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

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.

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Journal
Blood
Published
2026-10-26
DOI
https://doi.org/10.1182/blood.2026035181
Primary Topic
Hematopoietic Stem Cell Transplantation
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article
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article

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

Nuria Revilla, María Julia Montoro, Carolina Martínez‐Laperche, Mar Tormo et al.
Blood
Hematopoietic Stem Cell Transplantation
article

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

Nuria Revilla, María Julia Montoro, Carolina Martínez‐Laperche, Mar Tormo, Sara Alonso, Alberto Hernández‐Sánchez, Francisco José Ortuño, Lourdes Hermosín, David Valcárcel, Juan José Domínguez-García, Marta Santiago, Tzu Hua Chen‐Liang, Pascual Balsalobre, José Cervera, Guillermo Ramil López, Ana Alfonso Piérola, Miguel Piris‐Villaespesa, Elisa López‐Fernández, Guillermo Ortí, Iván Martín, Georgina Gener‐Ricos, Helena Pomares, Ana Rio‐Machín, Lucía López‐Corral, Francesc Bosch, Alberto Mussetti, María Díez‐Campelo, Cristina Bilbao, Marina Díaz‐Beyá, Marta Pratcorona, Ismael Buño, Gonzalo Carreño‐Tarragona, Francisca Hernández‐Mohedo, Lucía García-Mañó, Lurdes Zamora, Andrés Jerez, Laura Palomo, Miguel López‐Esteban, Sara Torres‐Esquius, Montserrat Arnán, María Gabarrós-Subirà, MARIA TERESA GOMEZ CASARES, Valle Gómez-García de Soria, Ferran Balbastre‐Úbeda, Rosa Ayala, Blanca Ferrer-Lores, Ana Iborra, María Jesús Pascual-Cascón, Francisco Beas, Guiomar Bautista
article en

Abstract

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.

Blood
Universidad de Las Palmas de Gran Canaria (ES), Universitat Autònoma de Barcelona (ES), Queen Mary University of London (GB), Universidad de Salamanca (ES), Instituto Cajal (ES), Hospital de Sant Pau (ES), Hospital General Universitario Gregorio Marañón (ES), Hospital Universitari i Politècnic La Fe (ES), Josep Carreras Leukaemia Research Institute (ES), Spanish National Cancer Research Centre (ES), Hospital General Universitario Morales Meseguer (ES), Hospital Clínico Universitario de Valencia (ES), Hospital Universitario de Gran Canaria Doctor Negrín (ES), Grupo Español de Trasplante Hematopoyético y Terapia Celular (ES), Complejo Hospitalario de Salamanca (ES), Marqués de Valdecilla University Hospital (ES), Hospital Universitario 12 De Octubre (ES), Hospital Universitario Puerta de Hierro Majadahonda (ES), Institut Català d'Oncologia (ES), Hospital Regional Universitario de Málaga (ES), Instituto de Investigación Marqués de Valdecilla (ES), Hospital Universitario Miguel Servet (ES), Hospital Clínic de Barcelona (ES), Hospital Universitario Virgen de las Nieves (ES), Vall d'Hebron Hospital Universitari (ES), Hospital Universitario de La Princesa (ES), Hospital Universitario Central de Asturias (ES), Instituto de Investigación Biomédica de Salamanca (ES), Clinica Universidad de Navarra (ES), Centro de Investigación del Cáncer (ES), Hospital Universitario Son Espases (ES), Hospital Universitari Germans Trias i Pujol (ES), Hospital Jerez Puerta del Sur (ES), INCLIVA Health Research Institute (ES), Centro de Investigación Biomédica en Red de Cáncer (ES), Hospital Universitario Ramón y Cajal (ES), Instituto de Investigación Sanitaria del Principado de Asturias (ES), Institut de Recerca Sant Pau (ES), Vall d'Hebron Institute of Oncology (ES), Instituto de Biología Molecular y Celular del Cáncer de Salamanca (ES), Hospital Universitario de Jerez (ES), Barts Cancer Institute (GB), Instituto de Investigación Sanitaria Gregorio Marañón (ES), Universidad Autónoma de Madrid (ES)
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Hematopoietic Stem Cell Transplantation
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