Disease biology rather than donor type determines transplant outcomes in KMT2A-rearranged AML

The relative contributions of donor selection and disease biology to transplant outcomes in KMT2A -rearranged ( KMT2A-r ) acute myeloid leukemia (AML) remain poorly defined. We retrospectively analyzed 241 consecutive patients with KMT2A-r AML undergoing first allogeneic hematopoietic stem cell transplantation (allo-HSCT) in complete remission (192 HID, 29 MSD, 20 MUD). We evaluated the impact of donor type, fusion partners, cooperating mutations, pre-transplant measurable residual disease (MRD), and disease status on post-transplant outcomes. After a median follow-up of 28.4 months, the estimated 2-year overall survival (OS), leukemia-free survival (LFS), cumulative incidence of relapse (CIR), and non-relapse mortality (NRM) were 80.0%, 78.9%, 9.5%, and 14.3%, respectively. Post-transplant outcomes were comparable across donor platforms. Likewise, transplant outcomes did not differ among major KMT2A fusion partners. In contrast, disease-related factors independently predicted prognosis. NRAS mutation remained independently associated with inferior OS (HR 2.70, P = 0.003) and LFS (HR 2.37, P = 0.008). Compared with transplantation in CR1, transplantation in ≥CR2 independently predicted worse OS (HR 2.71, P = 0.005), LFS (HR 2.40, P = 0.012), and higher NRM (HR 3.17, P = 0.006). Pre-transplant concurrent positivity by both MFC and RT-qPCR for KMT2A fusion transcripts (MFC+/RT-qPCR+) was the strongest adverse prognostic factor, independently predicting inferior survival and increased relapse, while isolated molecular positivity (MFC−/RT-qPCR+) also remained associated with inferior OS and LFS. An exploratory biologic risk stratification integrating NRAS mutation, transplantation in ≥CR2, and molecular MRD positivity effectively identified patients at high risk of treatment failure, with 2-year OS of 50.4% versus 85.6% and LFS of 48.6% versus 84.6% (both P < 0.0001). In KMT2A-r AML undergoing allo-HSCT in complete remission, post-transplant outcome is determined predominantly by leukemia biology rather than donor platform. These findings support a shift from donor-centered transplantation toward biology-driven risk assessment and individualized post-transplant management.