Absence of statistically significant correlation between disparity for the minor histocompatibility antigen HA-1 and outcome after allogeneic hematopoietic cell transplantation

Recipient disparity for the HA-1 minor histocompatibility antigen has been associated with acute graft-versus-host disease (GVHD) after marrow transplantation from an HLA-identical sibling.1 We have also shown a trend toward higher risk of grades II to IV acute GVHD in recipients mismatched for HA-1 among a selected HLA-A2–positive population (P = .08), but the odds ratio (2.1) was lower than the value (5.4) reported by Goulmy et al.1 2 In our earlier study, all patients received methotrexate and cyclosporine for GVHD prophylaxis and had either grade 0 or grades II to IV acute GVHD. The analysis excluded patients with grade I GVHD, those with renal failure requiring dialysis, and those who died within 80 days after the transplantation without having GVHD. These selection criteria were designed to provide high sensitivity for detecting an association between HA-1 disparity and the development of acute GVHD but did not allow an evaluation of other end points, such as chronic GVHD, leukemia relapse, and transplant-related mortality and survival.

We have extended our earlier results in order to evaluate these additional end points. DNA samples from both patients and donors (including the initial 237 pairs) were available for 613 HLA-A2–positive patients who received marrow from an HLA-identical sibling at the Fred Hutchinson Cancer Research Center (Seattle, WA) from 1981 to 1998. The availability of DNA samples and the use of methotrexate and cyclosporine for GVHD prophylaxis were the only inclusion criteria. Genotyping of HA-1 and sequencing of HLA-A2 were performed as previously described.2 

HA-1 disparity, defined as the presence of HA-1^H in the recipient but not in the donor, was detected in 80 (13%) of the 613 donor/recipient pairs. The HLA-A2 sequence was determined among the 80 patients mismatched for HA-1. Eight patients who did not have HLA-A*0201 were excluded from further analysis because the presentation of HA-1 is HLA-A*0201–restricted.3 In a multivariable logistic regression analysis, HA-1 disparity showed no statistically significant association with a higher incidence of acute or chronic GVHD, a lower risk of leukemia relapse, a higher risk of nonrelapse mortality, or any increase or decrease in survival (Table1). The low frequency of HA-1 disparity makes it very difficult to demonstrate statistically significant associations with outcome after hematopoietic stem cell transplantation. Our current results do not exclude the possibility that HA-1 disparity is associated with an increased risk of GVHD but the odds ratio for any such association is likely to be less than 2.6. Similarly, our current results do not exclude the possibility that HA-1 disparity is associated with a reduced risk of recurrent malignancy but the odds ratio for any such association is likely to be greater than 0.3. A very large multicenter study would be needed in order to have adequate statistical power to detect associations of this magnitude.

Supported in part by Grants AI33484, CA15704, CA18029 from the National Institutes of Health, Bethesda, MD