Canterbury DHB

Donor Searches

Usually the best donor for an allogeneic stem cell transplant is a genotypically HLA-identical sibling of the recipient. The chance of this occurring is 1 in 4 for any given sibling.

Approximately 25-30% of patients in need of a transplant have such a donor. If not, other related HLA-identical or partially identical family members may also be considered as potential donors. In this situation a choice will need to be made between a potential but probably mismatched family donor, a matched unrelated donor (MUD), and CORD stem cells.

Sibling Donor Searches

Each of the patient's available siblings should be HLA A and B typed if the patient may require a transplant in the future. It is advisable to ensure that there are no absolute contraindications to using a sibling as a bone marrow donor prior to testing them. Do not forget to tissue type the patient.

Note: It is policy to convey the tissue typing result only to that individual. The result should only be divulged to a third party e.g., potential recipient and or other family members after the individual concerned has given permission.

For further details of sibling donor searches see the following hyperlinks:

• Tissue typing procedure

  Contact the SCT Co-ordinator to arrange ABO, Rh and HLA A & B typing on the patient’s siblings as early in treatment as possible, if the patient could be considered for a transplant. The SCT Co-ordinator will ensure that the appropriate information sheet and consent forms are given to the family members. State name of patient and relationship to patient on form.

  Note:

  • All tissue typing is done in Auckland, and is arranged through the SCT Co-ordinator.
  • Two digit HLA A and B DNA typing and DRB1 molecular typing for patient, HLA-A and –B for sibs plus DRB1 on matching sib: 40 ml in CPDA (yellow top) tube, + 10 ml clotted (red top) tube. The sample must arrive in the Tissue Typing Laboratory by 4pm midday Monday - Thursday. No prior notification is necessary. Class I typing is usually performed first (on sibs) and class II typing performed on stored DNA once class I match identified. 5 ml EDTA should be taken at the same time for determination of ABO Rh group and serum stored for CMV serology and other as required.

  National Tissue Typing Laboratory

  71 Great South Road
  Epsom, Auckland
  Ph: 09 523 5731 (DDI) all enquiries.
  Fax: 09 523 5761

• National Specimen Requirements for Tissue Typing
• Blood tests to be done on a potential donor

  If an HLA A and B identical sibling is identified, the following tests are performed on both patient and donor.

  • HLA DR typing and confirmatory class 1 and II typing.
  • Direct RBC cross-match between patient and donor (if they are the same blood group). This is usually done on admission.
  • Screen for atypical RBC antibodies.
  • Serology: HBV, HCV, HIV 1+2, CMV, Syphilis, Toxoplasma, HSV, VZV, and EBV.

  If the sibling shares 3 out of 4 HLA A and B antigens with the patient and the patient is considered a suitable candidate for 5/6 HLA antigen matched related donor transplant, both should proceed to HLA DR typing. If they are DR identical, the remainder of the above tests should be performed.

  If more than one histocompatible sibling is identified the ABO group, CMV status and sex of the patient and siblings as well as the age, parity, medical and psychological health of the siblings are considered when deciding on the donor.

Extended Family Searches (EFS)

Guidance will be sought from the Tissue Typing experts as to the appropriateness of an extended family search.

The aim of an extended family search is to explore the possibility that relatives other than siblings may be suitable to act as a bone marrow donor for patients who do not have an HLA identical sibling.

• Conducting an extended family search will increase the chance of finding a family donor by approximately 6-7%.
• An extended family search is done because the patient's grandparents, and in some cases, uncles and aunts, can share one of the patient's haplotypes.
• There is a possibility that the other haplotype may have been introduced into the family via spouses hence the possibility that other relatives may be HLA identical (or mismatched by only one antigen) with the patient.
• As there is a low yield of success and potentially high costs involved in EFS, it is important to limit searches to where circumstances will result in higher chances of success (as described below) and to involve NZBS staff to advise as to whether such a strategy is appropriate.
• For further information, see NZBMDR process for donor identification (section 7).
• The tissue typing laboratory is to advise before proceeding with an extended family search.

One Antigen Mismatched Related SCT

For further details, see Family Mismatched SCT Donor Search.

Unrelated Donor (MUD) Searches

If no compatible family members are identified then the SCT Committee must decide whether a MUD SCT (or a Cord SCT) is appropriate for an individual patient.

• Following high resolution typing, a provisional ‘free’ computer search can be carried out by forwarding details to the New Zealand Bone Marrow Donor Registry (NZBMDR).
• This is done by (NZBMDR) searching a computerised file compiled by Bone Marrow Donors Worldwide (BMDW) available on the internet at www.bmdw.org.
• For a caucasian patient there is approximately a 70% chance of locating a MUD donor. This figure is much lower if the patient is of non-caucasian origin.

