Unravelling co-mutational patterns with prognostic implications in NPM1 mutated adult acute myeloid leukemia – a HARMONY study

NPM1-mutated (NPM1-mut) acute myeloid leukemia (AML) is generally associated with a more favorable outcome, although the presence of additional gene mutations can influence patient prognosis. We analyzed intensively-treated adult NPM1-mut AML patients included in the HARMONY Alliance database. A newly developed risk classification, which included combinations of co-mutations in FLT3-ITD, DNMT3A, IDH1/IDH2, and TET2 genes, was applied to a training cohort of NPM1-mut AML patients included in clinical trials (n = 1001), an internal validation cohort more representative of real-world settings (n = 762), and an external validation cohort enrolled in UK-NCRI trials (n = 585). The HARMONY classification considered 51.8% of the NPM1-mut AML training cohort patients as favorable, 24.8% as intermediate, and 23.4% as adverse risk, with median overall survival (OS) of 14.4, 2.2, and 0.9 years, respectively; p < 0.001), thereby reclassifying 42.7% of NPM1-mut patients into a different European LeukemiaNet (ELN) 2022 risk category. These results were confirmed both in an internal and external validation cohort. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) in first complete remission (CR1) showed the highest benefit in the NPM1-mut adverse-risk subgroup. The HARMONY classification provides the basis for a refined genetic risk stratification for adult NPM1-mut AML with potential clinical impact on allo-HSCT decision-making.

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Journal
Leukemia
Published
2026-01-14
DOI
https://doi.org/10.1038/s41375-025-02851-9
Primary Topic
Acute Myeloid Leukemia Research
Type
article
Field-Weighted Citation Impact
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article

Unravelling co-mutational patterns with prognostic implications in NPM1 mutated adult acute myeloid leukemia – a HARMONY study

María Abáigar, Rabea Mecklenbrauck, K. Mills, Klaus Hans Metzeler et al.
Leukemia
Acute Myeloid Leukemia Research
article

Unravelling co-mutational patterns with prognostic implications in NPM1 mutated adult acute myeloid leukemia – a HARMONY study

María Abáigar, Rabea Mecklenbrauck, K. Mills, Klaus Hans Metzeler, Jurjen Versluis, Marta Sobas, Lehmann Soren, Jesse M. Tettero, Amin Taha Turki, Lars Bullinger, Peter J.M. Valk, Ángela Villaverde Ramiro, Alberto Hernandez-Sanchez, Michael Heuser, Raúl Azibeiro, Nigel Russell, Christoph Röllig, Javier Martínez Elicegui, Eric Sträng, Hartmut Döhner, Gert Ossenkoppele, Gastone Castellani, Konstanze Döhner, Torsten Haferlach, Axel Benner, Brian JP Huntly, Marta Pratcorona, Guillermo Sanz, Christian Thiede, Jesús María Hernández-Rivas, Ian Thomas
article en

Abstract

NPM1-mutated (NPM1-mut) acute myeloid leukemia (AML) is generally associated with a more favorable outcome, although the presence of additional gene mutations can influence patient prognosis. We analyzed intensively-treated adult NPM1-mut AML patients included in the HARMONY Alliance database. A newly developed risk classification, which included combinations of co-mutations in FLT3-ITD, DNMT3A, IDH1/IDH2, and TET2 genes, was applied to a training cohort of NPM1-mut AML patients included in clinical trials (n = 1001), an internal validation cohort more representative of real-world settings (n = 762), and an external validation cohort enrolled in UK-NCRI trials (n = 585). The HARMONY classification considered 51.8% of the NPM1-mut AML training cohort patients as favorable, 24.8% as intermediate, and 23.4% as adverse risk, with median overall survival (OS) of 14.4, 2.2, and 0.9 years, respectively; p < 0.001), thereby reclassifying 42.7% of NPM1-mut patients into a different European LeukemiaNet (ELN) 2022 risk category. These results were confirmed both in an internal and external validation cohort. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) in first complete remission (CR1) showed the highest benefit in the NPM1-mut adverse-risk subgroup. The HARMONY classification provides the basis for a refined genetic risk stratification for adult NPM1-mut AML with potential clinical impact on allo-HSCT decision-making.

LeukemiaVol. 40(2)
University of Rome Tor Vergata (IT), Queen's University Belfast (GB), St Thomas' Hospital (GB), Uppsala University Hospital (SE), German Cancer Research Center (DE), Universidad de Salamanca (ES), Wellcome/MRC Cambridge Stem Cell Institute (GB), Heidelberg University (DE), University of Cambridge (GB), University Hospitals of the Ruhr-University of Bochum (DE), Instituto de Salud Carlos III (ES), Hospital de Sant Pau (ES), Karolinska Institutet (SE), Hospital Universitari i Politècnic La Fe (ES), Nicolaus Copernicus University (PL), Medizinische Hochschule Hannover (DE), University of Oxford (GB), Munich Leukemia Laboratory (Germany) (DE), IRCCS Azienda Ospedliero-Universitaria di Bologna Policlinico di Sant'Orsola (IT), Hospital Universitario 12 De Octubre (ES), Amsterdam Neuroscience (NL), MRC Weatherall Institute of Molecular Medicine (GB), Azienda USL di Bologna (IT), Instituto de Investigación Biomédica de Salamanca (ES), Centro de Investigación del Cáncer (ES), Collegium Medicum in Bydgoszcz (PL), Erasmus MC Cancer Institute (NL), Amsterdam University Medical Centers (NL), University Hospital Ulm (DE), Centro de Investigación Biomédica en Red de Cáncer (ES), University Hospital Carl Gustav Carus (DE), Martin Luther University Halle-Wittenberg (DE), Technische Universität Dresden (DE), Charité - Universitätsmedizin Berlin (DE), Cardiff University (GB), Ruhr University Bochum (DE), Leipzig University (DE), University of Bologna (IT)
European Federation of Pharmaceutical Industries and Associations, European Commission, Deutsche Forschungsgemeinschaft, Deutsche Krebshilfe, Instituto de Salud Carlos III
Openalex Percentile: Top 90%
Acute Myeloid Leukemia Research
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