Page 1808 - Hematology_ Basic Principles and Practice ( PDFDrive )

1612 Part X Transplantation

When no related donor is available or suitable, a search for an for two unrelated individuals who share the same HLA genotype to
unrelated donor is initiated. A search of all available international have different HLA haplotypes. The clinical significance of haplotype
registries today includes consideration of more than 25 million donors matching is described in the section entitled Beyond Classic HLA:
worldwide (http://www.nmdp.org; http://www.worldmarrow.org). Major Histocompatibility Complex Resident Variation.
In the assessment of every unrelated donor, matching for each HLA
genetic locus allele is considered. However, gene-by-gene identity for
HLA-A, HLA-B, HLA-C, HLA-DR, and HLA-DQ between two CLINICAL IMPORTANCE OF DONOR HLA MATCHING IN
unrelated individuals does not necessarily signify that the HLA alleles CASES OF UNRELATED DONOR HCT
are linked on the same chromosomal haplotype. Hence it is possible
The first successful human allogeneic BM transplantations were
performed in 1968. Early clinical experience in allogeneic transplan-
tation identified both HLA and non-HLA factors as important in
Principles of Patient-Donor Human Leukocyte Antigen defining posttransplantation complications. Donor HLA mismatch-
BOX 105.2
Matching and Selection ing was identified as a risk factor for graft failure after HCT from
relatives. Non-HLA factors associated with an increased risk of graft
Establish the Patient’s Haplotypes failure included transplantation of a lower BM cell dose, use of
When an allogeneic transplant is being considered a part of the treat- T cell–depleted BM, and transplantation of BM from a cross-match–
ment regimen for a patient, HLA typing of the patient and first degree
relatives is performed early in the planning process to identify suitable positive donor (presence of antidonor lymphocyte antibodies in the
related donors. Typing of family members provides two key pieces of patient’s serum pretransplant). HLA mismatching was also shown to
information: (1) the availability of an HLA genotypically-matched sibling increase the incidence and severity of acute GVHD.
or a suitable haploidentical related donor, and (2) confirmation of the Use of HLA-matched unrelated donors as the source of BM was
patient’s HLA tissue type. When both parents of the patient are avail- first applied in the case of a patient with severe aplastic anemia.
able for tissue typing, the family study allows confirmation of the Durable engraftment and immunologic reconstitution were early
paternal and maternal HLA haplotypes, and this information is invalu- barriers to successful unrelated donor HCT. As clinical experience
able for predicting the probability of finding unrelated donors. In the matured and tissue typing methods became more robust, unrelated
absence of parents, tissue typing of available siblings might yield suf- donor HCT was established as a therapeutic approach for treatment
ficient information for the four parental haplotypes.
of hematologic disorders when an HLA-identical sibling is not avail-
Characterize Human Leukocyte Antigens at High Resolution able. DNA-based methods have become established as the gold
DNA-based methods are the mainstay for tissue typing. Molecular standard for HLA testing because serologically identical recipients
methods provide information of allelic variants at HLA-A, HLA-B, and potential unrelated donors can be mismatched for one or more
HLA-C, HLA-DRB1, HLA-DQB1, and HLA-DPB1 that have been shown alleles that are identified by DNA testing methods.
to have biologic implications in graft-versus-host and host-versus-graft The collective worldwide experience demonstrates that patients
allorecognition. When a search for an unrelated donor yields potential have superior outcome after HLA-matched unrelated HCT than after
registry donors that lack high-resolution typing, often knowledge of the
patient’s haplotypes may help to direct typing of donors that have the HLA-mismatched transplantation (Table 105.6). The general recom-
highest probability of matching the patient’s alleles. mendations for donor selection are: (1) If the patient has many
potential 8/8 donors, additional matching for HLA-DQB1 (HLA
Determine the Presence of Antidonor Antibodies Against Mismatched 10/10) and HLA-DPB1 (HLA 12/12) may further enhance patient
Human Leukocyte Antigen Mismatches outcomes. (2) When an HLA 8/8– or 10/10–matched donor cannot
The risk of graft failure is significantly increased when the patient has be identified, use of a donor mismatched for a single allele can be
mounted an anti-HLA response against donor-mismatched antigens. considered (see Table 105.6). A mismatch for HLA-DQB1 alone
Screening donors with patient sera, especially when the donor has seems forgiving (HLA 9/10), but mismatch for HLA-DQB1 plus
known HLA mismatches, is an essential step of donor selection. When
no HLA-matched donors are available, avoiding the use of donors another locus appears to increase mortality. Among HLA-A, HLA-B,
whose HLA mismatches are the same specificity as the anti-HLA HLA-C, HLA-DRB1, HLA-DQB1 10/10−matched donors, criteria
antibodies in the patient may reduce the risk of graft failure. for the selection of donors with one HLA-DPB1 (HLA 11/12)
mismatch have recently become available, and provide additional
Identify Backup Donors means to optimize overall transplant outcomes. (3) Multiple mis-
Efficiency of the unrelated donor search process is highly dependent matches are less well tolerated and should be limited. (4) When
on the racial and ethnic background of the recipient and on the HLA-DRB1−mismatched donors are identified, assessment of HLA-
composition of the donor registries. The availability of unrelated donors
must also factor into the planning of the transplant, including the DRB3, HLA-DRB4, or HLA-DRB5 may help to uncover coincident
identification of a primary donor and backup donors. mismatching at these loci; cumulative mismatching at multiple HLA-
DRB genes increases risks after transplantation. (5) Permissible HLA

TABLE Impact of Specific Single-Locus HLA Mismatches on Risks After Unrelated Donor Transplantation
105.6
Mismatched Locus Graft Failure GVHD GVL Effect Survival Notes
HLA-A ↑ 27,28 ↑ 29,30 ↓ 29,31 Allele and antigen mismatches are similarly risky; in some reports,
antigen mismatches are riskier than allele mismatches.
HLA-B ↑ 28 ↑ 29,30 ↓ 31 Insufficient data on allele versus antigen mismatches.
HLA-C ↑ 28,32 ↑ 29,30,33,34 Yes 31 ↓ 31,33 Antigen mismatches much riskier than allele mismatches.
C*03:03,03:04 mismatch is low risk. GVL effect present.
HLA-DRB1 ↑↓ 29,30 ↓ 31 Insufficient data on allele versus antigen mismatches. Global trend
for lower survival.
HLA-DQB1 ↓ 29 Only when DQB1 is the only mismatched locus (HLA 9/10).
HLA-DPB1 ↑ 35–38 Yes 31 ↓ 31 GVL effect present.
HLA, Human leukocyte antigen; GVHD, graft-versus-host disease; GVL, graft-versus-leukemia.