Incidence and molecular underpinnings of donor-cell derived neoplasm among spanish transplantation centers
Abstract
Abstract Introduction After an allogeneic hematopoietic stem cell transplantation (allo-HSCT), a wide range of complications may occur. One of the less common, yet clinically significant, is the development of a donor-cell derived hematologic neoplasm (DCHN). Although their etiopathogenesis remains unclear, DCHNs are thought to arise from the combined effect of a genetic variant (either clonal hematopoiesis (CHIP) or germline variants) and the bone marrow microenvironment. The aim of this study was to assemble the largest national cohort of DCHNs to date, in order to characterize the disease, estimate the incidence and identify both somatic-CHIP and germline-predisposition variants. Methods We performed a multicenter retrospective study of patients diagnosed with DCHN. Donor origin of the neoplasm was suspected and confirmed by complete molecular donor chimerism (100%) and/or cytogenetic studies in cases of donor-recipient sex mismatch. A survey was distributed to Spanish centers performing allo-HSCTs in adults to collect essential clinical and genetic data related to the primary neoplasm (PN), peritransplant events and DCHN. When available, DNA from the donor (for related donors) and the DCHN was requested to perform: targeted-NGS panel enriched with frequently mutated genes in either myeloid or lymphoid neoplasms, depending on the DCHN lineage (x1400; CHIP characterization); and whole exome sequencing (WES) with a virtual panel of 455 predisposing genes (x100; germline predisposition). Results A total of 34 cases of DCHNs were identified across 23 Spanish transplant centers, diagnosed between 2007 and 2024. Notably, 63% of the cases (n=20) were diagnosed in the last 5 years, suggesting an increased awareness and detection of this complication. Regarding the transplant date, 68% of the allo-HSCTs were performed between 2013 and 2022 (n=21). Based on available National Transplant Organization (ONT) data, we estimated the incidence of DCHNs between 2020 and 2022 to be 0.29% of all transplants (n=8/2789), with a higher incidence in transplants from related (0.34%, n=6/1752) compared to unrelated donors (0.19%, n=2/1037). This aligns with the findings from our full cohort, where 31 of the 34 cases involved a related donor. The mean age at diagnosis of the PN was 48 years [range 18–73]. DCHNs diagnoses belonged to the myeloid (n=30) and the lymphoid lineage (n=3): acute myeloid leukemia (n=12), myelodysplastic syndrome (n=17), chronic myelomonocytic leukemia (n=1), mixed phenotype acute leukemia (n=1), cutaneous marginal zone B-cell lymphoma (n=1), cutaneous T-cell lymphoma (n=1) and lymphocytic lymphoma (n=1). Similarly, the PN that led to allo-HSCT were predominantly myeloid (n=24), while 9 were of lymphoid origin, including 4 acute lymphoblastic leukemias. Notably, in 9 cases, the DCHN appeared from a different hematopoietic lineage than the original neoplasia. Preparation for the transplant included in the 72% (n=23) of cases a reduced-intensity conditioning. Stem cell source was peripheral blood in 24 cases, bone marrow in 3, and cord blood in 2. At the time of donation, the mean age of the donors was 45 years [range 23-72]. The median latency between allo-HSCT and DCHN diagnosis was 50 months [range 16–390]. At data cutoff, 18 patients were deceased and 15 alive. The only remarkable cytogenetic characteristic was that chromosome 7 alterations were identified in 33.3% (n=10/30) of DCHNs. Genomic data was available for 28 DCHNs (23 paired with donor sample, 5 unpaired). Germline pathogenic variants in hematologic predisposition genes were detected in 11 donors and corresponding DCHN: DDX41 (n=6), CEBPA (n=2), biallelic CHEK2 (n=1), FH (n=1) and KMT2D (n=1). In two cases, donor material harbored CHIP-associated variants: one with a somatic SETBP1 mutation and the other with a monosomy 7 clone, both matching the clonal marker on the DCHN. Conclusions: Our findings confirm a strong predominance of DCHNs in related donor transplants. There is an increased awareness of the existence of DCHN and its implications, which can be deduced from the increase in diagnosed cases in the last five years. Germline predisposition was the main identifiable cause, present in 84.6% of genetically characterized cases. DDX41 and CEBPA accounted for 72.7% of these. Our findings support the implementation of routine germline screening in related donors, particularly targeting predisposition genes, to prevent donor-derived neoplasms.
