The impact of DNMT3A mutation on survival of AML patients receiving allotransplant in first remission depends on the karyotype and co-occurring mutations

Mutations in the DNMT3A gene are not yet classified as a distinct prognostic group in the latest European Leukemia Net (ELN) 2022 genetic risk classification of AML. We analyzed 1888 adult AML patients with ELN 2022 intermediate- or poor-risk cytogenetics who received their first allo-transplant in first complete remission between 2015 and 2022. Among patients with cytogenetically normal AML, the triple-positive mutation group (DNMT3A, NPM1, and FLT3-ITD) was the most frequent (n = 340, 29%), while DNMT3A co-occurrence with either FLT3 or NPM1 mutations alone was less common (4% and 9%, respectively). Patients with DNMT3A mutations were less likely to have a secondary AML (14% versus 24%, p < 0.001). DNMT3A mutations negatively affected post-transplant leukemia-free survival (LFS) in patients with normal karyotype and NPM1 mutation without FLT3-ITD (2-year LFS: 70% versus 90%, hazard ratio [HR]: 3.3, p = 0.006), and increased relapse incidence (RI) in FLT3-ITD and wild-type NPM1 subgroup (2-year RI: 30% versus 18%, HR: 2.32, p = 0.03). Notably, patients with normal karyotype and triple-positive mutation exhibited excellent 2-year LFS and OS (61% and 70%), indicating that allo-transplant overcomes the dismal outcome of this group. The impact of DNMT3A mutations on post-transplant outcomes in AML patients in first remission varies based on karyotype and co-mutations.