Incidence, molecular and clinical characteristics of donor-derived hematologic malignancies after allogeneic stem cell transplantation for myeloid malignancies

Allogeneic stem cell transplantation (allo-SCT) is the only potentially curative approach for several high-risk hematologic malignancies, but high relapse rates remain a challenge. Most relapses derive from the original malignant clone or its descendants. Occasionally, secondary blood cancers arise from transplanted donor cells and are referred to as donor-derived malignancies (DDMs). To assess the incidence of DDM at our center we performed a retrospective observational study on all evaluable patients allo-transplanted for myeloid malignancies in the Dept. of SCT of UMC Hamburg-Eppendorf between 1990 and 2024. Until the end of the observation (12/2025), we observed 791 relapses after 2827 allo-SCTs (28%). For 751 (94.9%) of the relapses, material was available for detailed molecular analysis. Three myeloid malignancies (CMML, MDS, AML) were unambiguously identified as DDMs (two from matched related, one from an unrelated donor) corresponding to low frequencies of 0.1% of all transplants and 0.4% of analyzed relapses. Notably, in no case we found mutations in typical germline predisposition genes (DDX41, RUNX1, GATA2, CEBPA), whereas mutations associated with CHIP (ASXL1, TET2, DNMT3A, CBL, U2AF1) were detected in all DDMs. In conclusion, comprehensive data from this - to our knowledge largest - single-center study covering almost 3,000 consecutive transplants over a period of 35 years supports a low overall incidence of DDMs and a potential role of donor-derived clonal hematopoiesis in their development.