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Human leukocyte antigen matching in unrelated donor hematopoietic cell transplantation
Human Leukocyte Antigen Matching in Unrelated Donor Hematopoietic Cell Transplantation Effie W. Petersdorf and Mari Malkki Hematopoietic cell transplantation (HCT) from unrelated donors is a curative therapy for many malignant and nonmalignant blood disorders. The success of unrelated HCT is influenced by the degree of human leukocyte antigen (HLA) compatibility between the donor and patient. When donor matching for HLA alleles is feasible, overall transplant outcome is superior. The presence of donor-recipient mismatching is associated with increased risk of post-transplant complications including graft rejection, acute and chronic graft-versus-host disease (GVHD), and mortality; these risks are increased with multiple HLA mismatches. For the majority of patients who lack HLA-matched unrelated donors, current research is focused on the identification of permissible HLA mismatches. The influence of nongenetic factors on the tolerability of HLA mismatching has recently become evident, demonstrating a need for the integration of both genetic and nongenetic variables in donor selection. Semin Hematol 42:76-84 © 2005 Elsevier Inc. All rights reserved.
T
he major histocompatibility complex (MHC) is the most comprehensively studied region of the human genome. Human leukocyte antigen (HLA) genes play a major etiologic role in autoimmunity and infectious diseases, and they determine tissue compatibility in transplantation.1 It is their function as the “HLA barrier” in allogeneic transplantation on which this review will focus. Elucidation of the polymorphism of HLA-A, -B, -C, -DR, -DQ, and DP2,3 has led to a better understanding of how HLA structure defines its function (see Norman and Parham in this issue for a fuller description of HLA diversity). The past two decades have seen a technologic revolution in tissue typing methods, from the historical use of serology to define HLA antigens4 to the modern DNA era, when single nucleotide differences between two unique HLA alleles of the same antigen can be detected using polymerase chain reaction (PCR)-based techniques.5 The increased precision of DNA-based typing has had dramatic consequences—in the clinical testing of transplant candidates and potential donors6 and in addressing new hypotheses on HLA structure and function. Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA. Supported by Grants CA18029, CA100019, and AI33484 from the National Institutes of Health (E.W.P.); and by Grants CA18029 and AI33484 from the National Institutes of Health, and from the Amy Strelzer Manasevit Scholars Program, National Marrow Donor Program (M.M.). Address correspondence to Effie W. Petersdorf, MD, Fred Hutchinson Cancer Research Center, Division of Clinical Research, D4-100, 1100 Fairview Ave N, Seattle, WA 98109. E-mail: [email protected]
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0037-1963/05/$-see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1053/j.seminhematol.2005.01.009
Although this review encompasses HLA genetics and transplantation, knowledge of the many nongenetic factors that also influence transplant outcome is increasingly important in the interpretation of independent risks conferred by HLA mismatching.7-9 Cytomegalovirus (CMV) seropositivity of the recipient and donor, stem cell dose, donor age, and immunosuppressive regimen all affect risks of graft-versushost disease (GVHD) and mortality.9 Overall transplant success is also influenced by the burden of malignant cells at the time the transplant is performed.7,8,10-16 Transplantation during active or advanced stages of malignancy has a higher likelihood of post-transplant disease recurrence compared to when disease is well controlled prior to transplantation. Although use of a well-matched donor is associated with improved overall survival, when patients lack matched donors, prolongation of the donor search may cause delays in transplantation and the potential for the disease to advance. This review of genomics of unrelated hematopoietic cell transplantation (HCT) focuses on how safety, efficacy and availability of unrelated HCT may be improved through a more complete understanding of the HLA barrier and of nonHLA factors that also influence transplant outcome.
High-Resolution Donor HLA Matching Improves Patient Survival Complete and precise donor-recipient HLA matching can optimize the results of unrelated HCT.17-48 Three major con-
HLA matching in unrelated donor HCT
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Table 1 Summary of Relative Risk (RR) of Mortality Conferred by Low-Resolution and High-Resolution Mismatches in the NMDP Dataset43 Low-Resolution Mismatch
High-Resolution Mismatch
HLA Locus
RR
CI
P Value
RR
CI
P Value
A B C DRB1
1.4 1.5 1.2 1.6
1.2–1.7 1.2–1.8 1.1–1.4 1.1–2.4
<.0001 .0003 .007 .009
1.3 1.1 1.0 1.2
1.0–1.6 0.9–1.3 0.7–1.3 1.0–1.4
.03 .4 .8 .03
cepts of donor HLA matching have been described in singlecenter and multicenter studies: (1) high-resolution DNA typing methods can uncover functionally relevant transplant determinants, and therefore these methods are required for donor evaluation; (2) the risks of graft rejection, GVHD, and mortality may be greater with serologic (antigen or low-level resolution) mismatches than with allele (high-resolution) mismatches, and therefore allele-mismatched donors should be prioritized over antigen-mismatched donors; and (3) the risks of graft rejection, GVHD, and mortality are increased with increasing numbers of HLA mismatches, and selection of the donor with the fewest mismatches may reduce complications.
Low- and High-Resolution DNA Mismatches Are Functional Before DNA-based typing methods became available for all HLA genes, donor-recipient HLA mismatching was defined using serologic methods. Serology was subsequently supplemented with PCR technology, first for DRB1 and DQB1,19,20,21,24,26,32,37 followed more recently by DNA methods for HLA-A, -B, and –C.16,28, 29,36,43,45 This continuum of technologic advances has had a major impact on shaping understanding of the importance of high-resolution mismatches, of additive effects of multi-locus HLA mismatching, and of the role of HLA-C as a transplantation determinant. Since HLA alleles and antigens differ in the location and nature of amino acid substitutions at residues that define peptide-binding motifs and contact with the T-cell receptor (TCR), hypotheses can be generated as to the relative immunogenecity of low (antigen) versus high (allele) combinations of mismatching. Potential differences between allele-associated and antigen-associated risks of GVHD and mortality have practical implications in the selection of a suitable mismatched donor when allele-matched donors are not available. The largest comprehensive analysis of donor-recipient HLA matching was performed by the National Marrow Donor Program (NMDP)43: 1,874 patients and their donors were typed for HLA-A, -B, -C, -DR, -DQ, and -DP alleles. For the HLA-DQ and -DP loci, the DQA and DPA genes were tested, and the presence of any mismatch in DQA or DQB, and DPA or DPB was considered a mismatch. The NMDP evaluated the impact of two levels of HLA matching: (1) high-resolution matches (also known as “allele”), defined as identical gene products, and (2) low-resolution matches (also known as “antigen”), in which the first two digits of the allele
name were converted to a “serologic equivalent.” Overall mortality risks conferred by mismatching at each locus are summarized in Table 1. Low-resolution mismatches at HLA-A, -B, -C, and -DRB1 each conferred increased risk of mortality. High-resolution mismatches at HLA-A and -DRB1 were also associated with increased death. The risk of grades III to IV acute GVHD was higher in the presence of HLA-A mismatching; a trend for higher acute GVHD risk was observed with HLA-B, -C, and -DR mismatching. Three new findings can be summarized from the NMDP study. First, mismatches for HLA-A, -B, -C, and -DRB1 are similarly associated with increased risk of GVHD and mortality. Donor registries and search algorithms should pay added attention in prospective donor selection to the HLA-C locus. Second, high-resolution mismatching, particularly at HLA-A and -DRB1, was associated with increased mortality. Allele mismatches have functional significance and high-resolution DNA typing methods are needed to evaluate potential unrelated donors. Third, the NMDP study found that low-resolution mismatching was associated with higher mortality compared to high-resolution mismatching. For patients whose only donors are mismatched, selection of donors with highresolution mismatches over those with low-resolution mismatches may lower post-transplant complications. A different question was addressed in a single-center study from Seattle.45 Among patients with two or more mismatches, risks were defined among patients with similar stage of disease at the time of transplantation. Traditional staging definitions were applied7,8,10-16,49: patients were defined as low-risk (chronic myeloid leukemia [CML] transplanted in chronic phase within 2 years of diagnosis) or higher risk (all other stages of CML, acute leukemia, and myelodysplastic syndrome [MDS]). With the matched low-risk patients as the reference group, single allelemismatched patients had a hazards ratio (HR) of 2.44 (95% confidence interval [CI], 1.41 to 4.22) and single antigen-mismatched patients had a HR of 2.15 (1.28 to 3.6). Using the matched higher risk patients as the reference group, the HR of mortality was 1.02 (.70 to 1.48) among single allele-mismatched patients and 1.12 (0.86 to 1.47) among single antigenmismatched patients. These results suggest that allele and antigen mismatches can elicit similar detrimental graft-versus-host responses that lead to increased mortality; with respect to graft failure, the host-versus-graft alloresponses provoked by allele mismatches may be different than those arising from antigen mismatches.36 Analysis of large transplant populations with a diversity of mismatches is needed to further define potential differences between allele and antigen mismatches in host-ver-
78 sus-graft and graft-versus-host complications after transplantation.
