By Gérard Socié, MD, PhD
2008-03-01
Dr. Socié indicated no relevant conflicts of interest.
Lee SJ, et al. High-resolution donor-recipient HLA matching contributes to the success of unrelated donor marrow transplantation. Blood. 2007;110:4576-83.
Shaw BE, et al. The importance of HLA-DPB1 in unrelated donor hematopoietic cell transplantation. Blood. 2007;110:4560-6.
In the last issue of Blood in 2007, two articles reported
results of transplants from unrelated donors using HLA matching. The
journal article by Stephanie Lee and coworkers addresses the relative
importance of various HLA loci and the resolution level at which they
are matched for unrelated donor transplantation. To address this
question, National Marrow Donor Program data from 3,857 U.S.
transplantations performed from 1988 to 2003 were analyzed.
Patient-donor pairs were fully typed for HLA-A, B, C, DRB1, DQB1, DQA1,
DPB1, and DPA1 alleles (see Figure). High-resolution DNA matching for
HLA-A, B, C, and DRB1 (8/8 match) was the minimum level of matching
associated with the highest survival. A single mismatch detected by
low- or high-resolution DNA testing at HLA-A, B, C, or DRB1 (7/8 match)
was associated with higher mortality (relative risk 1.25, p<0.0001)
and one-year survival of 43 percent compared to 52 percent for 8/8
matched pairs. Single mismatches at HLA-B or HLAC appear better
tolerated than mismatches at HLA-A or HLA-DRB1. Mismatching at two or
more loci compounded the risk. Mismatching at HLA-DP or DQ loci and
donor factors other than HLA type were not associated with survival.
In the second paper, Brownen Shaw, et al. examined the extent to
which transplant outcome may be improved with donor matching for
HLA-DP. The risks of acute GVHD, relapse, and mortality associated with
HLA-DPB1 allele mismatching were determined in 5,929 patients who
received a myeloablative HCT from an HLA-A, B, C, DRB1, DQB1 matched or
mismatched donor. There was a statistically significantly higher risk
of both grade II-IV aGVHD (OR=1.33, p<0.0001) and grade III-IV aGVHD
(OR=1.26, p=0.0007) after HCT from an HLA-DPB1 mismatched donor
compared to a matched donor. The increased risk of acute GVHD was
accompanied by a statistically significant decrease in disease relapse
(HR=0.82, p=0.01).
Historically, the selection of potential donors for hematopoietic
cell transplantation (HCT) relied on serological tests for
donor-recipient identity for classical HLA-A, B, and DR antigens.
Later, as molecular methods for typing HLA genes became available, the
degree of diversity of this region became apparent. When such typing
methods were applied to the analysis of HCT recipients and donors, many
serologically identical, unrelated donor recipients were found to
harbor mismatches between two unique alleles of the same antigen.
Clinical studies have demonstrated that such allelic differences are
clinically relevant, increasing the risks of graft failure, acute GVHD,
and mortality.
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The first study by Lee and coworkers clearly
highlights the fact that there is a 10 percent loss of survival with
any mismatch (although, of marginal significance for HLA-DQ), but also
that classical risk factors including patient age, race, disease stage,
and CMV status were as predictive of survival as donor HLA matching.
The second study by Shaw and coworkers confirms in a large number of
patients that DPB1 functions as a classical transplantation antigen.
The increased risk of GVHD associated with HLA-DPB1 mismatching is
accompanied by a lower risk of relapse.
Numerous studies have looked at the impact of HLA
matching and transplant outcomes. However, some older data did not
include molecular typing for all HLA alleles, thus bringing into
question some of the reported results. The data reviewed here (and
reported in a few other articles) have led to the current gold standard
of a fully matched "10/10" unrelated donor being one who is allele
matched for HLA-A, B, C, DRB1, and DQB1. Few patients have a 12/12
donor (also matched for HLA-DPB1), which means they may have less of a
risk of GVHD, but more of a risk of relapse. We already know that even
a 10/10 molecularly matched donor/recipient pair have three out of four
chances to be haplotype-mismatched1 and of greater
disparities if typed for other non-HLA gene polymorphism or for KIR…
Thus, in 2008, it’s probably time to stop using the term matched for an
unrelated donor (unless specified by the number of molecularly tested
loci). However, compelling evidence coming from large series strongly
suggests that transplant from 10/10 molecularly matched donors led to
results (survival) similar to those obtained with HLA-identical sibling
donors — a finding that, in the end, constitutes the only relevant
criterion for physicians.
- Petersdorf EW, Malkki M, Gooley TA, et al. MHC haplotype matching for unrelated hematopoietic cell transplantation. PLoS Med. 2007;4:e8.
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