HLA Typing and Matching


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HLA Typing and Matching

The outcomes of related and unrelated donor hematopoietic cell transplantation (HCT) are strongly affected by the degree of human leukocyte antigen (HLA) matching between the transplant recipient and the hematopoietic cell graft.

Several large-scale studies have demonstrated that a greater degree of HLA match between donor and recipient:

  • Improves overall transplant survival [1]
  • Reduces the incidence and severity of both acute and chronic GVHD [2]
  • Improves rates of engraftment [2,3,4] 

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.

NMDP HLA Matching Guidelines

 

Several large-scale studies on HLA and transplant outcomes have identified which HLA loci are critical to match in order to maximize the success of hematopoietic cell transplantation. [5,6,7,8,9]

The National Marrow Donor Program® (NMDP)/Be The Match® has developed and published adult donor (marrow and PBSC) and cord blood matching guidelines based on clinical research into the effect of HLA matching on hematopoietic cell transplantation (HCT) outcomes. [1]

The following data summarize the HLA- and cell-dose-related factors to be considered in the selection of unrelated donors and umbilical cord blood units. [1] Consideration may also be given to HLA-DP permissive versus non-permissive mismatching when choosing among donors who are comparable by other criteria. [9]

8/8 matched donor:

  • -A, -B, -C, -DRB1

No 8/8 options:

  • ≥4/6 cord blood unit with adequate cell dose
    • Consider: HLA antibodies, HLA-C, Noninherited Maternal Antigens (NIMA)
     
  • 7/8 Donor
    • Consider: HLA antibodies, number of mismatched secondary HLA loci (-DBQ1, DRB3/4/5, DP)

The NMDP/Be The Match recommends that whenever possible, transplant physicians should seek donors who are high-resolution matched at HLA-A, -B, -C, and -DRB1. However, unavailability of such a donor is not a contraindication for transplantation. If a mismatch is unavoidable, a single-locus mismatched donor (HLA-A, -B, -C, or -DRB1) can be used with acceptable risks of transplant-related mortality.

Access an online two-part educational activity on these HLA matching recommendations, including case studies.

Minimum HLA Matching Requirements

Although the NMDP/Be The Match recommends that whenever possible, transplant physicians should use donors who are high-resolution matched at HLA-A, -B, -C, and -DRB1 (8 of 8 loci match), such donors are not always available. The NMDP/Be The Match recommends that transplant physicians reevaluate alternative treatment options in these situations and decide whether to use a donor with a lower degree of HLA match, or select another graft source (e.g., unrelated cord blood transplantation, or partially matched related donor transplantation).

The following are the minimum matching requirements that must be met before the NMDP/Be The Match will permit a transplant using one of its adult donors or cord blood units. [1] 
  • Adult donors (marrow or PBSC): 6 of 8 loci match for HLA-A, -B, -C, and -DRB1; each of these loci must be typed at high resolution by DNA-based methods
  • Cord blood units: 4 of 6 loci match for HLA-A, -B (antigen level), and -DRB1 (allele level)

Note that individual transplant centers may have additional matching requirements, i.e. many centers require at least a 7 of 8 loci match for marrow or PBSC transplants. Recent research has also indicated that high-resolution HLA tissue typing of cord blood units can result in better transplant outcomes. [10]

Timing for Patient and Family HLA Typing

 

If allogeneic transplant is an option, high-resolution HLA typing of the patient and potential family donors should be completed early after diagnosis. If no matches are found, a preliminary search of the Be The Match Registry® should be done.

This is especially important in acute diseases such as acute myelogenous leukemia (AML) and acute lymphoblastic leukemia (ALL) due to the possibility that patients may experience rapid disease progression and will therefore need to proceed to transplant quickly.

The 2016 referral timing guidelines developed jointly by the NMDP/Be The Match and the American Society for Blood and Marrow Transplantation (ASBMT) recommend that adult and pediatric patients with AML and adults with ALL be HLA tissue typed at high-resolution HLA at diagnosis.

Optimal Timing of Transplant vs. Match

 

The lack of a fully matched donor (8 of 8 loci, i.e., matched at HLA-A, -B, -C, and -DRB1) does not preclude transplantation as a possible treatment option, because, even with a mismatched donor, transplant outcomes are generally better when patients are transplanted earlier in their disease rather than later. [11]

Results of a study of 3,857 unrelated donor transplants demonstrated that:

  • 6/8 HLA-matched patients transplanted in an early disease state do significantly better than fully matched 8/8 patients transplanted in advanced disease
  • Patients with intermediate-stage disease had a 38% greater risk of mortality than patients with early-stage disease
  • Patients with advanced disease had approximately twice the mortality risk as patients with early-stage disease [11]

The authors concluded that because disease stage at the time of transplant is the only factor under direct control of a clinician, an early referral is perhaps the single most important step that can affect survival. These findings were validated in a study of 8,003 unrelated donor transplants published in 2014. [9]

HapLogicSM Matching Algorithm Accelerates Searches

Our matching algorithm, HapLogic, automatically identifies the donors or CBUs on the Be The Match Registry with the highest potential to match the patient. This allows transplant physicians searching the Registry to more quickly and efficiently identify the best immunogenetically-matched donor or CBU for their patients.

HapLogic uses data on the frequencies of the haplotypes of the more than 13.5 million donors on the Be The Match Registry to predict the probability that a donor's or CBU's high-resolution tissue typing will match a patient. [1]

References

  1. Spellman SR, Eapen M, Logan BR, et al. A perspective on the selection of unrelated donors and cord blood units for transplantation. Blood. 2012; 120(2): 259-265. Access
  2. Petersdorf EW. Risk assessment in haematopoietic stem cell transplantation: Histocompatibility. Best Pract Res Clin Haematol. 2007; 20(2): 155-170. Access
  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. Access
  4. Crocchiolo R, Ciceri F, Fleischhauer K, et al. HLA matching affects clinical outcome of adult patients undergoing haematopoietic SCT from unrelated donors: A study from the Gruppo Italiano Trapianto di Midollo Osseo and Italian Bone Marrow Donor Registry. Bone Marrow Transplant. 2009; 44(9): 571-577. Access  
  5. Spellman S, Setterholm M, Maiers M, et al. Advances in the selection of HLA-compatible donors: Refinements in HLA typing and matching over the first 20 years of the National Marrow Donor Program Registry. Biol Blood Marrow Transplant. 2008; 14(9, Suppl.): 37-44. Access
  6. 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.): 45-53. Access
  7. Woolfrey A, Klein JP, Haagenson M, et al. HLA-C antigen mismatch is associated with worse outcome in unrelated donor peripheral blood stem cell transplantation. Biol Blood Marrow Transplant. 2011; 17(6): 885-892. Access
  8. Petersdorf EW, Gooley T, Malkki M, et al. Clinical significance of donor-recipient HLA matching on survival after myeloablative hematopoietic cell transplantation from unrelated donors. Tissue Antigens. 2007; 69(S1): 25-30. Access
  9. Pidala J, Lee SJ, Ahn KW, et al. Nonpermissive HLA-DPB1 mismatch increases mortality after myeloablative unrelated allogeneic hematopoietic cell transplantation. Blood. 2014; 124(16): 2596-2606. Access
  10. Eapen M, Klein JP, Ruggeri A, et al. Impact of allele-level HLA matching on outcomes after myeloablative single unit umbilical cord blood transplantation for hematologic malignancy. Blood. 2014; 123(1): 133-140. Access
  11. 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. Access