HLA-DQ and HLA-DP: To Match or Not to Match The importance of HLA-A, -B, -C, and -DR in transplantation has been well described16,23,27,29,36,38,40,45,46; however, there have been conflicting results as to the clinical significance of HLA-DQ and HLA-DP.16,29,30,35,37,40,41,43,50,51,52 The seemingly contradictory conclusions drawn from retrospective studies may be related to the different study questions and comparison groups used to measure differences in outcome associated with matching for these genes. As one example, the NMDP measured risks associated with HLA-DQ mismatching by comparing the risk of mortality associated with HLA-DQ disparity without class I disparity to HLA-DQ disparity with class I disparity43; no difference was observed. In a single-center study of donor-recipient pairs with at least two locus mismatches,45 the study hypothesis was whether patients with HLA-DQ mismatching in addition to mismatching at other HLA loci had increased mortality compared to patients with multi-locus mismatches not involving HLA-DQ. In comparison of 76 multi-locus mismatched patients with DQ mismatches against 143 multi-locus mismatched patients without HLA-DQ mismatches, the HR of mortality was 1.5 (1.04 to 2.16), indicating a trend for an additive DQ effect when there was additional HLA mismatching at other loci. Taken together, these results suggest that when patients have a choice of equivalently matched donors, selection of an HLA-DQB1 matched donor over a mismatched donor may decrease post-transplant complications. Analysis of HLA-DP in transplant populations has been hampered by the weak linkage disequilibrium (LD) between this locus and HLA-A, -B, and –DR.53 Weak LD results in a low frequency of fortuitous HLA-DP matching among otherwise HLA-matched donor-recipient pairs. Consequently, very large numbers of transplants must be studied to define a true independent effect conferred by HLA-DP mismatching. Early investigations were conflicting as to the significance of HLA-DP as a classical transplantation determinant. Recent studies, using DNA-based methods to define HLA-DP allele mismatching and restricting the study population to donor-recipient pairs who were allele-matched at all other HLA loci, have measured the effect contributed by HLA-DP alone. In a recent analysis of 627 HLA-identical siblings transplants, among which 30 (4.8%) were HLA-DP–mismatched due to recombination,44 the cumulative incidence of grades II to IV GVHD was higher in the DP-mismatched transplants and an independent risk factor for GVHD (relative risk [RR] ⫽ 2.68; 1.73 to 3.62; P ⫽ .02). In a single-center study,40 mismatching for HLA-DPA1 was a risk factor for increased mortality compared to DPA1 matching. In an analysis of HLA-A–, -B–, -C–, -DRB1–, -DRB3–, -DRB4 –, -DRB5–, and -DQB–matched pairs,51 42% of pairs were mismatched for HLA-DPB; two HLA-DPB1 mismatches were associated with increased risk of acute GVHD (RR ⫽ 8.25; 1.67 to 40.10; P ⫽ .01) and lower survival (RR ⫽ 4.97; 1.80 to 13.71; P ⫽ .002). The clinical importance of HLA-DP was also evaluated in 143 HLA-A–, -B– -C–, -DRB1–, and -DQB1–matched donor-
E.W. Petersdorf and M. Malkki recipient pairs41: acute GVHD occurred in 47% of HLA-DP– matched patients compared to 66% in HLA-DP–mismatched patients (P ⫽ .049), and relapse was higher in HLA-DP– matched patients (62%) compared with any HLA-DP mismatch (34%) (P ⫽ .001). These studies defined HLA compatibility as the donor and recipient sharing the identical genotype. An alternative approach to understanding class II–mediated alloreactivity in transplantation uses functional assays to map putative (non)permissible epitopes. Clones that recognized an HLA-DPB1*0901– mismatched allele were employed to define subsets of HLADPB1 alleles with permissive or nonpermissive sequences in one study of 118 transplants who were HLA-DP mismatched.52 Patients with nonpermissive HLA-DPB1 mismatches had an increased risk of acute GVHD and transplant-related mortality. For patients with early-stage or well-controlled disease and several HLA-matched donors, consideration of HLA-DP may further optimize transplant outcome.
Long-Term Effects of HLA Disparity Many studies have elucidated the role of donor HLA matching in early post-transplant complications. With a larger transplant experience and the maturation of longitudinal data, it is now possible to evaluate late effects conferred by donor HLA matching.47,48 For example, among 150 related, 70 unrelated, and 28 autologous transplant recipients, multivariate analysis showed increased risk of endocrinologic, cardiopulmonary, and neurologic consequences compared to 317 genotypically identical sibling transplants.47 A recent study by the Seattle transplant program has explored the impact of donor HLA mismatching on long-term events48: for 362 patients transplanted from unrelated donors, there was an association of donor HLA mismatching with prolonged therapy with imnmunosuppressive agents for chronic GVHD compared to HLA-matched transplant recipients. Nonrelapse mortality was also increased. The estimated hazard of mortality per locus was 0.8 for the time to discontinuation of immunosuppressive therapy. These results indicate a lower rate of discontinuation of immunosuppression with HLA mismatching and more prolonged treatment compared to HLA matching.
The Number of HLA Mismatches Influences Risks of Posttransplant Complications: Importance of Complete Characterization of HLA Alleles Using DNA-Based Methods As the number of class I and II HLA mismatches rises, the risks of graft failure, GVHD, and mortality increases.16,28,29,36,43 Additive or synergistic multi-locus effects are observed with class I mismatches, class II mismatches, and combinations of class I and class II mismatches. In the most recent analysis by the NMDP,43 the presence of high-resolution mismatches at
HLA matching in unrelated donor HCT
Figure 1 Incidence of clinically severe grades III to IV acute GVHD in the NMDP dataset.43 Donor-recipient pairs were HLA-A, -B serologically matched and DRB1 allele-matched. The number of mismatches represents high-resolution disparities detectable using DNA-base methods for class I genes.
HLA-A, -B, and -C among HLA-A,B serologically matched transplants was associated with increased risks of both GVHD and mortality (Figs 1 and 2). When an HLA-matched donor cannot be identified, limiting the number of HLA high-resolution disparities may lower transplant risks.
Optimizing Unrelated HCT: Importance of Disease Stage and Permissibility of HLA Mismatching The safety and efficacy of unrelated donor HCT is optimal when the burden of malignant cells is low.7,8,10,12,16 Unfortunately, many patients have active or advanced malignancy at the time of transplantation; a prolonged donor search increases the time during which disease may advance.54 Therefore, further information is needed on the limits of HLA mismatching. Analysis of these data may permit earlier transplantation when the disease is well controlled, while using mismatched donors when fully matched donors are not available. The Seattle program recently conducted a retrospective evaluation of 947 patients transplanted from unrelated donors following myeloablative conditioning.45 This study assumed that the impact of HLA mismatching is not the same across different stages of disease or levels of disparity, and disease stage was defined as low, intermediate, or high.7,8,10-16,49 In order to define a mismatch, the hazard of mortality associated with an allele mismatch (high-resolution) or antigen mismatch (low-resolution) first was compared to five-locus, 10-allele matches. Among patients with low-risk disease, the HR conferred by an allele mismatch was 2.44 (1.41 to 4.22), and that conferred by an antigen mismatch was 2.15 (1.28 to 3.60); thus allele and antigen mismatches each confer significant risk to mortality, and for this
79 reason a mismatch was defined as either allele or antigen. Among patients with low-risk disease, a single HLA mismatch was associated with significantly lower survival (HR ⫽ 2.27; 1.47 to 3.51). For patients with intermediate or highrisk disease, the impact of a single HLA mismatch was not as evident (HR ⫽ 1.0 [0.71 to 1.39] and HR ⫽ 1.19 [0.84 to 1.68], respectively) (Fig 3). The major reason for failure in the low-risk group was increased transplant-related mortality (HR ⫽ 2.13; 1.34 to 3.39), and for the high-risk transplants, recurrence of disease (HR ⫽ 1.37; 0.81 to 2.29). Single HLA mismatches were detrimental in low-risk patients. To define the risk conferred by individual HLA loci, the hazard of death was evaluated in the 82 single mismatched pairs according to the presence of single HLA-A, -B, -C, -DRB1, or -DQB1 mismatches. At no locus was mismatching favorable; moreover, disparity for HLA-C was associated with significantly increased hazard of death compared to complete matching (HR ⫽ 3.18; 1.74 to 5.82). There was no evidence that the increased death among the low-risk single HLA-C mismatches was due to NK-KIR ligand matching. Among HLA-C–mismatched/KIR ligand-matched patients, the HR of death was 3.06 (1.56 to 6.01) compared to HLA-C–mismatched/KIR ligand-mismatched patients whose HR was 3.55 (1.25 to 10.10). These results suggest that, in the setting of myeloablative conditioning regimens and use of T-replete donor stem cells, the detrimental effects of HLA-C mismatching are most likely caused by T-cell alloreactivity of donor-versus-host. Patients with newly diagnosed CML have the option of initial therapy with tyrosine kinase inhibitors.55 For CML patients who do not have HLA-matched unrelated donors, the Seattle program sought to define the potential gain of extending the donor search for a fully compatible donor against the harm of lengthening the time from diagnosis to transplantation. When fully matched unrelated donors are not available, extension of the search could yield one of four outcomes: (1) a better matched donor is identified and the
Figure 2 Kaplan-Meier probability of survival in the NMDP dataset.43 Donor-recipient pairs are HLA-A, -B serologically matched and DRB1 allele-matched. As in Fig 1, the number of mismatched refers to class I incompatibilities detected by molecular methods.
