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

Othman, Jad, Potter, Nicola, Ivey, Adam, Tazi, Yanis, Papaemmanuil, Elli, Jovanovic, Jelena, Freeman, Sylvie D., Gilkes, Amanda Frances, Gale, Rosemary E., Rapoz-D'Silva, Tanya, Runglall, Manohursingh, Kleeman, Michelle, Dhami, Pawan, Thomas, Ian, Johnson, Sean, Canham, Joanna ORCID: https://orcid.org/0000-0003-3482-0990, Cavenagh, James Durrell, Kottaridis, Panagiotis, Arnold, Claire, Ommen, Hans Beier, Overgaard, Ulrik Malthe, Dennis, Mike, Burnett, Alan Kenneth, Wilhelm-Benartzi, Charlotte S. ORCID: https://orcid.org/0000-0003-4927-6158, Huntly, Brian J.P., Russell, Nigel H. and Dillon, Richard James 2024. Molecular, clinical and therapeutic determinants of outcome in NPM1 mutated AML. Blood 10.1182/blood.2024024310
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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 outcome, however only FLT3-ITD mutation and adverse karyotype are currently used for risk stratification due to inconsistent results and uncertainty around how other factors should influence treatment, particularly given the strong prognostic impact of post-induction measurable residual disease (MRD). Here we analyzed a large group of patients with NPM1mut AML enrolled in prospective trials (NCRI AML17 and AML19, n=1357) to delineate the impact of baseline molecular and clinical features, post induction MRD status and treatment intensity on outcome. FLT3-ITD (HR 1.28, 95%CI 1.01-1.63), DNMT3A (HR 1.65, 95%CI 1.32-2.05), WT1 (HR 1.74, 95%CI 1272-2.38) and non-ABD NPM1 mutations (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 achieving 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 regimen was associated with improved outcomes in all subgroups, with greater benefits observed in the highest risk molecular subgroups.

Item Type: Article
Date Type: Published Online
Status: In Press
Schools: Medicine
Centre for Trials Research (CNTRR)
Publisher: American Society of Hematology (ASH Publications)
ISSN: 0006-4971
Date of First Compliant Deposit: 4 June 2024
Date of Acceptance: 15 April 2024
Last Modified: 04 Jun 2024 08:15
URI: https://orca.cardiff.ac.uk/id/eprint/168894

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