Cumulative burden of myelodysplasia-related gene mutations is associated with poor leukemia-free survival in ELN-2022 favorable-risk AML

Abstract Background: The new category acute myeloid leukemia (AML) with myelodysplasia-related (MDS-R) gene is designated as “adverse-risk” based on the 2022 European Leukemia Net (ELN) risk stratification. However, the significance of MDS-R gene mutations in favorable-risk AML remains unclear. Methods: We retrospectively analysed a cohort of 221 adult patients with de novo favorable-risk AML. Risk groups were classified according to the 2022 European Leukemia Net guideline. Results: A total of 47 AML patients (21.3%) harbored MDS-R mutations. ASXL1 mutation (17/47, 36.2%) was the most frequently identified, followed by BCOR (10/47, 21.3%), EZH2 (9/47, 19.1%), ZRSR2 (7/47, 14.9%), SRSF2 (7/47, 14.9%), STAG2 (5/47, 10.6%), SF3B1 (4/47, 8.5%), RUNX1 (4/47, 8.5%) and U2AF1 (1/47, 2.1%). The presence of MDS-R mutations was associated with older age (57 vs. 49, p = 0.005), lower white blood cell count (6.9 vs. 14.5, p = 0.015), and the presence of TET2 (27.7% vs. 10.9%, p = 0.004), MPL (6.4% vs. 0.6%, p = 0.031), and ETV6 (6.4% vs. 1.1%, p = 0.066) mutations. Response to induction therapy was comparable between patients with and without MDS-R mutations (46.8% vs. 44.3% achieved CR, p = 0.755; 29.8% vs. 35.6% achieved CRi/CRh, p = 0.454). However, patients with MDS-R mutations required more induction cycles to achieve CR (8.9% vs. 1.8%, p = 0.037). Our findings indicated that MDS-R mutations did not significantly impact 2-year overall survival (OS) (75.2% vs. 69.4%, p = 0.285) or leukemia-free survival (LFS) (58.9% vs. 52.5%, p = 0.640). However, patients with two or more MDS-R mutations had significantly poorer LFS than those with one MDS-R mutations (p = 0.004) or without MDS-R mutations (p = 0.001). By multivariable analysis, ≥2 MDS-R mutations was independently associated with worse LFS (HR 3.04, CI 1.33-6.92, P = 0.008). Conclusion: This retrospective study suggested that MDS-R gene mutations have no prognostic significance in favorable-risk AML，but the mutational burden (≥2 mutations) significantly impacts clinical outcomes. These results broaden our understanding of MDS-R alterations in AML leukemogenesis and refine risk stratification within ELN-2022 favorable-risk subtypes.