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E.W. Petersdorf and M. Malkki was similar to the survival of patients transplanted in late CP from an HLA-identical donor. These results suggest that the potential benefit of HLA matching was offset by the negative impact of advanced disease. If a donor search for a patient in late CP is extended in the hope of identifying a matched donor, survival using an HLA-matched donor in late CP is similar to that using an HLA-mismatched donor in late CP. If a matched donor is identified but the disease progresses beyond CP, the survival is lower; if a matched donor cannot be identified and transplantation is conducted using a mismatched donor in late CP, survival is similarly compromised. When a donor search is highly unlikely to yield matched donors for newly diagnosed CML, the increased mortality associated with a longer time interval from diagnosis to transplantation must be weighed carefully against the increased mortality with earlier transplantation with a mismatched donor, and also against the chance of disease progression to advanced-phase CML during a prolonged donor search.
Clinical Outcomes Following Related and Unrelated HCT The majority of patients who initiate an unrelated donor search do not have fully matched donors; of the patients who have mismatched donors, only a minority have donors with a single mismatch. In this circumstance, there is a choice between a mismatched haploidentical relative or continuation of a search for a potential matched or single allele-mismatched unrelated donor. Several investigations have compared the results of matched related, mismatched related, matched unrelated, and mismatched unrelated donor transplantation.42,56-58 In a multicenter analysis of 264 adults who received a myeloablative conditioning regimen for the treatment of acute lymphocytic leukemia,58 disease-free survival (DFS) of 103 patients who received a related and 118 who Figure 3 Kaplan-Meier probability of survival: the Seattle experience.45 Transplant pairs are 10/10 (solid line) or 9/10 (dotted line) allele matched at HLA-A, -B, -C, -DRB1, and -DQB1. Transplant pairs are designated low-risk (A), intermediate-risk (B), or high-risk (C).
disease remains stable; (2) a better matched donor is identified, but the disease advances; (3) a better matched donor is not identified, but the disease remains stable; and (4) a better matched donor is not identified and the disease progresses. To address the impact of matching and disease stage, 243 patients who received their transplant early in CP1 (within 2 years of diagnosis), 63 patients transplanted in late CP1 (more than 2 years from diagnosis), and 46 patients whose CML had progressed beyond CP1 at the time of transplantation were evaluated.45 Among each of these three groups, five-locus, 10-allele matched patients were compared to those with a single HLA-A, -B, -C, -DRB1, or -DQB1 mismatch (Fig 4). In summary, the overall survival of a patient receiving a transplant in early CP from a mismatched donor
Figure 4 The effect of HLA mismatching and phase of CML at the time of transplantation.45 Figure displays patients transplanted by the Seattle program according to whether the donor and patient are matched for 10/10 alleles or mismatched for a single HLA-A, -B, -C, -DRB1, or -DQB1 allele.
HLA matching in unrelated donor HCT received an HLA-A–, -B–, -DRB1–matched unrelated donor transplant was compared. Transplant-related mortality (TRM) at 5 years was 43% for the related and 50% for the unrelated transplants (P ⫽ .11); DFS was similar between related and unrelated donor recipients. In a side-by-side comparison of phenotypically matched unrelated, single antigen-mismatched unrelated, and haploidentical-mismatched related transplants, the three populations did not significantly differ in the rate of engraftment or incidence of acute or chronic GVHD.56 Matched and mismatched unrelated donor transplants had a lower incidence of relapse at 2 years compared to haploidentical related transplants (25%, 26%, and 42%, respectively). Compared to matched unrelated transplants, TRM was higher following mismatched unrelated and haploidentical transplantation compared to matched unrelated transplantation (45%, 42%, and 23%, respectively). Overall survival for matched unrelated donor transplants was 58% compared to 34% for mismatched unrelated and 21% for haploidentical transplantation. Thus the use of a phenotypically matched unrelated donor is associated with superior overall survival compared to use of mismatched unrelated or haploidentical related donors. Among 94 children who received either a matched sibling, haploidentical-mismatched related, or an unrelated donor transplant,42 overall survival was 80%, 62%, and 47%, respectively (P ⫽ .04). Subset analysis of the haploidentical transplants revealed improved survival with fewer HLA mismatched loci: 83%, 64% and 25% among 9/10, 7-8/10 and 5-6/10 matched patients, respectively (P ⫽ .0007). Survival rates after matched sibling, matched or single mismatched unrelated, and 9/10 matched haploidentical related transplantation in children were similar. In the absence of a matched sibling donor, these results show that transplantation using unrelated donors with zero or one mismatch, and haploidentical related donors with two or fewer mismatches provide excellent clinical results. Related and unrelated donor transplants have been made for the recent Japanese transplant experience.57 For 2,947 patients, overall survival after an allogeneic transplant from a one locus-mismatched related donor was associated with significantly lower overall survival compared to the use of a matched unrelated donor for standard-risk diseases. Among patients with higher risk diseases, comparable survival after HLA-matched and single locus-mismatched recipients was achieved. HLA class I and class II mismatches did not confer statistically significant differences in either risk of grades III to IV acute GVHD or mortality. Single locus-mismatched related donor transplants and matched unrelated donor transplants yielded comparable survival for patients with standard-risk disease. Higher age and disease risk category (high) were identified as independent risk factors for lower survival in multivariate analysis. A model that adjusted for the donor type (single locus-mismatched related; matched unrelated) did not qualitatively change the results (RR ⫽ .97; .71-1.20; P ⫽ .84). This analysis demonstrates that use of a single-locus related donor should give similar overall transplant outcome compared to a matched unrelated donor for patients with higher risk disease who do not have a matched
81 sibling. For higher risk patients who lack matched related donors, transplantation from a single locus-mismatched related donor is preferable to an unrelated donor transplant.
Towards a Definition of Tolerable Mismatches In the studies described above, mismatching was defined as the presence of donor-recipient differences in the polymorphic exon sequences of class I and II genes. Analysis of mismatching for the specific residues of the HLA molecule that are known to influence the peptide binding repertoire or that contact the TCR represents another approach to identifying permissible mismatches33– but requires very large numbers of HLA allele-typed donor-recipient pairs due to the extreme diversity of HLA alleles and the sharing of common epitopes. Functional assays have been used in the analysis of permissible epitopes, as in the example of the HLA-DP molecule assessed using alloreactive cytotoxic T lymphocytes.52 Clinical studies indicate the importance of understanding HLA function through its structure. Today, single nucleotide differences between a donor and recipient HLA allele can be readily defined and related to the putative protein sequence. The number, type, and location of amino acid substitutions have been identified as important elements in determining transplant outcome.33,36 Analysis of epitopes involved in peptide binding or TCR contact can also be assisted by new software tools that compare donor and recipient HLA alleles for all polymorphic positions.59 The International Histocompatibility Working Group (IHWG) in HCT was formed to define the significance of HLA genes in racially and ethnically diverse transplant patients and donors (www.ihwg.org). The IHWG-HCT is comprised of transplant centers, transplant registries, donor registries, and immunogenetics laboratories from North America, Europe, Asia, and Australia. HLA and clinical data for a total of 2,399 unrelated transplants have been collected and contributed to the IHWG effort.60 This project established high resolution analysis of HLA-A, -B, -C, -DRB1, -DQB1, and -DPB1 genes as the standard for HLA typing. Overall survival was the primary clinical end point. The distribution of HLA matching among the IHWG dataset was 45%, 29%, and 25% for 10/10, 9/10, and 8/10 or lower, respectively. As anticipated, the frequency of specific allele mismatches varied between Asian and Caucasian patients and donors. Multivariate regression models adjusting for disease and donor registry (Japan Marrow Donor Program [JMDP] v other registries) yielded increased hazard of death associated with the number of mismatched alleles compared to 10/10 allele matches: HR ⫽ 1.38 (1.21 to 1.58; P ⬍ .0001), HR ⫽ 1.50 (1.28 to 1.76; P ⬍.0001), and HR ⫽ 1.94 (1.63 to 2.31; P ⬍ .0001) for one, two, and three or more mismatches, respectively. Definition of locus-specific effects on mortality was performed for transplant pairs with a single HLA mismatch. Among Caucasian recipients, the presence of a single HLA-C mismatch conferred a HR of 1.52 (1.26 to 1.84; P ⬍.0001) to mortality compared to matching, whereas an HLA-A mismatch was not
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families, and between A1/A11 antigen specificities; these mismatches were not present in Japanese donor-recipient pairs. At the HLA-C locus, there was broader overlap in the specific combinations of allele mismatches in the Japanese and Caucasian populations than was observed at HLA-A. The IHWG analysis demonstrates that full understanding of the rules that govern permissibility of HLA mismatches should include side-by-side evaluation of ethnically and racially diverse transplant populations. Analysis of very large numbers of pairs which have been characterized at high resolution and for whom complete clinical data are available is of crucial importance in addressing locus-specific and allelespecific rules for mismatching.
