Canterbury DHB

Family Mismatched SCT Donor Search

One Antigen Mismatch Related Transplants

If one antigen-mismatched transplant from family members is considered, then patients who have ‘incomplete’ common haplotypes should also be considered for extended family searches. For example, a patient who has a B, DR haplotype occurring with a relatively high frequency in strong linkage disequilibrium, but with an A allele which does not usually occur on that haplotype eg. A3 – B8 – DR3.

The Australian Bone Marrow Donor Registry have constructed a list of the most common A-B, B-DR and A-DR haplotypes to guide a 1% probability of finding a 5/6 matched (A, B, DR) within an extended family. It has been estimated that the chance of identifying a related non-sibling donor increases by approximately 10% when a one locus mismatch is allowed.

Decisions will have to be made for each patient on whether to search the family for a 5/6-antigen match in cases where a 6/6-antigen match may be available on the unrelated registry.

If these criteria are applied routinely up to 90% of patients may qualify for an extended family search, with only a small fraction of searches identifying a potential donor with considerable time delay and financial cost.

It has to be noted that searching for A-DR or B-DR match on the non-shared haplotype by serology does not guarantee a DR-B1 subtype match. This will be particularly marked in the A-DR situation where B-DR linkage does not assist in DRB1 subtypes.

By undertaking an EFS, the majority of family members subtyped could be recruited onto the registry.

Order of Testing Family Members

Valuable time and resources can be saved by careful evaluation of the order in which family members are tested. The suggested order is as follows:

Using the family tissue typing form:

1. Obtain family details including contact addresses, DOB’s etc.
   1. Grandparents (if available) on the side of the family which the rare haplotype has been inherited.
   2. Spouse/partner of the patient, if they have children.
   3. Spouses/partner of siblings who share the rare haplotype (if they have children).
2. If one of the grandparents have the common haplotype then all children (ie, uncles and aunts of the patients) should then be tested to determine if any are HLA identical with the patient, ie, have inherited both the rare and common haplotype.
3. If uncles and aunts are not identical, the spouses of those with the rare haplotype and who have children should be tested to see if the common haplotype has been introduced by marriage.
4. If the common haplotype has been introduced into the family by marriage then the children (ie, cousins) of that marriage should be tested to determine if any have inherited the rare and common haplotype together (ie identical with patient).
5. If the grandparents do not have the common haplotype, then uncles and aunts cannot be identical with the patient. In this case the spouses are tested as in c).
6. If the spouse of the patient has the common haplotype and they have children, the children should be tested.
7. In cases where siblings of the patients have the rare haplotype, sisters or brothers-in-law should be tested to determine if the common haplotype has been introduced by marriage. In that case the children of that marriage ie, nephews and nieces should be tested
8. The above individuals should be Class I typed initially although samples can be taken at the same time for Class II which can be performed at a later stage if Class I identity is achieved. Serum should also be taken and stored for CMV testing and blood grouping.

Tissue typing results may be entered onto the NZBMDR computer if individuals are willing to be considered as potential matched unrelated donors for other patients. Appropriate forms may be obtained from the BMT case manager.

Acceptable HLA Mismatches in Related Donor Setting

If a genotypic or phenotypic HLA-identical (ie a fully HLA matched) relative is not available, a partially HLA-matched related donor may be acceptable. By definition this type of donor is genotypically HLA haploidentical with the recipient and differs from the recipient in at least one HLA antigen of the ‘non-shared’ HLA haplotype. The compromise reached on acceptable HLA mismatches in the related setting is summarised below.

Acceptable HLA Mismatches in the Related Donor Setting

• Underlying malignant disease
  • In GvH direction: up to one HLA mismatch ie 1 HLA-A or 1 HLA-B or 1 HLA-DRB1 (eg A2 vs A3 or DRB1*01 vs DRB1*08 etc).
  • In HvG direction: up to three HLA mismatches ie 1 HLA-A and/or 1 HLA-B and/or 1 HLA-DRB1, (eg an HLA haploidentical donor is accepted for an HLA homozygous patient for a ‘standard’ ie not non-myeloablative) transplant).
• Severe aplastic anaemia
  • BMT first line therapy: no HLA disparity ie. Donor/recipient HLA-identity is requested.
  • BMT second line therapy: one HLA mismatch in GvH and/or HvG direction ie after failure of 2 courses of immunosuppressive therapy: 1 HLA-A or 1 HLA-B or 1 HLA-DR in GvH and/or HvG direction.
• SCID and other inborn errors (liaise with Specialist Centre)
  • Up to 3 HLA mismatches in GvH and HvG direction ie 1 HLA-A and/or 1 HLA-B and/or 1 HLA-DRB1 in GvH and/or HvG direction (eg Any genetically HLA haploidentical relative like the father or the mother of the patient is a prospective donor).
  • If >1 mismatch is present in GvH direction T cell depletion of the graft is mandatory.
  • Additional mismatching (eg. as identified by class 1 molecular typing) will be noted, and the decision to proceed with a transplant from a partially matched related donor will be made in clinical conference, taking into account such factors as alternative donor options, transplant protocols, and other treatment possibilities.

Topic Code: 8952