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Chapter 105 Unrelated Donor Hematopoietic Cell Transplantation 1609

Clinical Relevance to Reaching Transplantation From the TABLE Common Definitions in Human Leukocyte Antigen
BOX 105.1 Initiation of an Unrelated Donor Search: Patient and 105.1 Genetics
Donor Factors
Term Definition Example
Outcome Patient Factors Donor Factors Allele Unique sequence of an DRB1*04:01 allele is a
Probability of the Increased age a HLA-A, HLA-B, HLA gene defined unique sequence defined as
patient reaching HLA-C, HLA-DRB1, by molecular DR4 by serologic methods
transplantation HLA-DQB1 match methods
status c Antigen Antibody-defined DR4 antigen is a serologically-
Advanced disease risk b protein defined protein product of
Probability of Karnofsky performance Donor availability d
patient survival status (KPS) a an HLA gene
Haplotype HLA genes inherited HLA-A1, HLA-B8, HLA-DR3 is
After the initiation of a search for an unrelated donor, older patients with more as a chromosomal a common haplotype among
advanced disease and no HLA-matched donor are associated with lower odds
of reaching transplantation. Patients whose Karnofsky performance status is unit white populations
90% to 100% and who have an available donor have significantly reduced Genotype Molecularly-defined Genotypically-matched donor
hazard of death. a
a Pidala J, Kim J, Schell M et al: Race/ethnicity affects the probability of finding HLA allele or and recipient are identical
an HLA-A, -B, -C and -DRB1 allele-matched unrelated donor and likelihood of sequence for the HLA alleles at a
subsequent transplant utilization. Bone Marrow Transplant 48:346–350, 2013. given HLA gene (e.g.,
b Disease risk as categorized by the Center for International Blood and Marrow HLA-DRB1*04:01)
Transplantation Research.
c Donor HLA matching remains the most significant risk factor for transplant Phenotype Serologically-defined Phenotypically-matched donor
outcomes. HLA protein or and recipient share the
d Identifying the primary donor with a backup will give flexibility in the
scheduling of a transplant. antigen same HLA antigen (e.g.,
Adapted from reference 3. HLA-DR4)
HLA, Human leukocyte antigen.

associated with transmissible elements akin to blood transfusion TABLE
donors. Special focus is placed on risks of transmission of hepatitis, 105.2 Polymorphism of Human Leukocyte Antigen Genes
human immunodeficiency virus (HIV), malaria, West Nile virus,
transmissible spongiform encephalitis (Creutzfeldt-Jacob disease), Antigens Alleles
and Chagas disease. Donor screening includes blood tests for HIV 1 HLA-A 24 3285
and 2, hepatitis B virus, hepatitis C virus, Treponema pallidum,
human T-cell lymphotrophic virus I and II, and cytomegalovirus. HLA-B 50 4077
Increased awareness for the health and safety of the unrelated HLA-C 9 2801
donor has led to the establishment of standards for donation. 13,14 HLA-DRB1 15 1825
These standards include donor recruitment, confidentiality, health HLA-DQB1 9 876
assessment and eligibility, donors as research participants, and adverse
events following donation. With the use of peripheral-blood stem HLA-DPB1 6 587
15
cells as a primary source of progenitor cells for transplantation, a HLA, Human leukocyte antigen.
comprehensive review of the long-term effects of granulocyte colony- Available at http://www.ebi.ac.uk/ipd/imgt/hla/stats.html.
stimulating factor has not revealed increased incidence of hematologic
malignancies among volunteer donors. 16

HLA-A2 antigen family). The second set of numbers provides the
PROCESS OF IDENTIFYING A SUITABLE unique protein that correspond to the subtype (HLA-A*02:101). The
UNRELATED DONOR third set of numbers indicate synonymous substitutions (HLA-
A*02:101:01). The last series of numbers give information on non-
Human Leukocyte Antigen Typing and Donor Matching coding variation often denoting expression (HLA-A*02:101:01:02
in the DNA Era: Genetics of the Human Leukocyte N). Letter suffixes are used to denote alleles that are not expressed
(also known as “null”; N), low cell surface expression (L), a soluble
Antigen Complex secreted molecule not present on the surface of the cell (S), a cyto-
plasmic product not expressed on the cell surface (C), a protein with
The advent of molecular techniques has made possible the definition aberrant expression (A), and a sequence of questionable expression
of unique sequence variants (alleles) that encode each HLA molecule (Q). This new nomenclature has no limits on the number of digits
that is recognized by an antibody (antigen; Table 105.1). Polymor- for each of the four categories and in this way, obviates the need for
phism ensures that a large array of foreign peptides can be presented constant renumbering.
to the immune system by HLA molecules. As of October 2015, more DNA genotyping was adopted as the standard technique for
than 3285 HLA-A, 4077 HLA-B, 2801 HLA-C, 1825 HLA-DRB1, selection of HLA-matched unrelated donors because unrelated
876 HLA-DQB1, and 587 HLA-DPB1 alleles have been defined in individuals who are matched for HLA antigens may not necessarily
diverse human populations (http://www.ebi.ac.uk/ipd/imgt/hla/ share the same HLA sequences. If HLA alleles can be expressed in
stats.html; Table 105.2). HLA nomenclature accommodates the any combination and if inheritance of alleles were random, then the
steady discovery of new human variants. The HLA prefix is followed total estimated number of possible five-locus HLA-A, HLA-B,
by a hyphen and the gene name (e.g., HLA-A). The gene is listed HLA-C, HLA-DRB1, and HLA-DQB1 genotypes would be exceed-
followed by an asterisk to separate the gene from the unique sequence ingly high, and the chances of identifying a fully matched donor
(HLA-A*). The unique sequence name embodies up to four kinds of would be very low. Clinical experience demonstrates that donor
information, each delimited by a colon. The first set of numbers after identification is successful, and is caused by the underlying genetic
the asterisk and before the first colon correspond to the serologic hallmark of the major histocompatibility complex known as linkage
antigen equivalent (e.g., HLA-A*02 refers to sequences of the disequilibrium (LD). LD refers to the observation that HLA alleles