HLA matching of CB: it's complicated

In this issue of Blood, Stevens and colleagues report that in single cord blood (CB) transplantations, donor-recipient human leukocyte antigen (HLA) mismatches in the graft-versus-host only (GVH-O) direction produce engraftment and survival comparable to HLA-matched CB units and are significantly better than units mismatched in the rejection-only (R-O) direction.¹ 

The authors studied the outcomes of 1202 CB transplantations facilitated by the New York Blood Center National Cord Blood Program (median age was 7.2 years). They showed important differences in outcomes in the small subgroups of patients with unidirectional mismatches. GVH-O and R-O mismatches were present in 4.8% and 3.3% of the transplantations, respectively. They describe in detail the GVH-O scenario, where the CB unit is homozygous for one HLA antigen/allele and the recipient is heterozygous at the same locus; matching in one of the alleles only. In contrast, for the R-O situation, the homozygosity occurs in the recipient and the CB unit is heterozygous at the same locus (the HLA mismatch occurs in the rejection direction).

The novel and stimulating results of this study demonstrate that recipients of transplantations with GVH-O mismatches had neutrophil and platelet engraftment rates that were comparable to recipients of transplantations matched in HLA-A, -B, and -DRB1. With the GVH-O mismatches, the time to engraftment was significantly faster and rate of engraftment higher than transplantations with R-O mismatches. Importantly, patients with hematologic malignancies given GVH-O CB grafts had lower transplantation-related mortality, overall mortality and treatment failure compared with those with one bidirectional mismatch, resulting in outcomes similar to those of matched CB grafts.

Despite the fact that formal documentation of donor engraftment was not available for a significant fraction of patients, R-O mismatches were associated with slower engraftment and higher rejection and relapse rates. Similarly, Petersdorf and coworkers observed higher rejection rates in allogeneic bone marrow transplantation for chronic myelogenous leukemia when the recipient was homozygous at the mismatched HLA class I loci.² 

The potential role of anti-HLA antibodies in rejection and delayed engraftment is not investigated here, but recipient sensitization (more common in multiparous women and/or multiply transfused individuals) is likely to interplay with HLA mismatches in this setting. Several studies have demonstrated that donor specific anti-HLA antibodies have a significant deleterious impact in outcome.^3-6  It is therefore possible that patients who are homozygous in a specific locus may have higher chances of presenting allo-antibodies that react with the mismatched antigen of the donor. It would therefore be important to address the question of the impact of the unidirectional mismatch in the rejection direction if anti-HLA antibody specificity was used to exclude donors that may be at higher risk of humoral rejection.

The present study investigated a heterogeneous group of patients with numerous diseases. It has been suggested that natural killer cell–mediated graft-versus-leukemia effect may reduce relapse and enhance engraftment after haploidentical transplantations for acute myelogenous leukemia, but do not have an impact in acute lymphocytic leukemia.⁷  The described beneficial Killer immunoglobulin-like receptor ligand mismatches occur more often in HLA-B or -C mismatched transplantations and would be manifested more often in the R-O situation. Therefore, natural killer–mediated graft-versus-leukemia effect could theoretically have a beneficial impact in the R-O vector. Interestingly, Stevens et al identified the opposite effect here, in which there was increased risk for relapse in transplantations with a mismatch in the R-O vector. The impact of a potentially beneficial Killer immunoglobulin-like receptor ligand effect cannot be ruled out here, however, because this study did not evaluate HLA-C and included patients with inherently different susceptibility to this effect.

The lower cell doses of the CB units compared with marrow or peripheral blood likely magnify the R-O direction mismatches—there is no margin for engraftment at these lower doses. It may be that centers are already trying to avoid R-O mismatches; only a small fraction of patients had them in this large retrospective analysis.

Given the caveat that HLA antibodies could have an impact, CB search algorithms in the single CB transplantation setting can be modified to identify unidirectional mismatches. It is now desirable to give priority to GVH-O mismatched units over other mismatches and avoid selecting R-O mismatches, if possible. Whether GVH-O and R-O mismatches will have an impact on double CB transplantations remains to be determined.