Toward a unified classification of acute myeloid leukemia, myelodysplasia-related: a multicenter retrospective study

The 5th Edition of the World Health Organization Classification of Haematolymphoid Neoplasms (WHO5th) and the 2022 International Consensus Classification (ICC) both recognize myelodysplasia-related acute myeloid leukemia (AML-MR) as a diagnostic entity increasingly defined by integrated genomic data. Although largely concordant, the two classifications differ in various ways that should be resolved to achieve future harmonization. To address the areas of uncertainty, we retrospectively analyzed 615 newly diagnosed AML cases from adult patients treated at two large cancer centers. We demonstrate that AML-MR, whether defined by gene mutations (MR-GM) or cytogenetic abnormalities (MR-CGA), constitutes a prognostically distinct group with inferior outcome compared to most AML subtypes, second only to TP53-mutated or EVI1-rearranged AML. Isolated RUNX1 mutations were not associated with antecedent myeloid neoplasia. Neither the number of mutated MR genes nor their variant allele frequency independently impacted outcomes. Trisomy 8 and del(20q) did not confer inferior outcomes and may warrant exclusion from MR-CGA. Complex karyotype without TP53 mutations did not worsen outcomes within AML-MR and may be considered equivalent to other MR-CGA. The adverse prognosis of AML-MR appeared to be at least partly driven by ASXL1 and/or EZH2 mutations. These findings provide evidence toward a unified schema across the WHO5th and ICC.