Extended HLA Haplotypes Linked to Survival After Hematopoietic Cell Transplantation

Extended HLA Haplotypes and Transplant Survival

• Extended HLA class I–class III–class II haplotypes affect mortality and relapse after haploidentical hematopoietic cell transplantation.

• A class III single-nucleotide polymorphism (rs915654) improves risk models for relapse and mortality when added to HLA matching.

• Patients with more favorable markers had better survival; the number of unfavorable markers also increased nonrelapse mortality.

• Findings were validated in an independent cohort of 1,141 transplants.

• Knowledge of extended haplotypes may refine donor selection beyond conventional HLA matching.

Study Snapshot

• Design: Retrospective cohort analysis with independent validation

• Population: 1,436 patients (discovery) and 1,141 patients (validation) receiving haploidentical related donor HCT

• Key exposure: Extended HLA haplotypes defined by class I, class II loci and class III SNP rs915654

• Primary outcomes: Mortality, relapse, nonrelapse mortality

• Key result: Inclusion of rs915654 improved mortality and relapse models (likelihood ratio test P = .004 for relapse, P = .01 for mortality)

• Sponsor/funding: Not explicitly stated in abstract

In hematopoietic cell transplantation (HCT), donor–recipient matching at HLA class I and class II loci is critical for outcomes. However, the influence of extended haplotypes spanning the entire major histocompatibility complex (MHC), including the class III region, has remained unclear. A new study published in Blood by Petersdorf et al. (2026) now demonstrates that extended HLA class I–class III–class II haplotypes significantly predict survival and relapse after haploidentical related donor transplantation.

Study Design and Population

The investigators analyzed 26 candidate single-nucleotide polymorphisms (SNPs) in the class III region of 1,436 patients and their haploidentical related donors. Through multivariable regression, they identified one SNP—rs915654—as particularly informative for mortality and relapse. Three-marker haplotypes consisting of one class I locus, one class II locus, and rs915654 were then defined for patients and donors separately. The findings were subsequently tested in an independent cohort of 1,141 haploidentical transplants.

Key Findings: Mortality and Relapse

The inclusion of rs915654 into relapse and mortality models that already contained patient HLA-E–DRB1 and donor HLA-B–DRB1 improved each model. For relapse, the likelihood ratio test yielded P = .06 and P = .004 for the two model comparisons; for mortality, the corresponding P values were .10 and .01. The risks of both mortality and relapse increased as the number of favorable patient and donor markers decreased. Notably, the number of unfavorable markers was also associated with higher nonrelapse mortality.

In the validation cohort, similar patterns were observed, confirming the robustness of the haplotype effect. The results suggest that not only the specific alleles but their extended haplotype context—including class III variation—modulates transplant success.

The Role of the Class III SNP rs915654

The class III region contains many genes involved in immune regulation and inflammation. By anchoring haplotypes to a functional SNP, the study provides a plausible biological link between MHC diversity and post-transplant outcomes. The authors propose that rs915654 serves as a marker for linked functional variation affecting immune responses relevant to graft-versus-host and graft-versus-leukemia effects.

Clinical Implications and Donor Selection

The team then defined HLA-A–C–B–DRB1–DQB1 haplotypes in terms of their expected number of favorable markers and explored their theoretical utility for donor selection. The data suggest that choosing a donor with an extended haplotype profile enriched for favorable markers could reduce the risk of relapse and improve survival. Although the study is retrospective, it provides a proof-of-concept that incorporating class III information into donor selection algorithms could complement traditional 10/10 or 12/12 matching.

Limitations and Next Steps

The study has important limitations. It is retrospective and focused exclusively on haploidentical related donors. The class III variation was captured by a single SNP, which may not represent the full functional diversity of the region. Prospective validation and extension to unrelated donor transplants are needed. Additionally, the practical implementation of haplotype-based selection requires robust genotyping and haplotype phasing protocols.

Nevertheless, the findings open a new avenue for improving transplant outcomes through more precise immunogenetic matching. As the authors conclude, “Extended HLA class I–class III–class II haplotypes influence the success of transplantation and inform the biology of the major histocompatibility complex in health and disease.”

Funding, Registration, and References

The abstract does not specify funding sources or trial registration. The study was published in Blood (2026;148(4):508–520; PMID: 42018610).

References

1. Petersdorf EW, McKallor C, Malkki M, et al. Extended HLA haplotypes and transplant survival. Blood. 2026;148(4):508–520. PMID: 42018610.