Translating HLA Research Findings to Clinical Practice A donor’s HLA match status should be used to help the physician and patient in risk assessment and then planning treatment options to reduce those risks. To facilitate donor searches in the era of DNA typing, the NMDP has developed guidelines for comparing HLA typing performed at low, intermediate, and high resolution.61,62 The use of search determinants as a name for HLA alleles and antigens can aid the physician and search coordinator in identifying potential donors who should be prioritized for evaluation and further HLA testing. Recommendations from the World Marrow Donor Association (WMDA)63 provide transplant physicians and search coordinators with procedures for optimizing donor selection and the tools needed to translate HLA typing data to donor identification. Figure 5 Single HLA-A (A) and HLA-C (B) mismatched alleles observed at greater than 4% frequency in JMDP and non-JMDP unrelated donor transplants. The total number of single HLA-A mismatches were 86 and 99 in JMDP and non-JMDP datasets, respectively. The total number of single HLA-C mismatches were 82 and 257 in JMDP and non-JMDP populations, respectively.
associated with a significant increase in risk (HR ⫽ 1.08; .80 to 1.46; P ⫽ .61). In contrast, Japanese recipients had an increased risk of mortality associated with an HLA-A mismatch (HR ⫽ 1.53; 1.1 to 2.1; P ⫽ .01) and not with HLA-C mismatching (HR ⫽ 1.03; .73 to 1.46; P ⫽ .85). Single HLA-A and single HLA-C mismatches that were observed at greater than 4% frequency displayed major differences in the kind of mismatches between the Japanese and Caucasian datasets (Fig 5). At the HLA-A locus, the most frequently mismatched antigen group was HLA-A2; however, the Japanese and Caucasian patients differed with respect to the specific HLA-A alleles: HLA-A*0201/0206 in the Japanese population, and HLA-A*0201/0205 in the Caucasians were the most common mismatches. Mismatching between HLA-A26 alleles was represented in both Japanese and Caucasian pairs but at different frequencies. Caucasian pairs were mismatched for alleles within the HLA-A3, A29, and A30 antigen
Conclusions We have reviewed the HLA factors that constitute optimal donor selection for transplantation, with a focus on myeloablative conditioning regimens and use of donor peripheral blood stem cells or bone marrow. As detailed in the articles by Gluckman, Hsu, van Rood, and Kodera in this issue, clinicians and patients have several different potential sources of stem cells from which to chose–related or unrelated donor, cord blood or blood or marrow, matched or mismatched–as well as an armamentarium of transplant conditioning and immunosuppressive regimens. Factors of importance in allogeneic transplantation must include consideration of HLA, as well as the transplant procedures and regimens. Individualization of donor selection to best meet the need of the patient is becoming increasingly important with the identification of non-HLA factors that also affect transplant outcome.
Acknowledgment We wish to thank our colleagues participating in the International Histocompatibility Working Group in Hematopoietic Cell Transplantation for their outstanding contributions (www.ihwg.org).
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References 1. Price P, Witt C, Allcock R, Sayer D, Garlepp M, Kok CC, et al: The genetic basis for the association of the 8.1 ancestral haplotype (A1, B8, DR3) with multiple immunological diseases. Immunol Rev 167:257274, 1999 2. Marsh SGE, Albert ED, Bodmer WF, Bontrop RE, Dupont B, Erlich HA, et al: Nomenclature for factors of the HLA system, 2002. Eur J Immunol 29:463-517, 2002 3. The MHC Sequencing Consortium: Complete sequence and gene map of a human major histocompatibility complex. Nature 401:921-923, 1999 4. National Institutes of Health: NIH lymphocyte microcytotoxicity technique, in NIAID Manual of Tissue Typing Techniques (Publication No. NIH 80-545). Atlanta, GA, Department of Health, Education, and Welfare, 1979 5. Schreuder GM, Hurley CK, Marsh SG, M Lau, M Maiers, Kollman C, et al: The HLA dictionary 1999: A summary of HLA-A, -B, -C, -DRB1/3/ 4/5, -DQB1 alleles and their association with serologically-defined HLA-A, -B, -C, -DR, and -DQ antigens. Hum Immunol 60:1157-1181, 1999 6. Hurley CK, Setterholm M, Lau M, Pollack MS, Norreen H, Howard A, et al: Hematopoietic stem cell donor registry strategies for assigning search determinants and matching relationships. Bone Marrow Transplant 33:443-450, 2004 7. Goldman JM: Chronic myeloid leukemia. Curr Opin Hematol 4:277285, 1997 8. Cornelissen JJ, Carston M, Kollman C, King R, Dekker AW, Lowenberg B, et al: Unrelated marrow transplantation for adult patients with poorrisk acute lymphoblastic leukemia: Strong graft-versus-leukemia effect and risk factors determining outcome. Blood 97:1572-1577, 2001 9. Ringdén O, Schaffer M, Le Blanc K, Hauzenberger D, Abedi MR, Olerup O, et al: Which donor should be chosen for hematopoietic stem cell transplantation among unrelated HLA-A, -B, and –DRB1 genomically identical volunteers? Biol Blood Marrow Transplant 10:128-134, 2004 10. Deeg HJ, Storer B, Slattery JT, Anasetti C, Doney KC, Hansen JA, et al: Conditioning with targeted busulfan and cyclophosphamide for hemopoietic stem cell transplantation from related and unrelated donors in patients with myelodysplastic syndrome. Blood 100:1201-1207, 2002 11. Hansen JA, Gooley T, Martin PJ, Appelbaum F, Chauncey TR, Clift RA, et al: Bone marrow transplants from unrelated donors for patients with chronic myeloid leukemia. N Engl J Med 338:962-968, 1998 12. Sierra J, Radich J, Hansen JA, Martin PJ, Petersdorf EW, Bjerke J, et al: Marrow transplants from unrelated donors for treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood 90: 1410-1414, 1997 13. Marks DI, Cullis JO, Ward KN, Lacey S, Szydlo R, Hughes TP, et al: Allogeneic bone marrow transplantation for chronic myelogenous leukemia using sibling and volunteer unrelated donors: A comparison of complications in the first 2 years. Ann Intern Med 119:207-212, 1993 14. Kodera Y, Morishima Y, Kato S, Sao H, Matsuyama T, Kawa K, et al: Analysis of 500 bone marrow transplants from unrelated donors (URBMT) facilitated by the Japan Marrow Donor Program: Confirmation of UR-BMT as a standard therapy for patients with leukemia and aplastic anemia. Bone Marrow Transplant 24:995-1003, 1999 15. McGlave PB, Shu XO, Wen W, Anasetti C, Nademanee A, Champlin R, et al: Unrelated donor marrow transplantation for chronic myelogenous leukemia: 9 years’ experience of the National Marrow Donor Program. Blood 95:2219-2225, 2000 16. Morishima Y, Sasazuki T, Inoko H, Juji T, Akaza T, Yamamoto K, et al: The clinical significance of human leukocyte antigen (HLA) allele compatibility in patients receiving a marrow transplant from serologically HLA-A, HLA-B and HLA-Dr matched unrelated donors. Blood 99: 4200-4206, 2002 17. Anasetti C, Amos D, Beatty PG, Appelbaum FR, Bensinger W, Buckner CD, et al: Effect of HLA compatibility on engraftment of bone marrow transplants in patients with leukemia or lymphoma. N Engl J Med 320:197-204, 1989 18. Fleischhauer K, Kernan NA, O’Reilly RJ, Dupont B, Yang SY: Bone
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marrow-allograft rejection by T lymphocytes recognizing a single amino acid difference in HLA-B44. N Engl J Med 323:1818-1822, 1990 Davies SM, Shu XO, Blazar BR, Flipovich AH, Kersey JH, Kirvit W, et al: Unrelated donor bone marrow transplantation: influence of HLA-A and -B incompatibility on outcome. Blood 86:1636-1642, 1995 Nademanee A, Schmidt GM, Parker P, Dagis AC, Stein A, Snyder DS, et al: The outcome of matched unrelated donor bone marrow transplantation in patients with hematological malignancies using molecular typing for donor selection and graft-versus-host disease prophylaxis regimen of cyclosporine, methotrexate, and prednisone. Blood 86: 1228-1234, 1995 Petersdorf EW, Longton GM, Anasetti C, Martin PJ, Mickelson EM, Smith AG, et al: The significance of HLA-DRB1 matching on clinical outcome after HLA-A, B, DR identical unrelated donor marrow transplantation. Blood 86:1606-1613, 1995 Spencer A, Szydlo RM, Brookes PA, Kaminski E, Rule S, van Rhee F, Ward KN, et al: Bone marrow transplantation for chronic myeloid leukemia with volunteer unrelated donors using ex vivo or in vivo T-cell depletion: Major prognostic impact of HLA class I identity between donor and recipient. Blood 86:3590-3597, 1995 Nagler A, Brautbar C, Slavin S, Bishara A: Bone marrow transplantation using unrelated and family related donors: The impact of HLA-C disparity. Bone Marrow Transplant 18:891-897, 1996 Petersdorf EW, Longton GM, Anasetti C, Mickelson EM, Smith AG, Martin PJ, et al: Definition of HLA-DQ as a transplantation antigen. Proc Natl Acad Sci U S A 93:15358-5363, 1996 Speiser DE, Tiercy JM, Rufer N, Grundschober G, Gratwohl A, Chapuis C, et al: High resolution HLA matching associated with decreased mortality after unrelated bone marrow transplantation. Blood 87:44554462, 1996 Gajewski J, Gjertson D, Cecka M, Tonai R, Przepiorka D, Hunt