Links

• Details on how to carry out a MUD search.

  MUD (Matched Unrelated Donor) searches are organised by the SCT coodinator ext 81255.

  Once a patient has been accepted by the SCT committee for MUD transplant, a formal MUD search is necessary.

  Patients must undergo confirmatory typing before the search, i.e., the patient is typed on a minimum of 2 occasions.

  To activate a search it is necessary to deposit $5,000 in an account for each patient. This needs to be approved by the SCT Committee and the Service Manager. Gradually, the donor registry spends this money and they issue statements periodically. These are forwarded to the Haematology Service Manager, who is able to organise the transfer of funds where necessary.

  High resolution DNA typing, for DRB1, DQB1, and DNA typing for HLA-A, B, and typing (serological/molecular) for HLA-C which incurs further costs, will be requested in potential fully-matched donors.

  Once a matched donor is found, more samples may be required from the patient and donor for confirmatory typing (both of them should have been typed at least twice). The confirmatory typing will need to be done at an ASHI accredited tissue typing laboratory (currently NZBS Auckland).

  Reports on searches are sent periodically to the SCT coordinator.

• Details of the selection of HLA matched and mismatched unrelated donors.
  • HLA loci to be typed: In the unrelated setting, HLA-A, HLA-B, and HLA-DRB1 typing of the recipient and his/her prospective donor(s) is compulsory (6 HLA loci), and would be a minimum requirement prior to consideration of unrelated donor transplant. However it is strongly recommended that recipient/donor pairs also undergo molecular DNA typing for HLA-A, B, molecular typing for HLA-C and high resolution typing for DRB1 and DQB1 (10 HLA loci, refer to tables 1,2).
  • A recent guideline produced by the NMDP (National Marrow Donor Program) recommends donor matching at HLA-A, B, C and DRB1 (3). Additional typing for HLA-DPB1 and HLA-DRB3-5 remains optional since the relevance of donor/recipient mismatches for these HLA loci for transplantation outcome is not (yet) clear. MLC testing is no longer used to identify potential unrelated donors.
  • Evidence currently exists that allelic mismatching for class I as well as class II antigens can influence the outcome of unrelated donor transplantation¹. However multiple class I alleles have been identified and the chance of finding a completely matched donor would therefore decrease, and the costs increase with further allelic typing. Further work is required to determine which combinations of allelic mismatches are permissible and which are not².
  • A recent publication¹ from the Seattle group on patients with CML transplanted with unrelated donors using a non T cell depletion method (CSA + MTX), has indicated the importance of optimal matching for these 10 alleles, at least for CML patients transplanted according to their protocol.
  • Mortality was significantly increased in recipients with multiple class 1 mismatches and with mismatches in both class I and class II alleles. Therefore acceptable matches included those with full alleleic matches, a single class I mismatch and a single class II mismatch, and such donors should be preferred for CML patients. In this setting graft failure was significantly increased with multiple class I mismatching (ie H v G direction) and with Class I and Class II mismatches and GvHD severity was highest with class II mismatching (ie G v H direction).

    The relevance of these data to transplantation in other circumstances eg acute leukaemia/aplasia is uncertain. For example graft failure is much less common for patients with acute leukaemia and greater degrees of class I disparity may be tolerated in this group. However, in aplastic anaemia transplants, where graft rejection is high, high degrees of class I matching are probably required. Preliminary data from Seattle (verbal communication E Petersdorf) indicate that the same conclusions as for CML can be drawn in other situations, at least in AML.

  • Optimising outcome after unrelated marrow transplantation by comprehensive matching of HLA class I and II alleles in the donor and recipient. EW Petersdorf et al, Blood 1998; 92: 3515-3520.
  • Current methodologies of human leukocyte antigen typing utilised for bone marrow donor selection. AM Little et al Current Opinion in Haematology 1998; 5: 419-428.

    ¹National Marrow Donor Program HLA-Matching Guidelines for Unrelated Marrow Transplants. Biol Blood Marrow Transplantation 2003; 9: 610-615.

• Full details of organising transport of donor stem cells.

Termination of MUD Search

In the event of SCT Committee deciding that MUD SCT is no longer appropriate for a patient, (e.g., because of death, disease progression, new therapeutic option), the search must be formally terminated using Form 115 (see the SCT Coordinator for this form) in the NZBMDR protocol which should be faxed as soon as possible to the office in Auckland.

This simple measure, which is often overlooked, will prevent wastage of money, time and energy. NZBMDR will then refund or invoice for outstanding funds.

Topic Code: 8893