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.

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2025
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