Strategies For Unrelated Donor Searches

Identification of a prospective unrelated stem cell donor is based principally on HLA matching. The patient should be initially typed for all relevant loci at allele/high resolution even though registry-matching algorithms are currently based on A, B, DR. This information can be used to indicate the probability that a matched donor will be found and may suggest the number of donors from a preliminary search that should be recruited for confirmatory or higher resolution testing. Since an increasing proportion of registry donors have been typed at high resolution and for more loci, the preliminary search results may already indicate well-matched donors that can be requested for confirmatory typing. Patients that have common HLA alleles and haplotypes more often find matched unrelated donors61-63 and one can expect that only a few donors need to be typed to find a well-matched donor over the HLA-A through DQ interval. In contrast, rare alleles or haplotypes may indicate that a greater number of donors need to be considered.

In some searches, a large number of donors are possible matches by low resolution typing, and the problem becomes identifying those that may be more likely to match the patient. These can sometimes be prioritized on the basis of additional loci that have been tested. As mentioned previously, the HLA complex displays a high level of linkage disequilibrium between loci. Thus, one may selectively perform confirmatory testing on donors who are listed as DRB1*13, DQB1*0604 or DRB1*13, DRB3*0301 for a patient who is DRB1*1302, since these are the most common associations for this allele. Another example would be typing B44, Cw5 prospective donors to enrich for the

B*4402 subtype as opposed to the other common B44 subtype of B*4403.

Some HLA alleles or haplotypes may be rare in the general population but more common in particular ethnic or racial groups. This information can be used to focus a donor search in those groups' registries that are more likely to have individuals that match the patient. Thus, for a patient who is DRB1*1503 one may focus confirmatory testing mainly on African American donors listed as DRB1*15 rather than DRB1*15 Caucasians since the frequency of this allele differs markedly in the two groups (>80% vs <5%, respectively). A number of references regarding HLA antigen or allele frequencies in different populations are available.57,58,140 In some cases, donors may be matched for a patient but have been incorrectly typed or listed on the registry. This problem is most apparent for donors who only have serologic-based typing as is more often seen for antigens that are difficult to assign by serologic typing.141 If no matches are indicated for a patient with one of these difficult antigens, one should consider repeating the registry search using a surrogate antigen that the proper antigen may have been mistyped as (e.g., A26 to replace A66). Some problem antigens may have been missed entirely in serologic typing and running a second registry search without that antigen may pick up a matched donor (e.g., A74, particularly when paired with another A19 group antigen).

Patients with null or expression variant alleles may be difficult to match in registry searches, although the indications that the more common variants may appear as part of extended haplotypes may be somewhat encouraging.16-18,72,73 Donors with expression variants mismatched to patients can be excluded on the basis of serologic- or DNA-based typing.

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