HLA Matching for Hematopoietic Cell Transplantation

The outcomes of related and unrelated donor hematopoietic cell transplants are strongly affected by the degree of human leukocyte antigen (HLA) matching between the transplant recipient and the donor or cord blood unit. HLA matching plays an important role in engraftment, incidence and severity of graft-versus-host disease (GVHD) and overall survival. In cord blood transplantation, however, several studies have shown that although degree of HLA match is important, a large cell dose is equally important, if not more so. [1-4]

Key factors contributing to the efficient selection of a closely matched donor are:
 

• Tissue typing the patient at a high resolution from the beginning
• Initiating the donor search early to allow time for more challenging searches — For more information on timing, see Effective Planning for Unrelated Donor Transplant.  

Tissue typing the patient and family

The first step in developing an effective donor search strategy is tissue typing the patient using DNA-based testing to identify the patient's HLA antigens at a high resolution (DNA methodology). Current data show significantly better post-transplant survival rates when patients and unrelated donors are matched at a high resolution. [5,6] Beginning with high-resolution patient typing enables a transplant center to select the best-matched donor and can reduce total search time and costs because the search strategy is based on complete information.

It may also be useful to identify DRB3, DRB4, and DRB5, although the benefit of matching at these loci has not been evaluated. [7] A 2007 study of 3,857 unrelated donor transplants found that mismatches at HLA-DQ or HLA-DP did not affect survival. [6]

The patient's immediate family (siblings, parents and children) should be tested along with the patient to:

• Identify potential related donors
• Confirm the patient's HLA assignments
• Define patient haplotypes, which are useful in developing a search strategy

Patient haplotypes and search strategies

The set of alleles inherited from each parent forms a haplotype, in which some alleles tend to be associated together. Identifying a patient's haplotypes can help predict the probability of finding matching donors and assist in developing a search strategy, because some alleles and haplotypes are more common than others and they are distributed at different frequencies in different racial and ethnic groups.

When searching for a donor, for some alleles, an allele-level match is more likely to be found among persons of a particular ethnicity. [7] The National Marrow Donor Program^® (NMDP) matching algorithm HapLogic^SM, is based on this principle, identifying the donors or cord blood units with the highest potential to match the patient. This allows transplant physicians searching the Be The Match Registry^® (operated by the NMDP) to identify more quickly and efficiently the best immunogenetically matched donor or cord blood unit for their patients.

Matching unrelated donors or cord blood units to patients

The transplant center is responsible for selecting an unrelated donor or cord blood unit for a patient. The National Marrow Donor Program recommends that when possible, patients and adult donors (marrow or PBSC) should be fully matched (8 of 8 loci) at high resolution for HLA-A, -B, -C, and -DRB1. Matching for cord blood units is less stringent, and the NMDP recommends fully matched (6 of 6) CBUs at HLA-A, -B (antigen level) and -DRB1 (allele level). [8-10]

This does not imply that availability of a partially matched donor or cord blood unit is a contraindication to transplant. Instead, a less-than-optimal match is another risk factor to be considered in developing the patient's treatment plan. [5,7,8]

The NMDP's minimum HLA matching requirements for adult donors (marrow or PBSC) or cord blood units are:

• Adult donors: A 6 of 8 match for HLA-A, -B, -C, and -DRB1. However, each of these loci must be typed at high resolution by DNA-based methods. [10] (See NMDP matching guidelines.)
• Cord blood units: A 4 of 6 match for HLA-A, -B (antigen level), and -DRB1 (allele level). [9]

These are the minimum matching requirements that must be met before the NMDP will permit a transplant using one of its adult donors or cord blood units. Transplant centers may have additional matching requirements for the transplants they perform.

Request a free preliminary search

Any physician can request a preliminary search to find out about potential marrow or PBSC donors or cord blood units on the Be The Match Registry. This preliminary search is free. Results of a preliminary search are available to the requesting physician the next business day after the NMDP receives the request. Early preliminary searches can indicate how challenging the patient's search for a donor may be and help in shaping the patient's treatment plan.