Article Details
Authors (39)
Maria Gabarros-Subira
1Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology, Hematologic Genetic Diagnosis and Counseling Unit, Barcelona, Spain
Sara Torres-Esquius
1Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology, Hematologic Genetic Diagnosis and Counseling Unit, Barcelona, Spain
Helena Pomares
1Institut Català d'Oncologia - Hospital Duran i Reynals, Hematology, Hospitalet de Llobregat, Spain
Francisco Beas
1Vall d'Hebron Hospital, Department of Hematology, BARCELONA, Spain
Julia Suárez-Gonzalez
3Hospital General Universitario Gregorio Marañón. Instituto de Investigación Sanitaria Gregorio Marañón, Genomics Unit, Madrid, Spain
Alberto Hernández Sánchez
Hematology Department. Hospital Universitario de Salamanca, IBSAL, IBMCC, CSIC, Centro de Investigación del Cáncer, Salamanca, Spain
Elisa Lopez-Fernandez
5University Hospital Virgen de las Nieves, Hematology Department, Granada, Spain
Guillermo Ramil López
3Hospital de la Santa Creu i Sant Pau. Universitat Autònoma de Barcelona and IIB Sant Pau, Hematology Department, Barcelona, Spain
María Hermosín-Ramos
25Hospital Universitario Jerez de la Frontera, Jerez de la Frontera, Spain., Hematology Department, Jerez de la Frontera, Spain
Gonzalo Carreño
22Hospital Universitario 12 de Octubre, Madrid, Spain
Ivan Martín Castillo
1Hospital Clínico Universitario-INCLIVA, Hematology Department, Valencia, Spain
Juan Domínguez García
1HOSPITAL UNIVERSITARIO MARQUÉS DE VALDECILLA, Hematology, Santander, Spain
Marta Santiago
11Hospital Universitari i Politècnic La Fe, CIBERONC, Hematology Department and Genetics Unit, Valencia, Spain
Maria Pascual
12Hospital Universitario Regional de Málaga, Hematology Department, Málaga, Spain
Marina Díaz-Beyá
7Hospital Clínic Barcelona, Hematopathology Section, Barcelona, Spain
Guiomar Bautista Carrascosa
14Hospital General Universitario Puerta del Hierro, Hematology Department, Madrid, Spain
Raul Teruel Montoya
15IMIB-Arrixaca, Hospital General Universitario Morales Meseguer, Hematology Department and Medical Oncology Unit, Murcia, Spain
Francisco José Ortuño
15IMIB-Arrixaca, Hospital General Universitario Morales Meseguer, Hematology Department and Medical Oncology Unit, Murcia, Spain
Susana Vives
18Hospital U. Germans Trias i Pujol ICO Badalona, Badalona, Spain
Lucia García Mañó
4Son Espases University Hospital, Department of Hematology, Palma de Mallorca, Spain
Maria Teresa Gomez Casares
Hospital Universitario de Gran Canaria Dr. Negrín, Las Palmas de Gran Canaria, Spain
Ana Alfonso-Pierola
7Department of Oncology-Hematology, CIMA Universidad de Navarra-IDISNA-CCUN. Centro de Investigación Biomédica en Red de Cáncer, CIBERONC. Clínica Universidad de Navarra, Pamplona, Spain
Miguel Piris-Villaespesa
20Hospital Universitario Ramón y Cajal, Hematology Department, Madrid, Spain
Nuria Revilla
21Hospital Universitario Fundación Jiménez Díaz, Instituto de Investigación Fundación Jiménez Díaz (IIS-FJD), Servicio Hematología, Madrid, Spain
Sara Alonso
22Hospital Universitario Central de Asturias, Hematology Department, Oviedo, Spain
Ana Iborra
23Hospital Universitario Miguel Servet, Hematology Department, Zaragoza, Spain
Blanca Ferrer Lores
9Hospital Clínico Universitario-INCLIVA, Hematology Department, Valencia, Spain
Rosa María Ayala Díaz
8Hospital 12 de Octubre (i+12), Centro Nacional de Investigaciones Oncológicas (CNIO), Universidad Complutense, Hematology Department, Madrid, Spain
José Cervera
32Hematology Service, Hospital Universitario y Politécnico La Fe, Valencia, Spain and CIBERONC, Instituto de Salud Carlos III, Madrid, Spain
Lucia Lopez Corral
1University Hospital of Salamanca, Hematology, Salamanca, Spain
Marta Pratcorona Canela
3Hospital de la Santa Creu i Sant Pau. Universitat Autònoma de Barcelona and IIB Sant Pau, Hematology Department, Barcelona, Spain
Ismael Buño
24Hospital General Universitario Gregorio Marañón. Instituto de Investigación Sanitaria Gregorio Marañón, Hematology Department, Madrid, Spain
Maria Julia Montoro
1Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology, Hematologic Genetic Diagnosis and Counseling Unit, Barcelona, Spain
Francisca Hernandez
5University Hospital Virgen de las Nieves, Hematology Department, Granada, Spain
Francesc Bosch Albareda
5Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology, Barcelona, Spain
Montserrat Arnan
Institut Català d’Oncologia, L’Hospitalet de Llobregat, Institut d’Investigació Biomèdica de Bellvitge, Universitat de Barcelona, Barcelona
David Valcárcel
Carolina Martinez-Laperche
24Hospital General Universitario Gregorio Marañón. Instituto de Investigación Sanitaria Gregorio Marañón, Hematology Department, Madrid, Spain
Andres Jerez
1Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology, Hematologic Genetic Diagnosis and Counseling Unit, Barcelona, Spain