What is the minimum number of Human Leukocyte Antigen (HLA) compatibilities required for a transplant?

Minimum HLA Compatibility Requirements for Transplantation

For optimal transplant outcomes, the minimum HLA compatibility requirements vary by donor source, with HLA-matched sibling donors (MSD) being preferred, followed by 8/10 matched unrelated donors (MUD), ≥4/6 matched cord blood for malignant diseases, and haploidentical donors as viable alternatives when better matches are unavailable. 1

HLA Matching Requirements by Donor Type

Matched Sibling Donors (MSD)

• HLA-matched sibling donors are generally the preferred choice for allogeneic hematopoietic stem cell transplantation (HSCT) due to complete HLA matching 1
• These donors typically provide the best outcomes with lower rates of graft-versus-host disease (GVHD) and transplant-related mortality 1

Matched Unrelated Donors (MUD)

• Requires high-resolution HLA matching with minimum 8/10 loci matches 1
• Nine to 10 loci matches are needed for HLA-A, B, C, DRB1, and DQ matches 1
• Five to six simultaneous loci matches are needed for A, B, and DRB1 matches 1
• High-resolution DNA matching for HLA-A, B, C, and DRB1 (8/8 match) is associated with the highest survival rates 2
• A single mismatch at HLA-A, B, C, or DRB1 (7/8 match) increases mortality risk (relative risk 1.25) and reduces 1-year survival from 52% to 43% 2

Cord Blood Transplantation (CBT)

• For malignant hematological diseases: ≥4/6 loci should be matched 1
• For non-malignant hematological diseases: ≥5/6 loci should be matched 1
• Cell dose requirements: Total nucleated cells (TNC) >2.5-4.0 × 10^7/kg and CD34+ cells >1.2-2.0 × 10^5/kg 1
• Extended HLA matching may yield better outcomes, with recent guidelines recommending minimum of 8 high-resolution (HLA-A, B, C, and DRB1) typing for both patient and CB unit 1
• For double cord blood transplantation, each unit should have minimum TNC of 1.5 × 10^7/kg and CD34+ cells of 1.0 × 10^5/kg 1

Haploidentical Donors (HID)

• Haploidentical donors share one HLA haplotype (approximately 50% HLA match) with the recipient 1
• Selection algorithm: children, male sibling, father, mismatched sibling with non-inherited maternal antigen (NIMA), mismatched sibling with non-inherited paternal antigen (NIPA), mother, and other collateral relatives 1
• Donors with donor-specific anti-HLA antibodies (DSAs) median fluorescence intensity (MFI) >10,000 should be avoided 1

Impact of HLA Mismatching on Outcomes

• Single mismatches at HLA-B or HLA-C appear better tolerated than mismatches at HLA-A or HLA-DRB1 2
• Mismatching at 2 or more loci compounds the risk of mortality 2
• Among cord blood transplants mismatched at 2 loci, mismatching at HLA-C and DRB1 is associated with the highest risk of mortality 1
• For kidney transplantation, the optimal cutoff for HLA eplet mismatch is <20 total eplet mismatches, with particular emphasis on minimizing HLA-DQ eplet mismatches to <7 3

Considerations for Donor Selection

• When selecting between multiple potential donors, consider these factors beyond HLA matching:

  • Donor-recipient age ratio (higher ratio increases transplant-related mortality) 1
  • Gender matching (female-to-male transplants increase risk) 1
  • ABO compatibility (major-mismatch increases risk) 1
  • CMV IgG serological status compatibility 1

• For MUD transplants with posttransplant cyclophosphamide GVHD prophylaxis:

  • MUD is preferred over haploidentical donors, especially for reduced-intensity conditioning regimens 4
  • With reduced-intensity regimens, MUD transplants show lower graft failure (3% vs 11%), lower acute GVHD, and better disease-free survival (55% vs 41%) compared to haploidentical transplants 4

Crossmatching Requirements

• Flow cytometry or a complement-dependent cytotoxicity (CDC) assay should be used for all patients 1
• A positive flow cytometry or anti-human globulin (AHG)-CDC crossmatch against either T cell or B cell donor targets, using sera with IgG antibodies to HLA antigens, is a contraindication to transplantation 1

Pitfalls and Caveats

• Relying solely on serological typing can lead to mistyping, particularly in African Americans (36.3% showed either HLA-A or HLA-B discrepancy) 1
• Molecular genotyping provides more accurate HLA typing and should be used when available 1
• It is strongly recommended not to re-expose a recipient to an HLA class II antigen of a previously rejected allograft 1
• Balancing cell dose and HLA matching is crucial, especially for cord blood transplantation, with cell dose often taking priority for adult and larger pediatric patients 1