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Advances in HLA Typing

More precise matching has improved transplant outcomes

The phasing out of serological tissue typing and its replacement with DNA-based tissue typing has increased the accuracy and specificity of HLA typing, which allows for more precise HLA matching between donors and transplant patients.

Several large-scale studies have demonstrated that more precise HLA matching between donor and patient significantly:

Improves overall transplant survival [1]
Reduces the incidence and severity of both acute and chronic GVHD [2]
Improves rates of engraftment [3]

HLA advances and donor selection criteria

Large-scale studies on HLA and transplant outcome have also demonstrated which HLA loci are critical to match in order to maximize the success of hematopoietic cell transplantation. Although matching at the three HLA loci traditionally associated with hematopoietic cell transplantation (HLA-A, -B, and -DR) can lead to successful transplantation outcomes, recent research has shown matching at HLA-C can also improve outcome. [4]

Based on research results of HLA matching and transplant outcomes, the NMDP makes the recommendations shown in Table 1.

HLA Locus	Tissue type patient?	Match donor and patient?
HLA-A	Yes, allele level	Yes
HLA-B	Yes, allele level	Yes
HLA-C	Yes, allele level	Yes
HLA-DRB1	Yes, allele level	Yes
DRB3, 4, and 5	Yes, for linkage	Unknown
HLA-DQA1 and B1	Yes	No
HLA-DPA1 and B1	Unclear	No

Table 1. HLA tissue typing recommended by the NMDP. [1]

The NMDP also recommends the following donor-selection strategy when less-than-perfect HLA-matched individuals are the only potential donors available to a patient:

Assume that HLA-A, -B, -C and -DRB1 are equally important
Accept one allele (DNA) mismatch over one antigen (serological) mismatch
Minimize the number of allele mismatches [1]

Therefore, lack of a well-matched donor (HLA matched or a single HLA-A, -B, -C, or -DRB1 mismatch) does not necessarily eliminate transplantation as a possible treatment option. In this situation, a physician should consider the success rate associated with the use of a slightly mismatched donor versus the use of other available treatment.

Cord blood can overcome HLA barriers to transplant

In addition, a cord blood unit (CBU) may be an appropriate source of transplant cells. HLA matching criteria are less stringent for cord blood transplants, and a 4 of 6 matched CBU may be available when no 5/6 or 6/6 HLA-matched adult donors are identified. [5,6] Due to the limited number of cells in some CBUs, cord blood transplantation has been used more in pediatric patients and less often in larger patients. [7] However, recent studies have reported sussessful outcomes of combining two CBUs for larger patients. [8,9] (See Hematopoietic Cell Sources Tailored to the Patient for a comparison of cell sources for transplantation.)

New matching algorithm accelerates searches

In 2006, the NMDP introduced a new enhanced matching algorithm that automatically identifies the donors or CBUs on the NMDP Registry with the highest potential to match the patient. This allows transplant physicians searching the NMDP Registry to identify more quickly and efficiently the best immunogenetically matched donor or CBU for their patients.

The new matching algorithm, named HapLogic^SM by the NMDP, is based on analyses of the haplotypes of millions of donors on the NMDP Registry. HapLogic uses advanced logic to predict a donor’s or CBU’s high-resolution match, and builds upon mathematical formulas that predict DR match in AB-typed donors. [5]

NMDP HLA matching guidelines

The NMDP has developed donor matching guidelines based on the clinical research into the effect of HLA on transplant outcome. [1] These guidelines were published in the October 2003 edition of Biology of Blood and Marrow Transplantation and can be viewed at http://www.bbmt.org.

HLA resources for your patients

The Patient Resources section of this Web site provides resources to help your patients understand HLA matching and the search process:

In addition, the NMDP has developed MatchView^SM, which allpws patients to enter their HLA type to see the number of potential donors and cord blood units they may have on the NMDP 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 the MatchView Physician Information.

References

Hurley CK, 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
Morishima Y, Sasazuki T, Inoko H. The clinical significance of human leukocyte antigen (HLA) allele compatibility in patients receiving a marrow transplant from serologically HLA-A, HLA-B, and HLA-DR matched unrelated donors. Blood. 2002; 99(11):4200-4206.
http://www.bloodjournal.org/cgi/content/full/99/11/4200
Petersdorf EW, Hansen JA, Martin PJ. Major-histocompatibility-complex class I alleles and antigens in hematopoietic-cell transplantation. N Engl J Med. 2001; 345(25):1794-1800.
http://content.nejm.org/cgi/content/abstract/345/25/1794
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 transplant outcome. Blood. 2004; 104(7):1923-1930.
http://www.bloodjournal.org/cgi/content/full/104/7/1923
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/abstract
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
Rocha V, Gluckman E. Clinical use of umbilical cord blood hematopoietic stem cells. Biol Blood Marrow Transplant. 2006; 12(1) Suppl. 1:34-41.
http://www.bbmt.org/article/PIIS1083879105006622/abstract
Majhail NS, Brunstein CG, Wagner JE. Double umbilical cord blood transplantation. Curr Opin Immunol. 2006; 18(5):571-575.
http://dx.doi.org/10.1016/j.coi.2006.07.015
Barker JN, Weisdorf DJ, DeFor TE, et al. Transplantation of 2 partially HLA-matched umbilical cord blood units to enhance engraftment in adults with hematologic malignancy. Blood. 2005; 105(3):1343-1347.
http://www.bloodjournal.org/cgi/content/full/105/3/1343