L, et al: The impact of T-cell depletion on the effects of HLA-DRB1 and DQB allele matching in HLA serologically identical unrelated donor bone marrow transplantation. Biol Blood Marrow Transplant 3:76-82, 1997 Petersdorf EW, Longton GM, Anasetti C, Mickelson EM, McKinney SK, Smith AG, et al: Association of HLA-C disparity with graft failure after marrow transplantation from unrelated donors. Blood 89:1818-1823, 1997 Petersdorf EW, Gooley TA, Anasetti C, Martin PJ, Smith AG, Mickelson E, et al: Optimizing outcome after unrelated marrow transplantation by comprehensive matching of HLA class I and II alleles in the donor and recipient. Blood 92:3515-3520, 1998 Sasazuki T, Juji T, Morishima Y, Kinukawa N, Kashiwabara H, Inoko H, et al: Effect of matching of class I HLA alleles on clinical outcome after transplantation of hematopoietic stem cells from an unrelated donor. N Engl J Med 339:1177-1185, 1998 Varney MD, Lester S, McCluskey J, Gao X, Tait BD. Matching for HLA DPA1 and DPB1 alleles in unrelated bone marrow transplantation. Hum Immunol 60:532-538, 1999 Davies SM, Kollman C, Anasetti C, Antin JH, Gajawski J, Casper JT, et al: Engraftment and survival after unrelated-donor bone marrow transplantation: A report from the National Marrow Donor Program. Blood 96:4096-4102, 2000 Prezpiorka D, Saliba R, Cleary K, Fischer H, Tonai R, Fritsche H, et al: Tacrolimus does not abrogate the increased risk of acute graft-versushost disease after unrelated-donor marrow transplantation with allelic mismatching at HLA-DRB1 and HLA-DQB1. Biol Blood Marrow Transplant 6:190-197, 2000 Ferrara GB, Bacigalupo A, Lamparelli T, Lanino E, Delfino L, Morabito A, et al: Bone marrow transplantation from unrelated donors: the impact of mismatches with substitutions at position 116 of the human leukocyte antigen class I heavy chain. Blood 98:3150-3155, 2001 Keever-Taylor CA, Bredeson C, Loberiza FR, Casper JT, Lawton C, Rizzo D, et al: Analysis of risk factors for the development of GVHD after T cell-depleted allogeneic BMT: Effect of HLA disparity, ABO incompatibility, and method of T-cell depletion. Biol Blood Marrow Transplant 7:620-630, 2001 Petersdorf EW, Gooley T, Malkki M, Anasetti C, Martin P, Woolfrey A,
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et al: The biological significance of HLA-DP gene variation in haematopoietic cell transplantation. Br J Haematol 112:988-994, 2001 Petersdorf EW, Hansen JA, Martin PJ, Woolfrey A, Malkki M, Gooley T, et al: Major histocompatibility complex class I alleles and antigens in hematopoietic cell transplantation. N Engl J Med 345:1794-1800, 2001 Petersdorf EW, Kollman C, Hurley CK, Dupont B, Nademanee A, Begovich AB, et al: Effect of HLA class II gene disparity on clinical outcome in unrelated donor hematopoietic cell transplantation for chronic myeloid leukemia: The US National Marrow Donor Program Experience. Blood 98:2922-2929, 2001 Van der Meer A, Allebes WA, Paarkekoopr J, Ruiter J, Joosten I: HLA-C mismatches induce strong cytotoxic T-cell reactivity in the presence of an additional DRB/DQB mismatch and affect NK cell-mediated alloreactivity. Transplant 72:923-929, 2001 Barker JN, Davies SM, DeFor TE, Burns LJ, McGlave PB, Miller JS, et al: Determinants of survival after human leucocyte antigen-matched unrelated donor bone marrow transplantation in adults. Brit J Haematol 118:101-107, 2002 Schaffer M, Aldener-Cannavá A, Remberger M, Ringdén O, Olerup O: Roles of HLA-B, HLA-C and HLA-DPA1 incompatibilities in the outcome of unrelated stem-cell transplantation. Tissue Antigens 2:243250, 2003 Shaw BE, Potter MN, Mayor NP, Pay AL, Smith C, Goldman JM, et al: The degree of matching at HLA-DPB1 predicts for acute graft-versushost disease and disease relapse following haematopoietic stem cell transplantation. Bone Marrow Transplant 31:1001-1008, 2003 Caillat-Zucman S, Le Deist F, Haddad E, Gannagé M, Dal Cortivo L, Jabado N, et al: Impact of HLA matching on outcome of hematopoietic stem cell transplantation in children with inherited diseases: A singlecenter comparative analysis of genoidentical, haploidentical or unrelated donors. Bone Marrow Transplant 33:1089-1095, 2004 Flomenberg N, Baxter-Lowe LE, Confer D, Fernandez-Vina M, Filipovich A, Horowitz M, et al: Impact of HLA class I and class II highresolution matching on outcomes of unrelated donor bone marrow transplantation: HLA-C mismatching is associated with a strong adverse effect on transplantation outcome. Blood 104:1923-1930, 2004 Gallardo D, Brunet S, Torres A, Alonso-Nieto M, Vallejo C, Jiménez A, et al: HLA-DPB1 mismatch in HLA-A-B-DRB1 identical sibling donor stem cell transplantation and acute graft-versus-host disease. Transplant 77:1107-1110, 2004 Petersdorf EW, Anasetti C, Martin PJ, Gooley T, Radich J, Malkki M, et al: Limits of HLA mismatching in unrelated hematopoietic cell transplantation. Blood 104:2976-2980, 2004 Tiercy J-M, Passweg J, van Biezen A, Zander A, Kröger N, Gratwohl A, et al: Isolated HLA-C mismatches in unrelated donor transplantation for CML. Bone Marrow Transplant 34:249-255, 2004 Baker SK, Gurney JG, Ness KK, Bhatia R, Forman SJ, Francisco L, et al: Late effects in survivors of chronic myeloid leukemia treated with hematopoietic cell transplantation: Results from the Bone Marrow Transplant Survivor Study. Blood 104:1898-1906, 2004 Stewart BL, Storer B, Storek J, Deeg HJ, Storb R, Hansen JA, et al: Duration of immunosuppressive treatment for chronic graft-versushost disease. Blood 104:3501-3506, 2004 Sierra J, Storer B, Hansen JA, Martin PJ, Petersdorf EW, Woolfrey A, et al: Unrelated donor marrow transplantation for acute myeloid leukemia: An update of the Seattle experience. Bone Marrow Transplant 26:397-404, 2000 Kato Y, Mitsuishi Y, Cecka M, Hopfield J, Hunt L, Champlin R, et al:
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HLA-DP incompatibilities and severe graft-versus-host disease in unrelated bone marrow transplants. Transplant 52:374-376, 1991 Loiseau P, Espérou H, Busson M, Sghiri R, Tamouza R, Hilarius M, et al: DPB1 disparities contribute to severe GVHD and reduced patient survival after unrelated donor bone marrow transplantation. Bone Marrow Transplant 30:497-502, 2002 Zino E, Frumento G, Marktel S, Sormani MP, Ficara F, Di Terlizzi S, et al: A T-cell epitope encoded by a subset of HLA-DPB1 alleles determines nonpermissive mismmatches for hematologic stem cell transplantation. Blood 103:1417-1424, 2004 Begovich AB, McClure GR, Suraj VC, RC Helmuth, N Fildes, TL Bugawan, HA, et al: Polymorphism, recombination, and linkage disequilibrium within the HLA class II region. J Immunol 148:249-258, 1992 Dini G, Grazia Valsecchi M, Micalizzi C, Busca A, Balduzzi A, Arcese W, et al: Impact of marrow unrelated donor search duration on outcome of children with acute lymphoblastic leukemia in second remission. Bone Marrow Transplant 32:325-331, 2003 Hughes TP, Kaeda J, Branford S, et al: Frequency of major molecular responses to imatinib of interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia. N Engl J Med 349:1421-1430, 2003 Drobyski WR, Klein J, Flomenberg N, Pietryga D, Vesole DH, Margolis DA, et al: Superior survival associated with transplantation of matched unrelated versus one-antigen-mismatched unrelated or highly leukocyte antigen-disparate haploidentical family donor marrow grafts for the treatment of hematologic malignancies: Establishing a treatment algorithm for recipients of alternative donor grafts. Blood 99:806-814, 2002 Kanda Y, Chiba S, Hirai H, Sakamaki H, Iseki T, Kodera Y, et al: Allogeneic hematopoietic stem cell transplantation from family members other than HLA-identical siblings over the last decade (19912000). Blood 102:1541-1547, 2003 Kiehl MG, Kraut L, Schwerdtfeger R, Hertenstein B, Remberger M, Kroeger N, et al: Outcome of allogeneic hematopoietic stem-cell transplantation in adult patients with acute lymphoblastic leukemia: No difference in related compared with unrelated transplant in first complete remission. J Clin Oncol 22:2816-2825, 2004 Elsner HA, DeLuca D, Strub J, Blasczyk: HistoCheck: Rating of HLA class I and II mismatches by an internet-based software tool. Bone Marrow Transplant 33:165-169, 2004 Petersdorf EW, Gooley T, Malkki M, Horowitz M for the IHWG in HCT: Impact of donor-recipient HLA matching on survival after myeloablative heamtopoietic cell transplantation from unrelated donors, in Hansen J, Dupont B (eds): HLA 2004: Immunobiology of the Human MHC, Proceedings of the 13th International Histocompatibility Workshop and Congress. Seattle, WA, IHWG Press, 2004 Hurley CK, Baxter Lowe LA, Logan B, Karanes C, Anasetti C, Wiesdorf D, et al: National Marrow Donor Program HLA-matching guidelines for unrelated marrow transplants. Biol Blood Marrow Transplant 9:610615, 2003 Hurley CK, Raffoux C, on behalf of the World Marrow Donor Association: World Marrow Donor Association: International standards for unrelated hematopoietic stem cell donor registries. Bone Marrow Transplant 34:103-110, 2004 Wiegand T, Raffoux C, Hurley CK, Kern M, Oudshoorn M, Raymond J, et al: A special report: suggested procedures for international unrelated donor search from the donor registries and quality assurance working groups of the World Marrow Donor Association (WMDA). Bone Marrow Transplant 34:97-101, 2004
