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

Hernández-Sánchez, Alberto, Villaverde Ramiro, Ángela, Sträng, Eric, Turki, Amin T., Abáigar, María, Versluis, Jurjen, Thomas, Ian, Sobas, Marta, Martínez Elicegui, Javier, Castellani, Gastone, Benner, Axel, Azibeiro, Raúl, Tettero, Jesse M., Mecklenbrauck, Rabea, Martínez-López, Joaquín, Pratcorona, Marta, Mills, Ken I., Sanz, Guillermo, Voso, Maria Teresa, Sören, Lehmann, Röllig, Christoph, Thiede, Christian, Metzeler, Klaus H., Döhner, Konstanze, Heuser, Michael, Haferlach, Torsten, Valk, Peter JM, Russell, Nigel, Hernández-Rivas, Jesús María, Huntly, Brian, Ossenkoppele, Gert, Döhner, Hartmut and Bullinger, Lars 2026. Unravelling co-mutational patterns with prognostic implications in NPM1 mutated adult acute myeloid leukemia – a HARMONY study. Leukemia 40 , pp. 418-428. 10.1038/s41375-025-02851-9

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Schools > Medicine Research Institutes & Centres > Centre for Trials Research (CNTRR)
Publisher:	Springer Nature [academic journals on nature.com]
ISSN:	0887-6924
Date of First Compliant Deposit:	19 January 2026
Date of Acceptance:	12 December 2025
Last Modified:	03 Mar 2026 14:34
URI:	https://orca.cardiff.ac.uk/id/eprint/184013

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