Effective search strategies

A preliminary search is a single "snapshot" of potential matches at a given time and does not include contact with or additional testing of a potential donor. To interpret preliminary search results and determine an effective search strategy, it is important to work with a knowledgeable HLA expert, either at a transplant center HLA laboratory or the NMDP.

• Even when the preliminary search ostensibly yields limited options, an HLA expert can develop a search strategy that may identify potential donors.
• If the preliminary search yields a number of potential donors, further testing of potential donors or cord blood units is still necessary to confirm an appropriate match, and contact with potential donors is needed to confirm availability.

For more information about the search process, see Searching for an Unrelated Donor or Cord Blood Unit.

HLA resources for your patients

The Patients & Families section of this website provides resources to help your patients understand HLA matching and the search process:

• HLA Matching: Finding the Best Donor or Cord Blood Unit  
• The Search Process  
• MatchView^® 

Using MatchView, patients enter their HLA type to see the number of potential donors and cord blood units they may have on the Be The Match Registry. Patients are encouraged to bring their results to their physician as a resource to discuss transplant as a treatment option.

Note: MatchView is not an alternative to a donor search conducted by a physician. For more information, see MatchView Physician Information.

References

1. Eapen M, Rubinstein P, Zhang MJ, et al. Outcomes of transplantation of unrelated donor umbilical cord blood and bone marrow in children with acute leukaemia: a comparison study. Lancet. 2007;369(9577):1947-1954.
   http://www.thelancet.com/journals/lancet/
   article/PIIS0140673607609155/abstract  
2. Arcese W, Rocha V, Labopin M, et al. Unrelated cord blood transplants in adults with hematologic malignancies. Haematologica. 2006; 91(2):223-230.
   http://www.haematologica.org/cgi/content/abstract/91/2/223  
3. Rocha V, Labopin M, Sanz G, et al. Transplants of umbilical-cord blood or bone marrow from unrelated donors in adults with acute leukemia. N Engl J Med. 2004; 351(22):2276-2285.
   http://content.nejm.org/cgi/content/full/351/22/2276  
4. Laughlin MJ, Eapen M, Rubinstein P, et al. Outcomes after transplantation of cord blood or bone marrow from unrelated donors in adults with leukemia. N Engl J Med. 2004; 351(22):2265-2275.
   http://content.nejm.org/cgi/content/full/351/22/2265  
5. Flomenberg N, Baxter-Lowe LA, Confer D, et al. Impact of HLA class I and class II high-resolution matching on outcomes of unrelated donor bone marrow transplantation: HLA-C mismatching is associated with a strong adverse effect on transplantation outcome. Blood. 2004; 104(7):1923-1930.
   http://www.bloodjournal.org/cgi/content/full/104/7/1923  
6. Lee SJ, Klein J, Haagenson M, et al. High-resolution donor-recipient HLA matching contributes to the success of unrelated donor marrow transplantation. Blood. 2007; 110(13):4576-4583.
   http://bloodjournal.hematologylibrary.org/cgi/content/
   full/110/13/4576  
7. Hurley C, Baxter-Lowe LA, Logan B, et al. National Marrow Donor Program HLA-matching guidelines for unrelated marrow transplants. Biol Blood Marrow Transplant. 2003; 9(10):610-615.
   http://www.bbmt.org/article/PIIS108387910300329X/fulltext  
8. Hurley CK, Wagner JE, Setterholm MI, Confer DL. Advances in HLA: Practical implications for selecting adult donors and cord blood units. Biol Blood Marrow Transplant 2006; 12(1, Suppl. 1): 28-33.
   http://www.bbmt.org/article/PIIS1083879105006890/fulltext  
9. Kamani N, Spellman S, Hurley CK, et al. State of the art review: HLA matching and outcome of unrelated donor umbilical cord blood transplants. Biol Blood Marrow Transplant. 2008; 14(1):1-6.
   http://www.bbmt.org/article/PIIS1083879107005721/fulltext  
10. Bray RA, Hurley CK, Kamani NR, et al. National Marrow Donor Program HLA matching guidelines for unrelated adult donor hematopoietic cell transplants. Biol Blood Marrow Transplant. 2008; 14(9, Suppl. 3):45-53.
    http://www.bbmt.org/article/S1083-8791(08)00274-7/fulltext