Molecular Underpinnings and Prevalence of Donor Cell-Derived Hematologic Neoplasms among Spanish Transplantation...

Donor cell-derived hematologic neoplasm (DDHN) is defined as a de novo hematologic malignancy originated from transplanted donor stem cells, distinct from the original recipient's disease (ORD). Its prevalence and biological mechanisms remain poorly defined. We conducted a nationwide study to estimate the prevalence of DDHN and characterize its clinical and molecular features. Twenty-four transplantation centers systematically reviewed their allogeneic hematopoietic stem cell transplantation (allo-HSCT) cohorts. DDHN diagnosis required cytogenetic or molecular donor-origin confirmation. Molecular studies included germline-augmented targeted NGS, whole-exome sequencing, and donor-recipient comparative analyses. We identified 39 DDHN cases diagnosed between 2007 and 2025. Among 8,465 allo-HSCT performed between 2013-2022, DDHN prevalence was 0.28%, with a marked predominance after related-donor compared with unrelated transplantation (0.41% vs. 0.06%, p=0.0026). Median latency from transplantation to DDHN diagnosis was 56 months. Most DDHN were myeloid neoplasms, predominantly myelodysplastic neoplasms (51%) and acute myeloid leukemia (36%). Molecular characterization, available in 33 cases, revealed germline predisposition as the predominant underlying mechanism. Pathogenic/likely pathogenic germline variants were identified in 10 cases, involving DDX41 (n=7), CEBPA (n=2), and CHEK2 (n=1), all after a related-donor transplantation. DDX41-associated DDHN showed recurrent somatic hits and low genomic complexity. Donor-derived clonal hematopoiesis was confirmed in only one myeloid case involving U2AF1. These findings support inherited germline predisposition as the potential main molecular driver of DDHN after related allo-HSCT, reinforcing the recommendation for comprehensive germline evaluation of patients at ORD diagnosis prior to transplantation, followed by targeted cascade screening of candidate related donors.