Mismatched Donor Transplants Reduced Relapse Risk

MISMATCHED unrelated donor transplant using posttransplant cyclophosphamide was associated with significantly lower relapse rates than matched related donor transplant in patients with high risk blood cancers, challenging traditional approaches to donor selection.

Matched related donors have long been regarded as the preferred option for allogeneic haematopoietic cell transplantation. However, advances in graft-versus-host disease prophylaxis with posttransplant cyclophosphamide have prompted renewed interest in whether mismatched unrelated donor transplants may provide stronger graft versus leukaemia effects without compromising overall outcomes. A new cohort study examined whether donor choice should be guided by disease biology as well as human leukocyte antigen matching.

Lower Relapse Observed in High Risk Disease

The retrospective study included 1,038 patients with acute leukaemia, myelodysplastic syndromes, or myeloproliferative neoplasms who underwent a first peripheral blood haematopoietic cell transplant between 2017 and 2024. Investigators compared outcomes in 306 patients receiving matched related donor transplants with 732 receiving mismatched unrelated donor transplant, with all patients receiving posttransplant cyclophosphamide.

Among patients with high or very high Disease Risk Index scores, mismatched unrelated donor transplantation was associated with a significantly lower hazard of relapse than matched related donor transplantation: hazard ratio: 0.56; 95% CI: 0.33–0.94; p=0.03. Reported relapse rates were 36% following mismatched unrelated donor transplantation compared with 56% after matched related donor transplantation.

Despite this reduction in relapse, disease-free survival: hazard ratio: 0.71; 95% CI: 0.46–1.11; p=0.14 and overall survival: hazard ratio: 0.85; 95% CI: 0.53–1.37; p=0.51 were comparable between the two groups.

Findings Could Influence Future Donor Selection

The study also demonstrated differences in graft-versus-host disease outcomes. Mismatched unrelated donor transplantation was associated with a lower risk of grade III–IV acute graft-versus-host disease: hazard ratio: 0.56; 95% CI: 0.32–0.98; p=0.04 but a higher risk of chronic graft-versus-host disease: hazard ratio: 2.82; 95% CI: 2.02–3.95; p<0.001.

The authors suggest these findings reflect enhanced alloreactivity associated with human leukocyte antigen mismatching in patients with aggressive disease. Rather than viewing donor hierarchy as fixed, the results indicate that mismatched unrelated donor transplant may offer a distinct risk benefit profile for selected patients with high risk haematological malignancies.

Although further prospective studies are needed, the findings suggest that future donor selection strategies could increasingly incorporate disease risk alongside donor matching, particularly as posttransplant cyclophosphamide continues to broaden the safe use of alternative donors in allogeneic transplantation.

Reference

Mehta RS et al. Mismatched unrelated vs matched related donor transplant with posttransplant cyclophosphamide among patients with blood cancers. JAMA Netw Open. 2026;9(7):e2623265.

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