We read with interest the study by Sanz et al., reporting comparable outcomes for patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic cell transplantation (HCT) from 7/8 mismatched unrelated donors (MMUD) and 8/8 matched unrelated donors (MUD) in the context of post-transplant cyclophosphamide (PTCy) prophylaxis.1 While this work is thought-provoking, we respectfully caution against broad extrapolation of equivalence between MMUD and MUD.
Not all HLA mismatches carry the same immunologic risk.2 Petersdorf et al. demonstrated that HLA-B leader mismatch was associated with inferior survival in patients receiving one-allele MMUD.2 Although this was observed in the pre-PTCy era, subsequent data from the Japanese Society for Transplantation and Cellular Therapy showed that HLA-B leader mismatch continued to negatively impact outcomes even with PTCy, being associated with significantly worse overall survival and a trend toward higher relapse in patients with ALL and lymphoma.3 In our retrospective cohort receiving PTCy in combination with ATG, MMUD with HLA-A or HLA-B mismatches was associated with markedly worse outcomes, whereas mismatches at other loci yielded survival comparable to 10/10 MUD. On multivariable analysis, HLA-A and HLA-B mismatches remained independent predictors of inferior survival and higher non-relapse mortality.4
These findings highlight that mismatches differ in their impact, and combining all 7/8 donors into a single group may obscure important locus-specific risks, even within a uniform disease population. Until larger studies provide detailed analyses by specific antigen- or allele-level mismatches, caution is warranted before assuming full equivalence between 7/8 MMUD and 8/8 MUD.
We therefore advocate for more nuanced reporting, ideally distinguishing HLA-A versus HLA-B versus HLA-C versus HLA-DRB1 mismatches, and further research to determine whether particular mismatches could be “permissible” in the PTCy era. This granularity will be crucial to inform donor selection accurately and safely.
Footnotes
- Received August 25, 2025
- Accepted September 1, 2025
Correspondence
Disclosures
No conflicts of interests to disclose.
Contributions
References
- Sanz J, Ferhat AT, Kulagin A. Selection of unrelated donors for allogeneic transplantation using post-transplant cyclophosphamide in acute lymphoblastic leukemia: an analysis by the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation. Haematologica. 2026; 111(3):981-989. Google Scholar
- Petersdorf EW, Carrington M, O’hUigin C. Role of HLA-B exon 1 in graft-versus-host disease after unrelated haemopoietic cell transplantation: a retrospective cohort study. Lancet Haematol. 2020; 7(1):e50-60. Google Scholar
- Kanaya M, Hashimoto D, Nakamae H. P1261: negative impact of HLA-B leader mismatch on outcomes of HCT with PTCy for lymphoid malignancies: a retrospective analysis from the Japanese society for transplantation and cellular therapy. Hemasphere. 2023; 7(Suppl):e4940030. Google Scholar
- Novitzky-Basso I, Remberger M, Chen C. Anti-thymocyte globulin and post-transplant cyclophosphamide do not abrogate the inferior outcome risk conferred by human leukocyte antigen-A and -B mismatched donors. Eur J Haematol. 2022; 108(4):288-297. Google Scholar
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