T
he major histocompatibility complex (MHC) is the most comprehensively studied region of the human genome. Human leukocyte antigen (HLA) genes play a major etiologic role in autoimmunity and infectious diseases, and they determine tissue compatibility in transplantation.1 It is their function as the “HLA barrier” in allogeneic transplantation on which this review will focus. Elucidation of the polymorphism of HLA-A, -B, -C, -DR, -DQ, and DP2,3 has led to a better understanding of how HLA structure defines its function (see Norman and Parham in this issue for a fuller description of HLA diversity). The past two decades have seen a technologic revolution in tissue typing methods, from the historical use of serology to define HLA antigens4 to the modern DNA era, when single nucleotide differences between two unique HLA alleles of the same antigen can be detected using polymerase chain reaction (PCR)-based techniques.5 The increased precision of DNA-based typing has had dramatic consequences—in the clinical testing of transplant candidates and potential donors6 and in addressing new hypotheses on HLA structure and function. Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA. Supported by Grants CA18029, CA100019, and AI33484 from the National Institutes of Health (E.W.P.); and by Grants CA18029 and AI33484 from the National Institutes of Health, and from the Amy Strelzer Manasevit Scholars Program, National Marrow Donor Program (M.M.). Address correspondence to Effie W. Petersdorf, MD, Fred Hutchinson Cancer Research Center, Division of Clinical Research, D4-100, 1100 Fairview Ave N, Seattle, WA 98109. E-mail: [email protected]
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0037-1963/05/$-see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1053/j.seminhematol.2005.01.009
Although this review encompasses HLA genetics and transplantation, knowledge of the many nongenetic factors that also influence transplant outcome is increasingly important in the interpretation of independent risks conferred by HLA mismatching.7-9 Cytomegalovirus (CMV) seropositivity of the recipient and donor, stem cell dose, donor age, and immunosuppressive regimen all affect risks of graft-versushost disease (GVHD) and mortality.9 Overall transplant success is also influenced by the burden of malignant cells at the time the transplant is performed.7,8,10-16 Transplantation during active or advanced stages of malignancy has a higher likelihood of post-transplant disease recurrence compared to when disease is well controlled prior to transplantation. Although use of a well-matched donor is associated with improved overall survival, when patients lack matched donors, prolongation of the donor search may cause delays in transplantation and the potential for the disease to advance. This review of genomics of unrelated hematopoietic cell transplantation (HCT) focuses on how safety, efficacy and availability of unrelated HCT may be improved through a more complete understanding of the HLA barrier and of nonHLA factors that also influence transplant outcome.
High-Resolution Donor HLA Matching Improves Patient Survival Complete and precise donor-recipient HLA matching can optimize the results of unrelated HCT.17-48 Three major con-
HLA matching in unrelated donor HCT
77
Table 1 Summary of Relative Risk (RR) of Mortality Conferred by Low-Resolution and High-Resolution Mismatches in the NMDP Dataset43 Low-Resolution Mismatch
High-Resolution Mismatch
HLA Locus
RR
CI
P Value
RR
CI
P Value
A B C DRB1
1.4 1.5 1.2 1.6
1.2–1.7 1.2–1.8 1.1–1.4 1.1–2.4
<.0001 .0003 .007 .009
1.3 1.1 1.0 1.2
1.0–1.6 0.9–1.3 0.7–1.3 1.0–1.4
.03 .4 .8 .03
cepts of donor HLA matching have been described in singlecenter and multicenter studies: (1) high-resolution DNA typing methods can uncover functionally relevant transplant determinants, and therefore these methods are required for donor evaluation; (2) the risks of graft rejection, GVHD, and mortality may be greater with serologic (antigen or low-level resolution) mismatches than with allele (high-resolution) mismatches, and therefore allele-mismatched donors should be prioritized over antigen-mismatched donors; and (3) the risks of graft rejection, GVHD, and mortality are increased with increasing numbers of HLA mismatches, and selection of the donor with the fewest mismatches may reduce complications.
Low- and High-Resolution DNA Mismatches Are Functional Before DNA-based typing methods became available for all HLA genes, donor-recipient HLA mismatching was defined using serologic methods. Serology was subsequently supplemented with PCR technology, first for DRB1 and DQB1,19,20,21,24,26,32,37 followed more recently by DNA methods for HLA-A, -B, and –C.16,28, 29,36,43,45 This continuum of technologic advances has had a major impact on shaping understanding of the importance of high-resolution mismatches, of additive effects of multi-locus HLA mismatching, and of the role of HLA-C as a transplantation determinant. Since HLA alleles and antigens differ in the location and nature of amino acid substitutions at residues that define peptide-binding motifs and contact with the T-cell receptor (TCR), hypotheses can be generated as to the relative immunogenecity of low (antigen) versus high (allele) combinations of mismatching. Potential differences between allele-associated and antigen-associated risks of GVHD and mortality have practical implications in the selection of a suitable mismatched donor when allele-matched donors are not available. The largest comprehensive analysis of donor-recipient HLA matching was performed by the National Marrow Donor Program (NMDP)43: 1,874 patients and their donors were typed for HLA-A, -B, -C, -DR, -DQ, and -DP alleles. For the HLA-DQ and -DP loci, the DQA and DPA genes were tested, and the presence of any mismatch in DQA or DQB, and DPA or DPB was considered a mismatch. The NMDP evaluated the impact of two levels of HLA matching: (1) high-resolution matches (also known as “allele”), defined as identical gene products, and (2) low-resolution matches (also known as “antigen”), in which the first two digits of the allele
name were converted to a “serologic equivalent.” Overall mortality risks conferred by mismatching at each locus are summarized in Table 1. Low-resolution mismatches at HLA-A, -B, -C, and -DRB1 each conferred increased risk of mortality. High-resolution mismatches at HLA-A and -DRB1 were also associated with increased death. The risk of grades III to IV acute GVHD was higher in the presence of HLA-A mismatching; a trend for higher acute GVHD risk was observed with HLA-B, -C, and -DR mismatching. Three new findings can be summarized from the NMDP study. First, mismatches for HLA-A, -B, -C, and -DRB1 are similarly associated with increased risk of GVHD and mortality. Donor registries and search algorithms should pay added attention in prospective donor selection to the HLA-C locus. Second, high-resolution mismatching, particularly at HLA-A and -DRB1, was associated with increased mortality. Allele mismatches have functional significance and high-resolution DNA typing methods are needed to evaluate potential unrelated donors. Third, the NMDP study found that low-resolution mismatching was associated with higher mortality compared to high-resolution mismatching. For patients whose only donors are mismatched, selection of donors with highresolution mismatches over those with low-resolution mismatches may lower post-transplant complications. A different question was addressed in a single-center study from Seattle.45 Among patients with two or more mismatches, risks were defined among patients with similar stage of disease at the time of transplantation. Traditional staging definitions were applied7,8,10-16,49: patients were defined as low-risk (chronic myeloid leukemia [CML] transplanted in chronic phase within 2 years of diagnosis) or higher risk (all other stages of CML, acute leukemia, and myelodysplastic syndrome [MDS]). With the matched low-risk patients as the reference group, single allelemismatched patients had a hazards ratio (HR) of 2.44 (95% confidence interval [CI], 1.41 to 4.22) and single antigen-mismatched patients had a HR of 2.15 (1.28 to 3.6). Using the matched higher risk patients as the reference group, the HR of mortality was 1.02 (.70 to 1.48) among single allele-mismatched patients and 1.12 (0.86 to 1.47) among single antigenmismatched patients. These results suggest that allele and antigen mismatches can elicit similar detrimental graft-versus-host responses that lead to increased mortality; with respect to graft failure, the host-versus-graft alloresponses provoked by allele mismatches may be different than those arising from antigen mismatches.36 Analysis of large transplant populations with a diversity of mismatches is needed to further define potential differences between allele and antigen mismatches in host-ver-
78 sus-graft and graft-versus-host complications after transplantation.
