Page 1809 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 105 Unrelated Donor Hematopoietic Cell Transplantation 1613

mismatches have been proposed as defined by polymorphism for These novel observations suggest that the underlying mechanisms
selected HLA class I residues that participate in selecting the peptide leading to GVL may involve T- and/or NK-mediated effects of these
repertoire or direct contact with the T-cell receptor. (6) Polymor- two loci.
phisms outside of the classic HLA loci may be clinically significant. Beyond HLA-A, HLA-B, HLA-C, HLA-DR, and HLA-DQ genes,
a series of class II genes known as HLA-DRB3, DRB4, and DRB5
HUMAN LEUKOCYTE ANTIGEN−MATCHED UNRELATED exist on certain HLA-DRB1 haplotypes and have recently been
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shown to contribute to clinical outcome. HLA-DRB3 is linked to
DONOR HEMATOPOIETIC CELL TRANSPLANTATION HLA-DR3, DR5, and DR6 haplotypes; DRB4 to HLA-DR4, DR7,
and DR9 haplotypes, and DRB5 to DR2 haplotypes. When a patient
The impact of more complete and precise donor HLA matching is and donor are mismatched HLA-DRB1, the probability of additional
dramatic. Overall survival after transplantation for the treatment of mismatching at DRB3/4/5 is increased on these specific HLA-DR
acute myeloid leukemia, myelodysplastic syndrome, acute lympho- haplotypes. The cumulative impact of multiloci mismatching inclu-
blastic leukemia, and CML from an HLA 8/8-matched unrelated sive of DRB3/4/5 on mortality was significant, particularly when
donor can approach the results observed after HLA-identical sibling three or more mismatches are present. These data suggest that when
transplantation (http://www.marrow.org). For all modalities, the an HLA-DRB1−mismatched donor is identified, additional charac-
underlying disease diagnosis and stage of disease at transplantation terization of HLA-DRB3/4/5 on relevant HLA-DR haplotypes, is
remain the most important prognostic features that affect disease-free warranted.
survival. The general rules for donor HLA matching are applicable
to different graft sources (BM or peripheral blood stem cells) and to
different intensities of the conditioning regimen (ablative, reduced Selection of Mismatched Donors: Emerging Concepts
intensity, nonmyeloablative) in which HLA matching is globally for Permissible Mismatches
associated with better outcome than HLA mismatching. 39,40
Given that many patients have only HLA-mismatched unrelated
2
SINGLE-LOCUS MISMATCHED UNRELATED donors, research efforts have been focused on identifying properties
of HLA mismatches that do not increase risks to patients, also
HEMATOPOIETIC CELL TRANSPLANTATION known as “permissible HLA mismatches” (Box 105.3). Three major
Early studies of patients receiving HLA antigen-matched, MLC-
compatible unrelated donor HCT uniformly reported a relatively Research in Progress: New Immunogenetic Factors for
high incidence of acute GVHD and transplant-related mortality BOX 105.3 Consideration in Transplantation
(TRM) compared with transplantations from HLA-identical siblings.
The possibility that undetected donor−recipient mismatching for Permissible HLA Mismatches
HLA allele variants could be responsible for increased complications When an HLA-matched donor is not available, criteria for the selection
in cases of unrelated donor HCT suggested that the safety and success of mismatched donors is needed. There are currently four concepts
of unrelated donor transplantations could be improved by further for evaluating HLA-mismatched donors. Extensive registry and trans-
advances in HLA typing and donor matching and prompted close plant center data suggest that where possible, limiting the total
examination of serologically identical unrelated transplant pairs using number of HLA mismatches is associated with lower posttransplant
DNA typing methods. complications.
Second, defining a given patient–donor mismatch as “allele” (detect-
The importance of high-resolution matching of unrelated donors able by high-resolution DNA methods, for example HLA-A*02:01) or
for HLA-A, HLA-B, HLA-C and HLA-DRB1 was confirmed by “antigen” (equivalent to the serologic phenotype of the antigen, for
several large analyses (see Table 105.6). In summary, when an HLA- example HLA-A2) has utility in lower risks, particularly for the HLA-C
matched donor is not available, distinguishing allele mismatches and locus where HLA-C allele mismatches have less associated risk of
antigen mismatches at HLA-A, HLA-B, and HLA-C provides an mortality than HLA-C antigen mismatches.
algorithm for the prioritization of mismatched donors; in general, A third area of active research is the definition of residues of class I
avoidance of antigen mismatches is preferred. and II molecules and their amino acid substitutions that are associated
The importance of the HLA-DP locus has been demonstrated in with transplant risks. Hypervariable positions having direct influence
several recent analyses in which the role of specific HLA-DPβ epit- on the peptide-binding region of the molecule have been most com-
monly studied and show that some amino acid substitutions at certain
opes as well as level of HLA-DP expression have been shown to have positions are more detrimental than others. The most noteworthy resi-
clinical relevance, as described later. Population studies have shown dues identified to date include residues 99 and 116 of HLA-C and
that HLA-DP is unique among other HLA genes because of very residue 9 of HLA-B. The ability of T cells to recognize these epitopes
weak LD between HLA-DP and HLA-A, HLA-B, HLA-C, HLA-DR, lends functional support to this model.
and HLA-DQ. As a result, fewer than 20% of HLA-A, HLA-B, A fourth new concept is the role of the level of HLA expression.
HLA-C, HLA-DRB1, and HLA-DQB1−matched unrelated donor Mismatched patient HLA-C antigens that are expressed at lower levels
pairs are also matched for HLA-DP. Retrospective examination of on the cell surface are associated with lower risk of graft-versus-host
HLA-DP has required very large transplant populations so that suf- disease than patient antigens expressed at higher levels. Mismatching
ficient numbers of HLA-DP–matched pairs could be compared with between low-expression donor HLA-DP and high-expression patient
HLA-DP alleles is associated with high risks of clinically significant
mismatched pairs. Furthermore, the measured effects attributed to GVHD.
single loci in early studies likely measured additive effects of HLA-DP
with HLA-A, HLA-B, and HLA-DR. HLA-DP does function as a Haplotypes
classic transplantation antigen with respect to GVHD. Mismatching The Japanese transplant experience strongly suggests a role for highly
for two DPB1 allele increases the risk of acute GVHD compared with conserved HLA haplotypes and transplant outcome.
one or no HLA-DP mismatch. Analysis of the structural basis of HLA Novel Markers
alloreactivity sheds light on specific epitopes encoded by HLA-DP Surveys of the major histocompatibility complex with the aid of single
exon 2 that are responsible for increased GVHD risk. 41 nucleotide polymorphism markers have uncovered undetected varia-
New information from the Japan Marrow Donor Program tion that is associated with transplant outcome. These data suggest
(JMDP) suggests that the beneficial graft-versus-leukemia (GVL) that HLA haplotype encode additional genes that have clinical relevance.
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effect is not equally apparent for every HLA mismatch. In a retro- Future research into the identification of the causative genes will shed
spective analysis of 7898 Japanese patients transplanted with T-cell light on the pathways involved in graft-versus-host allorecognition.
replete marrow from Japanese unrelated donors, only HLA-C and GVHD, Graft-versus-host disease; HLA, human leukocyte antigen.
HLA-DPB1 mismatching were associated with lower risk of relapse.