This study of HLA-matching and outcomes of unrelated donor PBSC transplantation shows that HLA-mismatching in general, and HLA-C antigen and HLA-B allele and antigen mismatching in particular, are associated with statistically worse outcomes compared to 8/8 HLA-matched unrelated donors. No statistically significant association between HLA-mismatching and relapse or chronic GVHD were observed. Mismatching at HLA-DQ was not associated with statistically significantly worse outcomes and so was subsequently disregarded in determining HLA-matching. Overall, these results are similar to previous reports of the effects of HLA-mismatching in bone marrow transplantation within largely Caucasian populations.1,2
Most patients included in the previously reported sequential retrospective studies of high-resolution HLA matching received bone marrow grafts. Compared to marrow, PBSC contains on average 10-fold more CD3+ cells and 4-fold higher CD34+ cells.10
The relative contribution of cell subsets also differ, for example in PBSC the CD3:CD34 ratio is approximately 3-fold and the CD14:CD34 ratio approximately 25-fold higher, respectively, and the proportion of CD4 cells that have an anti-inflammatory (Th2) phenotype increases compared to marrow.11-14
Other studies have indicated relatively more DC2 dendritic cells and skewing of the DC1:DC2 ratio to DC2 cells within PBSC.14
All PBSC donors receive G-CSF while most unrelated bone marrow donors do not. The differences in cellular characteristics of the two products suggest, at a minimum, that the effect of HLA mismatching shown for bone marrow transplants can not be assumed to be applicable to PBSC products.
Although our results could not define an “optimal” mismatch for a PBSC transplant, they clearly show that mismatching for HLA-C antigen is associated with lower survival and higher TRM in either the single or the double mismatch setting. This conclusion is consistent with the observations from both the Flomenberg and Lee studies.2
In the Lee study, HLA-C antigen mismatch was associated with worse survival (RR 1.22, 95% CI 1.06-1.39, p=.004), as was mismatch at HLA-A antigen (RR 1.24, 95% CI 1.02-1.52, p<.001) and HLA-DRB1 allele (RR 1.42, 95% CI 1.13-1.80, p=.003), compared to the 8/8 matches.2
Our study of PBSC also showed a statistically significant relationship between HLA-B mismatching and a higher risk for grades III-IV acute GVHD although there was no association with survival. It is notable that the higher rates of severe acute GVHD observed in HLA-C antigen and HLA-B antigen and allele mismatched pairs did not translate into higher chronic GVHD or lower relapse rates. We hypothesize that this could be due to the higher TRM generally associated with grade III-IV acute GVHD, the fact that chronic GVHD is more closely linked with prevention of relapse, or that small sample sized limited power.
The main limitation of this study is the small number of observations in some of the subgroups, which may lead to erroneous estimation of the effect of a specific HLA-mismatch and limited power in comparisons. In addition, the median follow-up of 2 years is relatively short compared to the studies of HLA-matching in bone marrow transplantation. Nonmyeloablative/RIC transplants comprised 35% of our study population but are approximately 50% of procedures currently being performed. As the number of PBSC transplants increases and follow-up lengthens, a subsequent analysis will be important to update our observations, and to consider other factors such as KIR status15-19
or HLA-DP matching that could affect outcome.19,20
For example, in the bone marrow setting, the earlier Flomenberg study (2004, n=1,874)1
did not observe an increased risk associated with single allele mismatches whereas the larger Lee study (2007, n=3,857) found an adverse outcome was associated with either a single allele or antigen mismatch.2
Neither the Flomenberg nor Lee bone marrow studies included substantial numbers of nonmyeloablative (NM) or reduced intensity conditioning (RIC) transplants, which typically use PBSC grafts. A reasonable concern with these conditioning regimens is that rejection of a mismatched graft or risk for relapse might be amplified because host T or NK cells might survive less intensive conditioning. Our analysis showed that HLA-C antigen mismatching is associated with higher risk for mortality and transplant-related mortality, but not relapse after NM/RIC PBSC HCT, similar to myeloablative HCT procedures (relapse data not shown). Unfortunately, we lack data on KIR genotyping to allow refined analysis of possible natural killer effects.
In the instance when HLA-C antigen mismatching cannot be avoided, one might wonder whether a marrow graft might be better tolerated than PBSC. In an exploratory analysis, we did not detect any advantage to marrow as the cell source from a donor with an isolated HLA-C antigen mismatch. We caution that this retrospective analysis could not take into consideration all factors between the groups that might introduce bias. Our presentation of these results is not intended to address the question of whether one graft source is preferable to another but to provide the best available data pending larger studies. In an analysis by Eapen et al, outcomes of 7/8 matched bone marrow and 7/8 matched peripheral blood appeared similar although direct comparisons were not performed and locus specific data were not provided.21
In October 2009, the Blood and Marrow Transplant Clinical Trials Network finished enrollment of a 550 patient, prospective, multi-center, randomized trial to assess the risks and benefits of bone marrow versus PBSC from unrelated donors. A planned subgroup analysis of HLA-mismatched grafts has been included in the study design, the results of which will be important for addressing the issues raised in our analysis.
It is important to remember that these results are not meant to imply that an HLA-mismatched graft should not be used, only that higher risks than 8/8 HLA-matched donors should be recognized if present. For many patients, the best hope for long-term disease-free survival will still be allogeneic transplantation, even if from a less than optimal donor.