Germline DDX41 defines a distinct subgroup in MDS undergoing transplantation with reduced relapse and improved survival

Germline DDX41 variants are a recognized cause of adult myelodysplastic neoplasms (MDS), characterized by distinct biological features and favorable prognosis. The independent effect of DDX41 status on outcomes after allogeneic transplantation, the role of conditioning intensity, and treatment-related toxicity risk remain unresolved. To address this gap, we analyzed 1,514 patients with MDS undergoing transplantation prior to routine DDX41 testing alongside a wild-type comparator, providing an unbiased benchmark for this molecular subgroup. Forty-nine patients (3.2%) carried pathogenic/likely pathogenic (P/LP) germline DDX41 variants; 19 (39%) had an additional somatic DDX41 mutation, most commonly p.R525H. P/LP DDX41 cases were older (median 63 vs 59 years) and showed lower IPSS-M risk with absent TP53 mutations (0% vs 21%). In terms of outcome, 2-year relapse incidence was significantly lower in P/LP DDX41 (17% vs 34%, p=0.01). In multivariable analysis, the presence of a DDX41 P/LP variant independently associated with lower risk of relapse (hazard ratio 0.43, 95% CI 0.21-0.88; p=0.02), concentrated in the reduced-intensity/nonmyeloablative stratum. Adjusted models showed significantly improved disease-free survival (DFS) for P/LP DDX41 (hazard ratio 0.62, 95% CI 0.41-0.95; p=0.03) and no significant association with non-relapse mortality (NRM) or graft-versus-host disease (GVHD). In summary, these findings identify DDX41-associated MDS as a transplant subgroup with superior DFS regardless of conditioning intensity driven by reduced relapse risk and lack of excess NRM and GVHD supporting incorporation of germline DDX41 status into transplant planning.