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). 
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. 
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. 
Table 1. Unrelated donor selection guidelines
|Multiple HLA-A, -B, -C, - DRB1 (8/8) HLA matched unrelated donors available||8/8 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
|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*
|Attached segment identity testing||Mandatory|
|Use of RBC-replete unitsa,b||Not Recommended|
|Cryovolumec||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|
|Resolution of HLA-typing||Minimum of 8 high-resolution (HLA-A,-B,-C,-DRB1) for both patient & CBU|
>/= 4/6 HLA-A,-B antigen, -DRB1 high-resolution (Traditional Match) & >/= 4/8 high-resolution match
|Unit-unit HLA-match for double unit CBT||Not required|
|Avoidance of units against which recipient has DSAd||Conflicting results in hematological malignancies; Avoid if non-malignant diagnosis|
Cryopreserved Cell Dosee,f,g
|Single unit CBT: Minimum dose/kg|
TNC >/= 2.5 x 107/kg
|Double unit CBT: Minimum dose/kg/unit|
TNC 1.5 x 107/kg for each unit
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. 
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 early on 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. 
- Adult donors (bone 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). For confirmatory typing, high resolution at HLA-A,-B, -C and-DRB1 must be reported for the CBU and recipient.
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. 
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 .
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.
- 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. 
- 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
- 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
- The National Marrow Donor Program/ Be The Match 24th Edition Standards and Glossary. January 1, 2018.
- 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
- NMDP/Be The Match and ASBMT Recommended Timing for Transplant Consultation. Download (PDF)
- 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
- 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