Comparative Analysis of ICC and WHO Classifications Reveals Molecular and Clinical Convergence Between AML‐MR and MDS/AML

The 2022 WHO and ICC classifications introduced conflicting definitions for myelodysplasia-related acute myeloid leukemia (AML-MR) and myelodysplastic syndrome/AML (MDS/AML), leading to diagnostic uncertainty. This study compared the molecular and clinical characteristics of these entities to clarify their relationship. We conducted a multicenter retrospective study of 568 AML and 75 MDS/AML patients from a Chinese cohort, with findings validated in two independent public cohorts (n = 524). Molecular features, treatment responses, and overall survival (OS) were compared across subgroups defined by WHO and ICC criteria. AML-MR and MDS/AML patients exhibited overlapping molecular features, including frequent ASXL1 (25.0% vs. 22.7%) and TP53 mutations (19.4% vs. 12.0%), as well as a high incidence of complex karyotypes (24.4% vs. 21.3%). Non-AML-MR cases had significantly lower frequencies of these alterations but were enriched for NPM1 and FLT3 mutations (all p < 0.05). AML-MR patients had significantly shorter OS than Non-AML-MR patients across both classification systems (median OS: 10.3 vs. > 22 months, p < 0.001), but comparable remission rates (p = 0.514) and OS (10.3 vs. 13.3 months, p = 0.425) to MDS/AML. IPSS-R and IPSS-M showed no prognostic discrimination in either group (p > 0.05), while ELN 2022 showed limited predictive performance. In response, we developed a modified risk stratification model that categorized patients into three risk groups with distinct survival outcomes (median OS: 21.7, 8.5, and 5.7 months; p < 0.0001). This model remained discriminatory within the AML-MR (13.7 vs. 8.5 vs. 5.6 months, p = 0.001) and MDS/AML (31.2 vs. 11.7 vs. 6.3 months, p = 0.0044) subgroups and was validated in external cohorts (p < 0.01). AML-MR and MDS/AML form a biological continuum with shared molecular and clinical features, supporting the ICC classification update. Our integrated model may improve prognostic stratification and guide clinical decision-making for these high-risk patients.