Unrelated Donor Hematopoietic Cell Transplantation

Published on 04/03/2015 by admin

Filed under Hematology, Oncology and Palliative Medicine

Last modified 22/04/2025

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Chapter 47 Unrelated Donor Hematopoietic Cell Transplantation

Effie W. Petersdorf, Claudio Anasetti

Table 47-1 Common Definitions in Human Leukocyte Antigen Genetics

Term	Definition	Example
Allele	Unique sequence of an HLA gene defined by molecular methods	DRB1*04:01 allele is a unique sequence defined as DR4 by serologic methods
Antigen	Antibody-defined protein	DR4 antigen is a serologically defined protein product of an HLA gene
Haplotype	HLA genes inherited as a chromosomal unit	HLA-A1, HLA-B8, HLA-DR3 is a common haplotype among white populations
Genotype	Molecularly defined HLA allele or sequence	Genotypically matched donor and recipient are identical for the HLA alleles at a given HLA gene (e.g., HLA-DRB1*04:01)
Phenotype	Serologically defined HLA protein or antigen	Phenotypically matched donor and recipient share the same HLA antigen (e.g., HLA-DR4)

HLA, Human leukocyte antigen.

Table 47-2 Vector of Mismatch

GVH, Graft versus host; HVG, host versus graft.

* These combinations contain bidirectional (both HVG and GVHD) mismatch vectors.

† Unidirectional mismatches.

Criteria for an Interpretable Study on the Role of Human Leukocyte Antigen Matching in Cases of Unrelated Donor Transplantation

DNA-based methods have become established as the gold standard for HLA testing. Research studies aimed at defining the importance of HLA mismatching in transplant outcome ideally examine donor–recipient transplant pairs that are fully typed for HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DQB1, and HLA-DPB1 at the sequence level. In this way, the relative risks of HLA disparity on a given clinical endpoint can be more accurately measured. Many non-HLA variables have an impact on the same clinical endpoints that are also affected by HLA disparity including whether the underlying disease is malignant or nonmalignant, whether the conditioning regimen is ablative or reduced intensity, and the specific regimen used to prevent GVHD. These nongenetic variables may contribute risks that diminish the ability to discern HLA-specific effects and require multivariate models to adjust or stratify for these variables to assess independence of HLA effects on the clinical endpoint of interest. Finally, the study should have sufficient statistical power to detect a significant difference in outcome when one truly exists. Very large numbers of transplants are required to adjust for HLA and non-HLA variables.

Table 47-3 Principles of Donor Human Leukocyte Antigen Matching Using High-Resolution DNA Typing Methods

1. When feasible, four-locus HLA-A, HLA-B, HLA-C, and HLA-DRB1 matching is optimal.

2. Although there are no “good” mismatches, HLA-C antigen mismatches are particularly detrimental.

3. Multiple mismatches are less well tolerated and should be limited.

4. Permissible HLA mismatches can be defined by specific class I and class II residues that participate in peptide repertoire or direct contact with the T-cell receptor.

5. Haplotype matching of HLA-A, HLA-B, HLA-C, HLA-DRB1 allele-identical donors and recipients may lower posttransplant risks of clinically severe acute GVHD.

GVHD, Graft-versus-host disease; HLA, human leukocyte antigen.

Human Leukocyte Antigen Selection Criteria for Unrelated Donors

DNA typing can uncover additional allele disparity between HLA-A, HLA-B, HLA-DR phenotypically matched unrelated donors and recipients. Both GVHD and mortality are increased with use of phenotypically matched unrelated donors compared with related donor–recipient pairs. The difference in outcome can be attributed in part to the effects of mismatching for HLA-A, HLA-B, HLA-C, and HLA-DRB1 alleles and to the degree of HLA-A, HLA-B, HLA-DRB1 haplotype identity between the donor and recipient. Routine testing of potential donors should include DNA typing for HLA-A, HLA-B, HLA-C, and HLA-DRB1 at the intermediate resolution (antigen-equivalent) level. After the best-matched unrelated donors are identified, routine testing should include allele (sequence)-level typing for these genes. When a matched donor is not available, then the number of mismatches should be limited to one or two, with a single HLA-DQB1 mismatch being the best tolerated.

Table 47-4 Importance of HLA Mismatching on Survival After Unrelated Donor Transplantation

* HLA-A, C, B, DRB₁.

Data from Lee SJ, Klein J, Haagenson M, et al: High-resolution donor-recipient HLA matching contributes to the success of unrelated donor marrow transplantation. Blood 110:4576, 2007.