Mutational patterns and prognosis in younger versus older AML patients with myelodysplasia-related gene mutations undergoing allogeneic hematopoietic stem cell transplantation

Abstract Introduction The international consensus classification (ICC) has identified nine specific mutations, including ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1 and ZRSR2, as myelodysplasia-related gene (MRG) mutations in acute myeloid leukemia (AML). AML patients with MRG mutations are generally older at diagnosis and are assigned as adverse-risk according to the 2022 European LeukemiaNet (ELN) classification when favorable-risk genetic alterations are absent. However, the prognostic impact of MRG mutation profiles in AML patients undergoing allo-HSCT remains to be elucidated, particularly regarding age-dependent differences in both co-mutation patterns and transplant outcomes. Methods We retrospectively analyzed the AML patients with MRG mutations who underwent allo-HSCT at our institution from January 2018 to December 2023, with available genetic alteration data at diagnosis and follow-up data. Age thresholds for younger versus older groups were determined using survival-optimal cutoff analysis with log-rank tests across the 15th-85th percentile age distribution (Recipient age: 55 years, Donor age: 38 years). In this study, AML with MRG mutations was defined by the presence of one or more of the nine ICC-designated MRG mutations, irrespective of TP53 mutation status. Sample similarities were assessed by Jaccard distance based on the mutation status of MRG and TP53, followed by dimensionality reduction via t-SNE and subsequent clustering with the DBSCAN algorithm. The resulting clusters were designated as MRG&TP53-based clusters. Results Our analysis included 321 AML with MRG mutation patients, stratified by age into younger (≤55 years, n=260) and older (>55 years, n=61) group. Older AML recipients with MRG mutations demonstrated significantly inferior 5-year post-transplant overall survival (OS) compared to younger recipients (62.5% vs 76.2%, p=0.001). Similarly, recipients receiving grafts from older donors (>38 years, n=155) showed worse 5-year post-transplant OS than those with younger donors (≤38 years, n=151) (69.6% vs 78.5%, p=0.011). No significant differences were observed between younger and older recipients in induction response rates, complete remission (CR) status and bone marrow minimal residual disease (MRD) statues before allo-HSCT. Post-transplant complication including CMV or EBV reactivation and GvHD incidence were also no difference between younger and older recipients. HLA-haploidentical and HLA-matched donor distributions were no difference between younger and older recipient group, but haploidentical transplantation was associated with better 5-year post-transplant OS (75.4% vs 65.1%, p=0.042) without increased transplantation-related mortality (10.2% vs 10.8%, p=0.920). High MRG mutation burden (≥2 mutations) was more frequent in older versus younger recipients (50.8% vs 29.6%, p=0.032). Unsupervised clustering identified 11 distinct molecular subgroups (MRG&TP53-based clusters) based on MRG and TP53 mutation patterns. Among them, ASXL1plus cluster, which was characterized with ASXL1 mutation present in 85.7% of cases and co-occurrence of 1-2 additional MRG or TP53 alterations, predominated in older recipient group (29.5% vs 11.9%, p=0.032). Besides, SF3B1 cluster, which was characterized with isolated SF3B1 mutation without other MRG mutations but with non-MRG alteration, exhibited a worst 5-year post-transplant relapse-free survival (p=0.051). Furthermore, distinct co-mutation patterns were observed between younger and older group: FLT3-ITD predominated in younger recipients (16.9% vs 3.3%, p=0.011), whereas IDH2 mutation were more frequent in older recipients (10.4% vs 24.6%, p=0.006). Conclusion These findings revealed that older AML recipients with MRG mutations maintain poorer outcomes compared to younger recipients, even after allo-HSCT. However, older patients receiving haploidentical transplantation had improved survival compared to those receiving matched transplantation, whereas no donor-type effect was observed in younger recipients. Recipients with an isolated SF3B1 mutation exhibited the worst prognosis among all recipients with MRG mutations.