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

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.

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Journal
Leukemia
Published
2026-02-09
DOI
https://doi.org/10.1038/s41375-026-02874-w
Primary Topic
Acute Myeloid Leukemia Research
Type
article
Field-Weighted Citation Impact
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article

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

Rabea Mecklenbrauck, Klaus Hans Metzeler, Brian J.P. Huntly, Marta Sobas et al.
Leukemia
Acute Myeloid Leukemia Research
article

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

Rabea Mecklenbrauck, Klaus Hans Metzeler, Brian J.P. Huntly, Marta Sobas, Jesse M. Tettero, Amin Taha Turki, Kenneth Ialn Mills, Lars Bullinger, M. Heuser, Peter J.M. Valk, Ángela Villaverde Ramiro, Razif Gabdoulline, I. Thomas, Steffi Lehmann, Laura Tur Giménez, Guadalupe Oñate, Alberto Hernandez-Sanchez, Javier Martínez Elicegui, Eric Sträng, Gastone Castellani, Konstanze Döhner, Axel Benner, Felicitas R. Thol, Gert J. Ossenkoppele, Florian H. Heidel, Jesus María Hernández-Rivas, Torsten Haferlach, Hartmut Döhner, Lisa Pleyer
article en

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.

LeukemiaVol. 40(3)
University of Rome Tor Vergata (IT), Queen's University Belfast (GB), German Cancer Research Center (DE), Universidad de Salamanca (ES), Wellcome/MRC Cambridge Stem Cell Institute (GB), Heidelberg University (DE), University of Cambridge (GB), Paracelsus Medical University (AT), University Hospitals of the Ruhr-University of Bochum (DE), Hospital de Sant Pau (ES), Erasmus MC (NL), Karolinska Institutet (SE), Nicolaus Copernicus University (PL), Medizinische Hochschule Hannover (DE), University of Oxford (GB), Munich Leukemia Laboratory (Germany) (DE), MRC Weatherall Institute of Molecular Medicine (GB), University Hospital Leipzig (DE), Instituto de Investigación Biomédica de Salamanca (ES), Collegium Medicum in Bydgoszcz (PL), Erasmus MC Cancer Institute (NL), Amsterdam University Medical Centers (NL), University Hospital in Halle (DE), University Hospital Ulm (DE), Martin Luther University Halle-Wittenberg (DE), Charité - Universitätsmedizin Berlin (DE), Cardiff University (GB), GMV Innovating Solutions (Spain) (ES), Ruhr University Bochum (DE), Leipzig University (DE), University of Bologna (IT)
José Carreras Leukämie-Stiftung, Deutsche Krebshilfe, Instituto de Salud Carlos III
Openalex Percentile: Top 60%
Acute Myeloid Leukemia Research
DOIOpen Access PDFOpenAlex
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