Prognostic impact of myelodysplasia-related gene mutations in FLT3-ITD-mutated acute myeloid leukemia

Mecklenbrauck, Rabea, Ramiro, Angela Villaverde, Strang, Eric, Gabdoulline, Razif, Martinez Elicegui, Javier, Sobas, Maria, Pleyer, Lisa, Turki, Amin, Voso, Maria Teresa, Benner, Axel, Hernandez-Sanchez, Alberto, Tettero, Jesse M., Tur Gimenez, Laura, Metzeler, Klaus H., Onate, Guadalupe, Lehmann, Soren, Huntly, Brian J. P., Thomas, Ian, Thol, Felicitas R. and Heidel, Florian H. 2026. Prognostic impact of myelodysplasia-related gene mutations in FLT3-ITD-mutated acute myeloid leukemia. Leukemia 10.1038/s41375-026-02874-w

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Abstract

The inclusion of nine myelodysplasia-related gene (MRG) mutations (ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, ZRSR2) as adverse risk factors in the ELN risk classification has reshaped classification in acute myeloid leukemia (AML). AML with FLT3-ITD mutations and co-occurring MRG alterations is now classified to the ELN adverse risk group although supporting evidence remains limited. Among 4,078 patients with AML with available molecular information included in the HARMONY platform, 862 harbored FLT3-ITD mutations and underwent intensive chemotherapy. Of these, 171 (20%) exhibited co-occurring MRG mutations at diagnosis. In this cohort, MRGs were not independently associated with relapse-free survival (RFS) or overall survival (OS). In the FLT3-ITD/NPM1 co-mutated subgroup, MRG mutations were rare (9%) and showed no prognostic impact. Conversely, in FLT3-ITD/NPM1 wildtype AML, MRG mutations were predictive of shorter RFS (HR 1.37, 95%CI 1.01 – 1.88, p = 0.046) and OS (HR 1.34, 95%CI 1.02–1.74, p = 0.032) in multivariable analysis with survival times comparable to the ELN adverse risk category. The allelic ratio of FLT3-ITD did not further stratify OS and RFS in this subgroup. These findings suggest that the prognostic relevance of MRG mutations in FLT3-ITD AML is modulated by NPM1 co-mutational status and mirror findings in AML lacking FLT3-ITD.

Item Type:	Article
Date Type:	Publication
Status:	In Press
Schools:	Schools > Medicine Research Institutes & Centres > Centre for Trials Research (CNTRR)
Additional Information:	For the full list of authors, please refer to the article webpage https://doi.org/10.1038/s41375-026-02874-w
Publisher:	Springer Science and Business Media LLC
ISSN:	0887-6924
Date of First Compliant Deposit:	16 February 2026
Date of Acceptance:	27 January 2026
Last Modified:	16 Feb 2026 12:38
URI:	https://orca.cardiff.ac.uk/id/eprint/184879

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