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Advances in HLA Typing

More precise matching improves transplant outcomes

The widespread use of DNA-based tissue typing has increased the accuracy and specificity of HLA typing, which allows for more precise HLA matching between donors and 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. [1,4]

Table 1 shows updated NMDP matching recommendations that are based on research examining HLA match and transplant outcomes.

HLA Locus Tissue type patient? Match donor and patient?
A Yes, allele level Yes
B Yes, allele level Yes
C Yes, allele level Yes
DRA No No
DRB1 Yes, allele level Yes
DRB3, 4, and 5 Yes (DRB1 association) Unknown
DQA1 No No
DQB1 Yes (DRB1 association) Uncertain
DPA1 No No
DPB1 No Uncertain
Table 1. HLA tissue typing recommended by the NMDP. [1]

Transplant timing is also important

However, the lack of a fully matched donor (8/8 matched, i.e., matched at HLA-A, -B, -C, -DRB1) does not preclude transplantation as a possible treatment option, because transplant outcomes are generally better when patients are transplanted earlier in their disease rather than later.

The NMDP therefore recommends not delaying transplant in the hopes of finding a better matched donor later. The NMDP bases this recommendation on a 2007 study of 3,857 transplants demonstrating that 6/8 patients transplanted in an early disease stage do better than fully matched 8/8 patients transplanted in advanced disease stage. [5] Because disease stage at the time of transplant is the only factor under direct control of a physician, an early referral is perhaps the single most important step that can affect survival. (See the NMDP Clinical Fact Sheet on Outcomes in Unrelated Hematopoietic Cell Transplantation for additional data.)

Cord blood can overcome HLA barriers to transplant

In addition, a cord blood unit (CBU) may be an appropriate source of transplant cells if a fully matched adult marrow or PBSC donor is not available. HLA matching criteria are less stringent for cord blood transplants, and a 4/6 matched CBU is permissible. [6,7]

Due to the limited number of cells in some CBUs, however, cord blood transplantation has been used more in pediatric patients and less often in larger patients. [8] However, recent studies have reported successful outcomes of combining two CBUs for larger patients. [9,10] (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 its Be The Match Registry SM operated by the National Marrow Donor Program® (NMDP)  with the highest potential to match the patient. This allows transplant physicians searching the registry to identify more quickly and efficiently the best immunogenetically matched donor or CBU for their patients.

The new matching algorithm, named HapLogicSM by the NMDP, is based on analyses of the haplotypes of millions of donors on the Be The Match 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 HLA-A, -B-typed donors. [6]

New NMDP HLA matching guidelines

The NMDP has developed donor matching guidelines based on the clinical research into the effect of HLA matching on transplant outcomes. [1] These guidelines were published in a supplement to the September 2008 issue of Biology of Blood and Marrow Transplantation (BBMT). View Saving Lives through Blood and Marrow Transplantation: 20 years of the NMDP.

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® which allows patients to 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 the MatchView Physician Information.

References

  1. 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
  2. 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
  3. 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
  4. 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
  5. Lee S, 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://dx.doi.org./10.1182/blood-2007-06-097386
  6. 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
  7. 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
  8. 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
  9. 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
  10. 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

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Quick Reference: Referral Guidelines and Post-Transplant Guidelines