HLA-DQ and HLA-DP: To Match or Not to Match The importance of HLA-A, -B, -C, and -DR in transplantation has been well described16,23,27,29,36,38,40,45,46; however, there have been conflicting results as to the clinical significance of HLA-DQ and HLA-DP.16,29,30,35,37,40,41,43,50,51,52 The seemingly contradictory conclusions drawn from retrospective studies may be related to the different study questions and comparison groups used to measure differences in outcome associated with matching for these genes. As one example, the NMDP measured risks associated with HLA-DQ mismatching by comparing the risk of mortality associated with HLA-DQ disparity without class I disparity to HLA-DQ disparity with class I disparity43; no difference was observed. In a single-center study of donor-recipient pairs with at least two locus mismatches,45 the study hypothesis was whether patients with HLA-DQ mismatching in addition to mismatching at other HLA loci had increased mortality compared to patients with multi-locus mismatches not involving HLA-DQ. In comparison of 76 multi-locus mismatched patients with DQ mismatches against 143 multi-locus mismatched patients without HLA-DQ mismatches, the HR of mortality was 1.5 (1.04 to 2.16), indicating a trend for an additive DQ effect when there was additional HLA mismatching at other loci. Taken together, these results suggest that when patients have a choice of equivalently matched donors, selection of an HLA-DQB1 matched donor over a mismatched donor may decrease post-transplant complications. Analysis of HLA-DP in transplant populations has been hampered by the weak linkage disequilibrium (LD) between this locus and HLA-A, -B, and –DR.53 Weak LD results in a low frequency of fortuitous HLA-DP matching among otherwise HLA-matched donor-recipient pairs. Consequently, very large numbers of transplants must be studied to define a true independent effect conferred by HLA-DP mismatching. Early investigations were conflicting as to the significance of HLA-DP as a classical transplantation determinant. Recent studies, using DNA-based methods to define HLA-DP allele mismatching and restricting the study population to donor-recipient pairs who were allele-matched at all other HLA loci, have measured the effect contributed by HLA-DP alone. In a recent analysis of 627 HLA-identical siblings transplants, among which 30 (4.8%) were HLA-DP–mismatched due to recombination,44 the cumulative incidence of grades II to IV GVHD was higher in the DP-mismatched transplants and an independent risk factor for GVHD (relative risk [RR] ⫽ 2.68; 1.73 to 3.62; P ⫽ .02). In a single-center study,40 mismatching for HLA-DPA1 was a risk factor for increased mortality compared to DPA1 matching. In an analysis of HLA-A–, -B–, -C–, -DRB1–, -DRB3–, -DRB4 –, -DRB5–, and -DQB–matched pairs,51 42% of pairs were mismatched for HLA-DPB; two HLA-DPB1 mismatches were associated with increased risk of acute GVHD (RR ⫽ 8.25; 1.67 to 40.10; P ⫽ .01) and lower survival (RR ⫽ 4.97; 1.80 to 13.71; P ⫽ .002). The clinical importance of HLA-DP was also evaluated in 143 HLA-A–, -B– -C–, -DRB1–, and -DQB1–matched donor-
E.W. Petersdorf and M. Malkki recipient pairs41: acute GVHD occurred in 47% of HLA-DP– matched patients compared to 66% in HLA-DP–mismatched patients (P ⫽ .049), and relapse was higher in HLA-DP– matched patients (62%) compared with any HLA-DP mismatch (34%) (P ⫽ .001). These studies defined HLA compatibility as the donor and recipient sharing the identical genotype. An alternative approach to understanding class II–mediated alloreactivity in transplantation uses functional assays to map putative (non)permissible epitopes. Clones that recognized an HLA-DPB1*0901– mismatched allele were employed to define subsets of HLADPB1 alleles with permissive or nonpermissive sequences in one study of 118 transplants who were HLA-DP mismatched.52 Patients with nonpermissive HLA-DPB1 mismatches had an increased risk of acute GVHD and transplant-related mortality. For patients with early-stage or well-controlled disease and several HLA-matched donors, consideration of HLA-DP may further optimize transplant outcome.
Long-Term Effects of HLA Disparity Many studies have elucidated the role of donor HLA matching in early post-transplant complications. With a larger transplant experience and the maturation of longitudinal data, it is now possible to evaluate late effects conferred by donor HLA matching.47,48 For example, among 150 related, 70 unrelated, and 28 autologous transplant recipients, multivariate analysis showed increased risk of endocrinologic, cardiopulmonary, and neurologic consequences compared to 317 genotypically identical sibling transplants.47 A recent study by the Seattle transplant program has explored the impact of donor HLA mismatching on long-term events48: for 362 patients transplanted from unrelated donors, there was an association of donor HLA mismatching with prolonged therapy with imnmunosuppressive agents for chronic GVHD compared to HLA-matched transplant recipients. Nonrelapse mortality was also increased. The estimated hazard of mortality per locus was 0.8 for the time to discontinuation of immunosuppressive therapy. These results indicate a lower rate of discontinuation of immunosuppression with HLA mismatching and more prolonged treatment compared to HLA matching.
The Number of HLA Mismatches Influences Risks of Posttransplant Complications: Importance of Complete Characterization of HLA Alleles Using DNA-Based Methods As the number of class I and II HLA mismatches rises, the risks of graft failure, GVHD, and mortality increases.16,28,29,36,43 Additive or synergistic multi-locus effects are observed with class I mismatches, class II mismatches, and combinations of class I and class II mismatches. In the most recent analysis by the NMDP,43 the presence of high-resolution mismatches at
HLA matching in unrelated donor HCT
Figure 1 Incidence of clinically severe grades III to IV acute GVHD in the NMDP dataset.43 Donor-recipient pairs were HLA-A, -B serologically matched and DRB1 allele-matched. The number of mismatches represents high-resolution disparities detectable using DNA-base methods for class I genes.
HLA-A, -B, and -C among HLA-A,B serologically matched transplants was associated with increased risks of both GVHD and mortality (Figs 1 and 2). When an HLA-matched donor cannot be identified, limiting the number of HLA high-resolution disparities may lower transplant risks.
Optimizing Unrelated HCT: Importance of Disease Stage and Permissibility of HLA Mismatching The safety and efficacy of unrelated donor HCT is optimal when the burden of malignant cells is low.7,8,10,12,16 Unfortunately, many patients have active or advanced malignancy at the time of transplantation; a prolonged donor search increases the time during which disease may advance.54 Therefore, further information is needed on the limits of HLA mismatching. Analysis of these data may permit earlier transplantation when the disease is well controlled, while using mismatched donors when fully matched donors are not available. The Seattle program recently conducted a retrospective evaluation of 947 patients transplanted from unrelated donors following myeloablative conditioning.45 This study assumed that the impact of HLA mismatching is not the same across different stages of disease or levels of disparity, and disease stage was defined as low, intermediate, or high.7,8,10-16,49 In order to define a mismatch, the hazard of mortality associated with an allele mismatch (high-resolution) or antigen mismatch (low-resolution) first was compared to five-locus, 10-allele matches. Among patients with low-risk disease, the HR conferred by an allele mismatch was 2.44 (1.41 to 4.22), and that conferred by an antigen mismatch was 2.15 (1.28 to 3.60); thus allele and antigen mismatches each confer significant risk to mortality, and for this
79 reason a mismatch was defined as either allele or antigen. Among patients with low-risk disease, a single HLA mismatch was associated with significantly lower survival (HR ⫽ 2.27; 1.47 to 3.51). For patients with intermediate or highrisk disease, the impact of a single HLA mismatch was not as evident (HR ⫽ 1.0 [0.71 to 1.39] and HR ⫽ 1.19 [0.84 to 1.68], respectively) (Fig 3). The major reason for failure in the low-risk group was increased transplant-related mortality (HR ⫽ 2.13; 1.34 to 3.39), and for the high-risk transplants, recurrence of disease (HR ⫽ 1.37; 0.81 to 2.29). Single HLA mismatches were detrimental in low-risk patients. To define the risk conferred by individual HLA loci, the hazard of death was evaluated in the 82 single mismatched pairs according to the presence of single HLA-A, -B, -C, -DRB1, or -DQB1 mismatches. At no locus was mismatching favorable; moreover, disparity for HLA-C was associated with significantly increased hazard of death compared to complete matching (HR ⫽ 3.18; 1.74 to 5.82). There was no evidence that the increased death among the low-risk single HLA-C mismatches was due to NK-KIR ligand matching. Among HLA-C–mismatched/KIR ligand-matched patients, the HR of death was 3.06 (1.56 to 6.01) compared to HLA-C–mismatched/KIR ligand-mismatched patients whose HR was 3.55 (1.25 to 10.10). These results suggest that, in the setting of myeloablative conditioning regimens and use of T-replete donor stem cells, the detrimental effects of HLA-C mismatching are most likely caused by T-cell alloreactivity of donor-versus-host. Patients with newly diagnosed CML have the option of initial therapy with tyrosine kinase inhibitors.55 For CML patients who do not have HLA-matched unrelated donors, the Seattle program sought to define the potential gain of extending the donor search for a fully compatible donor against the harm of lengthening the time from diagnosis to transplantation. When fully matched unrelated donors are not available, extension of the search could yield one of four outcomes: (1) a better matched donor is identified and the
Figure 2 Kaplan-Meier probability of survival in the NMDP dataset.43 Donor-recipient pairs are HLA-A, -B serologically matched and DRB1 allele-matched. As in Fig 1, the number of mismatched refers to class I incompatibilities detected by molecular methods.
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E.W. Petersdorf and M. Malkki was similar to the survival of patients transplanted in late CP from an HLA-identical donor. These results suggest that the potential benefit of HLA matching was offset by the negative impact of advanced disease. If a donor search for a patient in late CP is extended in the hope of identifying a matched donor, survival using an HLA-matched donor in late CP is similar to that using an HLA-mismatched donor in late CP. If a matched donor is identified but the disease progresses beyond CP, the survival is lower; if a matched donor cannot be identified and transplantation is conducted using a mismatched donor in late CP, survival is similarly compromised. When a donor search is highly unlikely to yield matched donors for newly diagnosed CML, the increased mortality associated with a longer time interval from diagnosis to transplantation must be weighed carefully against the increased mortality with earlier transplantation with a mismatched donor, and also against the chance of disease progression to advanced-phase CML during a prolonged donor search.
