The current analysis focused on whether transplant-outcomes would be different if umbilical cord blood unit selection considered matching at HLA-C in addition to HLA-A, -B and -DRB1, as is the practice when selecting an unrelated adult donor. We report three major findings that are novel and to our knowledge not reported previously: 1) mismatching at HLA-C is an independent risk factor for transplant-related mortality when transplants are matched at HLA-A, -B, -DRB1 or mismatched at a single HLA-A, -B or -DRB1 locus; 2) mismatching at HLA-DRB1 when transplants are mismatched at a single HLA-A, -B or –C locus is an independent risk factor for transplant-related mortality; and 3) mismatching at any one or more loci considering matching at HLA-A, -B, -C, -DRB1 is an independent risk factor for transplant-related mortality. The observed effect of mismatching at HLA-C and –DRB1 are independent of patient age, cytomegalovirus serostatus and disease status at transplantation, the other significant factors associated with transplant-related mortality. We did not observe significant differences in transplant-related mortality rates between transplantations mismatched at two, three and four HLA-loci suggesting the absence of an additive adverse effect of mismatching beyond two-loci. The absence of an additive effect on mortality for transplantations mismatched at two or more HLA-loci has been described after adult unrelated donor transplantation.2
Mismatching at one or multiple loci was associated with lower risks of relapse with no evidence that incremental increases in HLA disparity had a significant impact on relapse as reported by others.26
Consequently, higher transplant-related mortality after mismatched transplantations was offset by lower relapse risks resulting in overall survival rates that were not significantly different except for patients who received umbilical cord blood units mismatched at the HLA-C locus and a single mismatch at the HLA-DRB1 locus. The absence of a statistically significant effect on overall mortality despite higher transplant-related mortality risks after transplants with a single mismatch at HLA-C or HLA-DRB1 may also be attributed to the relatively small subgroups: only 20 donor-recipient pairs were mismatched at one HLA-C locus and 46 donor-recipient pairs, mismatched at one HLA-DRB1 locus compared to 69 donor-recipient pairs matched at HLA-A, -B, -C, -DRB1.
In contrast to that reported after mismatched adult unrelated donor transplantation,2,10
HLA disparity was not associated with higher risks of acute or chronic graft-versus-host disease except for umbilical cord blood transplantations mismatched at two or more HLA-loci with a mismatch at HLA-A. Graft-versus-host disease rates are low after mismatched umbilical cord blood transplantation8,9
and any differences with multiple mismatching may be negligible except when one of the disparities occurs at HLA-A. Mismatching at three or four HLA-loci had an adverse effect on neutrophil recovery consistent with other reports.27,28
In the current analysis, 65% of patients were aged ≤16 years and 75% of umbilical cord blood units contained >3 × 107
total nucleated cells per kilogram patient weight. The use of larger units for transplantation may have negated the adverse effects of mismatching at one or two HLA-loci.27,28
We tested for an effect of donor sex on hematopoietic recovery and chronic graft-versus-host disease and found none.
In the report by Koegler and colleagues on 122 donor-recipient pairs, the only other report that examined extended HLA typing for umbilical cord blood transplantation, there was no significant association between graft failure, graft-versus-host disease and mortality.29
We hypothesize the apparent discrepancy between our results and those of Koegler and colleagues is related to study power rather than the biology of HLA disparity.
This report includes 803 donor-recipient pairs but there are a number of limitations. First, the statistical power to evaluate the impact of mismatching at specific loci and in some subgroups with limited number of events was low. Second, we did not consider allele-level HLA typing at HLA-A, -B or –C. This was not available for all patients. Among those for whom these data were available, about half of donor-recipient pairs were mismatched at three or more HLA-loci, which prevented us from exploring further. Our findings suggest that altering current selection strategies for umbilical cord blood units may ameliorate some of the excess transplant-related mortality associated with umbilical cord blood transplantation. If a unit matched at HLA-A, -B, -C and –DRB1 is not available, selecting a unit matched at HLA-C is preferred; in particular avoiding a mismatch at HLA-C in the presence of a single mismatch at HLA-DRB1 significantly lowers mortality risks. Changing current selection standards would also allow us to address the effect of matching at the allele-level in the future. However, changing the current selection strategy requires that cord blood banks have HLA-C typing in addition to HLA-A, -B, and –DRB1 for units available for search. Donor-recipient pairs mismatched at HLA-C are likely to be mismatched at HLA-Bas there is a high degree of linkage disequilibrium between these loci.30
Therefore, until HLA-C typing is available at search, selecting units matched at HLA-B will increase the likelihood of a match at HLA-C for most but not all cases and HLA-C typing can be performed at time of confirmatory testing. Despite the substantial investment from governments to develop public cord blood banks, our findings support the need for even greater investment. The additional burden of HLA-C typing and the need to build an even larger inventory of cord blood units that will allow for matching at HLA-C will add to the existing financial burden of the public cord blood banks.
Panel: Research in context
The medical literature was searched in 2009 and 2010 for articles on umbilical cord blood transplantation using Medline. Search terms included HLA-match, unrelated donor transplantation and umbilical cord blood. Several reports on the association between HLA-matching and survival after adult unrelated donor transplantation show higher survival rates after transplantations matched at HLA-A, -B, -C and –DRB1.1–3, 11, 12
Transplant-related mortality after umbilical cord blood transplantation with myeloablative transplant conditioning regimens is high and remains an important obstacle to a successful outcome. There are several strategies being explored to address this with all efforts thus far focused on delivering higher total nucleated cell doses to facilitate hematopoietic recovery.14–18
Literature review identified a single publication29
that examined for an association between closer HLA matching and transplant-outcomes.
However, this report included only 122 donor-recipient pairs. Therefore, our aim was to test whether closer HLA-matching of donor-recipient pairs by considering matching at HLA-A, -B, -C and –DRB1 would improve transplant-related mortality. Current accepted criteria for umbilical cord blood unit selection considers total nucleated cell dose and donor-recipient matching at HLA-A, -B and –DRB1. Therefore, we focused on two questions: first, what is the impact on outcomes if matching at the HLA-C locus is considered as an additional factor to current selection algorithm which considers matching at HLA-A, -B, -DRB1; second, how different are the outcomes if a mismatched umbilical cord blood unit (mismatched at one or more HLA-loci) is used instead of a unit that is matched at HLA-A, -B, -C and –DRB1?
We observed higher transplant-related mortality for transplantations matched at HLA-A, -B, -DRB1 or mismatched at a single HLA-A, -B or -DRB1 locus and mismatched at HLA-C and transplantations mismatched at a single HLA-A, -B or –C locus and mismatched at HLA-DRB1. Consideration of matching at HLA-C in addition to HLA-A, -B and –DRB1 is warranted in some situations; avoiding a mismatch at HLA-C in the presence of a single mismatch at HLA-DRB1 minimizes mortality risks. These data suggest that we re-evaluate the current strategy for umbilical cord blood unit selection and support the need for even greater investment in public cord blood banks because of the importance of HLA matching on transplant-related mortality.