., Papaemmanuil E; Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY., Jovanovic J; Department of Medical and Molecular Genetics, King's College London, London, United Kingdom., Freeman SD; Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom., Gilkes A; Department of Haematology, Cardiff University, Cardiff, United Kingdom., Gale R; Department of Haematology, University College London Cancer Institute, London, United Kingdom., Rapoz-D'Silva T; Department of Haematology, University College London Cancer Institute, London, United Kingdom., Runglall M; Department of Medical and Molecular Genetics, King's College London, London, United Kingdom.; Department of Haematology, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom., Kleeman M; Genomics Facility, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom., Dhami P; Genomics Facility, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom., Thomas I; Centre for Trials Research, Cardiff University, Cardiff, United Kingdom., Johnson S; Centre for Trials Research, Cardiff University, Cardiff, United Kingdom., Canham J; Centre for Trials Research, Cardiff University, Cardiff, United Kingdom., Cavenagh J; St Bartholomew's Hospital, Barts Health NHS Trust, London, United Kingdom., Kottaridis P; University College London Hospital NHS Foundation Trust, London, United Kingdom., Arnold C; Clinical Haematology, Belfast City Hospital, Belfast, United Kingdom., Ommen HB; Department of Haematology, University Hospital, Aarhus, Denmark., Overgaard UM; Department of Haematology, Copenhagen University Hospital, Copenhagen, Denmark., Dennis M; The Christie NHS Foundation Trust, Manchester, United Kingdom., Burnett A; Paul O'Gorman Leukaemia Centre, Glasgow University, Glasgow, Scotland., Wilhelm-Benartzi C; Centre for Trials Research, Cardiff University, Cardiff, United Kingdom., Huntly B; Department of Haematology and Cambridge Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom., Russell NH; Department of Haematology, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom., Dillon R; Department of Medical and Molecular Genetics, King's College London, London, United Kingdom.; Department of Haematology, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2024 Aug 15; Vol. 144 (7), pp. 714-728.
DOI:	10.1182/blood.2024024310
Abstrakt:	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.)
Databáze:	MEDLINE
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