Impact of <i>NPM1</i> co-mutation on post-transplant outcomes in MRG-mutated AML.

Abstract

6562 Background: Myelodysplasia-related gene (MRG) mutations are classified as adverse risk per ELN 2022, and allogeneic cell transplantation (allo-HCT) is recommended. However, it remains unclear whether post-transplant outcomes in MRG-mutated AML are inferior compared with other ELN-defined higher-risk AML without MRG mutations, and whether the presence of a favorable co-mutation NPM1 modifies prognosis after transplantation. Methods: We conducted a retrospective study of adult patients with AML who underwent allo-HCT at our institution between January 2015 and January 2025. MRG mutations defined per ELN. Patients were categorized into four molecular groups: MRG-mutated/NPM1 wild-type (MRG^mutNPM1^wt), MRG-mutated/NPM1-mutated (MRG^mutNPM1^mut), MRG–wild-type/NPM1-mutated (MRG^wtNPM1^mut), and MRG–wild-type/NPM1 wild-type (MRG^wtNPM1^wt).Overall survival (OS) and RFS were calculated using the Kaplan–Meier. Adjusted OS and RFS were estimated using propensity score matching accounting for age, sex, remission status at transplant (CR1 vs others), and conditioning intensity. Results: A total of 146 patients with complete molecular and cytogenetic data were included. Forty-two percent were MRG^wtNPM1^wt, 16% were MRG^wtNPM1^mut, 23% were MRG^mutNPM1^mut, and 19% were MRG^mutNPM1^wt. Cytogenetic risk distribution was 11% favorable, 71% intermediate, and 18% adverse. Among patients with favorable cytogenetics, 86% were either MRG^wtNPM1^wt or MRG^mutNPM1^mut, and none had MRG^mutNPM1^wt disease. In contrast, among patients with adverse cytogenetics, 17% had MRG^mutNPM1^wt, 23% had MRG^mutNPM1^mut, and 45% had MRG^wtNPM1^wt disease (p = 0.07).There was no significant difference in OS across molecular subgroups, with median OS of 70 months (95% CI 40–NR) for MRG^wtNPM1^mut, 101 months (95% CI 20–NR) for MRG^mutNPM1^mut, 69 months (95% CI 27–NR) for MRG^mutNPM1^wt, and 94 months (95% CI 59–NR) for MRG^wtNPM1^wt (p = 0.5). However, patients with MRG^mutNPM1^wt demonstrated a trend toward inferior RFS, with a median RFS of 17 months (95% CI 13–NR), compared with RFS not reached in the MRG^wtNPM1^mut, MRG^mutNPM1^mut, and MRG^wtNPM1^wt groups (p = 0.1). These findings remained consistent after propensity score adjustment. Conclusions: Our findings suggest that the presence of an NPM1 mutation may mitigate post-transplant relapse risk in patients with MRG-mutated AML. In contrast, patients with MRG-mutated/NPM1 wild-type disease appear to have inferior relapse-free survival after allo-HCT compared with other ELN-defined adverse-risk AML subgroups. These results indicate biologic heterogeneity within adverse-risk AML and highlight the need for refined post-transplant risk stratification and relapse-prevention strategies in MRG-mutated/NPM1 wild-type AML.