HLA Typing and Matching


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HLA Typing and Matching

Multiple pre- and post-transplant factors including patient, disease stage, and transplant-related aspects can impact transplant outcomes. The degree of human leukocyte antigen (HLA) matching between the transplant recipient and the hematopoietic cell graft has a significant impact the outcomes of related and unrelated donor hematopoietic cell transplantation (HCT). [1]

NMDP and CIBMTR HLA Matching Guidelines

The National Marrow Donor Program® (NMDP)/Be The Match® and the Center for International Blood and Marrow Transplant Research® (CIBMTR), jointly with the NMDP Histocompatibility Advisory Group, has developed and published 2019 matching guidelines for allogeneic hematopoietic transplantation. 

The Histocompatibility Advisory Group is a key opinion leader panel representing donor registry, laboratory methods and science, and clinical transplantation expertise.  This publication covers adult donor (bone marrow and peripheral blood stem cell (PBSC)) and cord blood unit (CBU) matching evidence-based guidelines based on clinical research on the effect of HLA donor-recipient matching on hematopoietic cell transplantation (HCT) outcomes and includes HLA typing recommendations and guidance on the search and selection process. [1]

View Blood publication (open access)

The following charts summarize the HLA- and cell-dose-related factors to be considered in the selection of unrelated donors and umbilical cord blood units, however reading the entire manuscript is encouraged for context. [1]

Table 1. Unrelated donor selection guidelines

 Multiple HLA-A, -B, -C, - DRB1 (8/8) HLA matched unrelated donors available8/8 match unavailable; multiple 7/8 unrelated donors available
1. Resolution of typing HLA-A,-B,-C,-DRB1 High-resolution, matches for antigen recognition domains

High-resolution, matches for antigen recognition domains for 7 matched alleles
Select HLA-C*03:03 versus C*03:04 mismatch, if present;
No other preference for mismatched loci (HLA-A/B/C/DRB1) or other allele combinations

2.Donor age Select donors of younger age Select donors of younger age
3. Permissive mismatching HLA-DPB1 Select matched/permissive DPB1 mismatch based on the algorithm developed by Crivello et al68,70 (http://www.ebi.ac.uk/cgi- bin/ipd/imgt/hla/dpb_v2.cgi) Select matched/permissive DPB1 mismatch based on the algorithm developed by Crivello et al68,70(http://www.ebi.ac.uk/cgi- bin/ipd/imgt/hla/dpb_v2.cgi)
4. Matching HLA- DRB3/4/5 and -DQB1 Minimize mismatches Minimize mismatches
5. Vector of mismatch N/A Select donor with single allele mismatched at patient’s homozygous locus (HLA-A/B/C/DRB1), if applicable
6. Donor-specific antibody (DSA) in patient Avoid mismatches of allotypes targeted by DSA, including DQA1 and DPA1 Avoid mismatches of allotypes targeted by DSA, including DQA1 and DPA1
7. Transplant center practice may differ in additional considerations to use in the selection among multiple donors equivalent for the characteristics above

When an 8/8 donor is not an available option, 7/8 matched unrelated donors, related haploidentical donors and umbilical cord blood represent alternative options for which patient- and provider-level factors are used in graft selection. 

Cord Blood Unit Selection Guidelines

The cord blood unit selection guidelines were developed by the American Society of Transplantation and Cellular Therapy Cord Blood Special Interest Group.

Table 2. Unrelated cord blood unit selection guidelines*

 Guidelines
Bank Practices 
Attached segment identity testing Mandatory
Use of RBC-replete units Not Recommended
Cryovolume Should be considered, especially if the unit is to be diluted post thaw
Year of cryopreservation More recent units may be linked to optimal banking practices depending on the bank
Bank location Domestic or international units fulfilling selection criteria
Bank accreditation and/or licensure Should be considered
HLA-Match 
Resolution of HLA-typing Minimum of 8 high-resolution (HLA-A, -B, -C, and -DRB1) for both patient and CB unit
Donor-recipient HLA match ≥4/6 HLA-A and -B antigen, -DRB1 high-resolution (traditional match), and ≥4/8 high-resolution match
(some centers investigating use of 4/6 and 3/8 units if adequate dose)
Unit-unit HLA match for double unit CBT Not required
Avoidance of units against which recipient has DSA Conflicting results in hematological malignancies; avoid if nonmalignant diagnosis
Cryopreserved Cell Dose 
Single-unit CBT: minimum dose/kg TNC ≥2.5 x 107/kg and CD34+ cells ≥1.5 x 105/kg
(Some centers recommend higher CD34+ dose as minimum)
Double-unit CBT: Minimum dose/kg/unit TNC 1.5 x 107/kg for each unit and CD34+ cells ≥1.0 x 105/kg for each unit
(some centers recommend higher CD34+ doses for each unit as minimum)

Republished with permission of American Society of Hematology, from Blood, HLA Typing and Matching, Optimal Timing of Transplant vs. Match, Dehn J, et al. 134(12), 2019]; permission conveyed through Copyright Clearance Center, Inc.

Best practices in cord blood selection from 6 experienced US transplant centers is available as a practical ‘how to’ guide for cord blood unit selection and was published by Barker et al. on behalf of the American Society for Transplantation and Cellular Therapy (formerly known as American Society for Blood and Marrow Transplantation) and the National Marrow Donor Program/Be The Match. [2]

    Note that individual transplant centers may have additional matching requirements, i.e. many centers require at least a 7 of 8 loci match for bone marrow or PBSC transplants. Research has also indicated that high-resolution HLA tissue typing of cord blood units can result in better transplant outcomes. [4]

    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 myeloid 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 referral timing guidelines developed jointly by the NMDP/Be The Match and the American Society for  Transplantation and Cellular Therapy (ASTCT) recommend that adult and pediatric patients with AML, adults with myelodysplastic syndromes and adolescent and adults with ALL be HLA tissue typed at high-resolution HLA at diagnosis [5].

    Optimal Timing of Transplant vs. Match

    Results of a study of 8,003 unrelated donor transplants demonstrated a significant interaction between 8/ 8 HLA match and disease stage at the time of transplant on outcomes.[6]

    • For patients with an 8/8 HLA-matched donor, 2,528 patients transplanted in an early disease state had a 71% (95% CI 69-73) 1-year survival rate while 1,444 patients transplanted in advanced disease incurred a 41% (95% CI 39-44) overall survival rate at 1 year 
    • Patients with intermediate-stage disease had a 40% greater risk of mortality than patients with early-stage disease
    • At 3- and 5-years post-transplant, 8/8 HLA-matched patients with early-stage disease experienced survival rates of more than twice the rates of 8/8 HLA-matched patients with advanced disease: 56% vs. 27%, and 50% vs. 22%, respectively (p <0.001).

    This study confirmed the results of an earlier study by Lee et al. where researchers concluded that an early referral is perhaps the single most important step that can affect survival. [7]

    References

    1. Dehn J, Spellman S, Hurley CK, et al. Selection of unrelated donors and cord blood units for hematopoietic cell transplantation: guidelines from NMDP/CIBMTR. Blood. 2019 . Open Access
    2. Barker JN, Kurtzberg J, Ballen K, et al. Optimal Practices in Unrelated Donor Cord Blood Transplantation for Hematologic Malignancies. Bio Blood Marrow Transplant. 2017; 23(6):882-896. Access
    3. The National Marrow Donor Program/ Be The Match 24th Edition Standards and Glossary. January 1, 2018.
    4. 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
    5. NMDP/Be The Match and ASBMT Recommended Timing for Transplant Consultation. Download (PDF)
    6. 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
    7. 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