Clinical Outcomes Following Related and Unrelated HCT The majority of patients who initiate an unrelated donor search do not have fully matched donors; of the patients who have mismatched donors, only a minority have donors with a single mismatch. In this circumstance, there is a choice between a mismatched haploidentical relative or continuation of a search for a potential matched or single allele-mismatched unrelated donor. Several investigations have compared the results of matched related, mismatched related, matched unrelated, and mismatched unrelated donor transplantation.42,56-58 In a multicenter analysis of 264 adults who received a myeloablative conditioning regimen for the treatment of acute lymphocytic leukemia,58 disease-free survival (DFS) of 103 patients who received a related and 118 who Figure 3 Kaplan-Meier probability of survival: the Seattle experience.45 Transplant pairs are 10/10 (solid line) or 9/10 (dotted line) allele matched at HLA-A, -B, -C, -DRB1, and -DQB1. Transplant pairs are designated low-risk (A), intermediate-risk (B), or high-risk (C).
disease remains stable; (2) a better matched donor is identified, but the disease advances; (3) a better matched donor is not identified, but the disease remains stable; and (4) a better matched donor is not identified and the disease progresses. To address the impact of matching and disease stage, 243 patients who received their transplant early in CP1 (within 2 years of diagnosis), 63 patients transplanted in late CP1 (more than 2 years from diagnosis), and 46 patients whose CML had progressed beyond CP1 at the time of transplantation were evaluated.45 Among each of these three groups, five-locus, 10-allele matched patients were compared to those with a single HLA-A, -B, -C, -DRB1, or -DQB1 mismatch (Fig 4). In summary, the overall survival of a patient receiving a transplant in early CP from a mismatched donor
Figure 4 The effect of HLA mismatching and phase of CML at the time of transplantation.45 Figure displays patients transplanted by the Seattle program according to whether the donor and patient are matched for 10/10 alleles or mismatched for a single HLA-A, -B, -C, -DRB1, or -DQB1 allele.
HLA matching in unrelated donor HCT received an HLA-A–, -B–, -DRB1–matched unrelated donor transplant was compared. Transplant-related mortality (TRM) at 5 years was 43% for the related and 50% for the unrelated transplants (P ⫽ .11); DFS was similar between related and unrelated donor recipients. In a side-by-side comparison of phenotypically matched unrelated, single antigen-mismatched unrelated, and haploidentical-mismatched related transplants, the three populations did not significantly differ in the rate of engraftment or incidence of acute or chronic GVHD.56 Matched and mismatched unrelated donor transplants had a lower incidence of relapse at 2 years compared to haploidentical related transplants (25%, 26%, and 42%, respectively). Compared to matched unrelated transplants, TRM was higher following mismatched unrelated and haploidentical transplantation compared to matched unrelated transplantation (45%, 42%, and 23%, respectively). Overall survival for matched unrelated donor transplants was 58% compared to 34% for mismatched unrelated and 21% for haploidentical transplantation. Thus the use of a phenotypically matched unrelated donor is associated with superior overall survival compared to use of mismatched unrelated or haploidentical related donors. Among 94 children who received either a matched sibling, haploidentical-mismatched related, or an unrelated donor transplant,42 overall survival was 80%, 62%, and 47%, respectively (P ⫽ .04). Subset analysis of the haploidentical transplants revealed improved survival with fewer HLA mismatched loci: 83%, 64% and 25% among 9/10, 7-8/10 and 5-6/10 matched patients, respectively (P ⫽ .0007). Survival rates after matched sibling, matched or single mismatched unrelated, and 9/10 matched haploidentical related transplantation in children were similar. In the absence of a matched sibling donor, these results show that transplantation using unrelated donors with zero or one mismatch, and haploidentical related donors with two or fewer mismatches provide excellent clinical results. Related and unrelated donor transplants have been made for the recent Japanese transplant experience.57 For 2,947 patients, overall survival after an allogeneic transplant from a one locus-mismatched related donor was associated with significantly lower overall survival compared to the use of a matched unrelated donor for standard-risk diseases. Among patients with higher risk diseases, comparable survival after HLA-matched and single locus-mismatched recipients was achieved. HLA class I and class II mismatches did not confer statistically significant differences in either risk of grades III to IV acute GVHD or mortality. Single locus-mismatched related donor transplants and matched unrelated donor transplants yielded comparable survival for patients with standard-risk disease. Higher age and disease risk category (high) were identified as independent risk factors for lower survival in multivariate analysis. A model that adjusted for the donor type (single locus-mismatched related; matched unrelated) did not qualitatively change the results (RR ⫽ .97; .71-1.20; P ⫽ .84). This analysis demonstrates that use of a single-locus related donor should give similar overall transplant outcome compared to a matched unrelated donor for patients with higher risk disease who do not have a matched
81 sibling. For higher risk patients who lack matched related donors, transplantation from a single locus-mismatched related donor is preferable to an unrelated donor transplant.
Towards a Definition of Tolerable Mismatches In the studies described above, mismatching was defined as the presence of donor-recipient differences in the polymorphic exon sequences of class I and II genes. Analysis of mismatching for the specific residues of the HLA molecule that are known to influence the peptide binding repertoire or that contact the TCR represents another approach to identifying permissible mismatches33– but requires very large numbers of HLA allele-typed donor-recipient pairs due to the extreme diversity of HLA alleles and the sharing of common epitopes. Functional assays have been used in the analysis of permissible epitopes, as in the example of the HLA-DP molecule assessed using alloreactive cytotoxic T lymphocytes.52 Clinical studies indicate the importance of understanding HLA function through its structure. Today, single nucleotide differences between a donor and recipient HLA allele can be readily defined and related to the putative protein sequence. The number, type, and location of amino acid substitutions have been identified as important elements in determining transplant outcome.33,36 Analysis of epitopes involved in peptide binding or TCR contact can also be assisted by new software tools that compare donor and recipient HLA alleles for all polymorphic positions.59 The International Histocompatibility Working Group (IHWG) in HCT was formed to define the significance of HLA genes in racially and ethnically diverse transplant patients and donors (www.ihwg.org). The IHWG-HCT is comprised of transplant centers, transplant registries, donor registries, and immunogenetics laboratories from North America, Europe, Asia, and Australia. HLA and clinical data for a total of 2,399 unrelated transplants have been collected and contributed to the IHWG effort.60 This project established high resolution analysis of HLA-A, -B, -C, -DRB1, -DQB1, and -DPB1 genes as the standard for HLA typing. Overall survival was the primary clinical end point. The distribution of HLA matching among the IHWG dataset was 45%, 29%, and 25% for 10/10, 9/10, and 8/10 or lower, respectively. As anticipated, the frequency of specific allele mismatches varied between Asian and Caucasian patients and donors. Multivariate regression models adjusting for disease and donor registry (Japan Marrow Donor Program [JMDP] v other registries) yielded increased hazard of death associated with the number of mismatched alleles compared to 10/10 allele matches: HR ⫽ 1.38 (1.21 to 1.58; P ⬍ .0001), HR ⫽ 1.50 (1.28 to 1.76; P ⬍.0001), and HR ⫽ 1.94 (1.63 to 2.31; P ⬍ .0001) for one, two, and three or more mismatches, respectively. Definition of locus-specific effects on mortality was performed for transplant pairs with a single HLA mismatch. Among Caucasian recipients, the presence of a single HLA-C mismatch conferred a HR of 1.52 (1.26 to 1.84; P ⬍.0001) to mortality compared to matching, whereas an HLA-A mismatch was not
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families, and between A1/A11 antigen specificities; these mismatches were not present in Japanese donor-recipient pairs. At the HLA-C locus, there was broader overlap in the specific combinations of allele mismatches in the Japanese and Caucasian populations than was observed at HLA-A. The IHWG analysis demonstrates that full understanding of the rules that govern permissibility of HLA mismatches should include side-by-side evaluation of ethnically and racially diverse transplant populations. Analysis of very large numbers of pairs which have been characterized at high resolution and for whom complete clinical data are available is of crucial importance in addressing locus-specific and allelespecific rules for mismatching.
Translating HLA Research Findings to Clinical Practice A donor’s HLA match status should be used to help the physician and patient in risk assessment and then planning treatment options to reduce those risks. To facilitate donor searches in the era of DNA typing, the NMDP has developed guidelines for comparing HLA typing performed at low, intermediate, and high resolution.61,62 The use of search determinants as a name for HLA alleles and antigens can aid the physician and search coordinator in identifying potential donors who should be prioritized for evaluation and further HLA testing. Recommendations from the World Marrow Donor Association (WMDA)63 provide transplant physicians and search coordinators with procedures for optimizing donor selection and the tools needed to translate HLA typing data to donor identification. Figure 5 Single HLA-A (A) and HLA-C (B) mismatched alleles observed at greater than 4% frequency in JMDP and non-JMDP unrelated donor transplants. The total number of single HLA-A mismatches were 86 and 99 in JMDP and non-JMDP datasets, respectively. The total number of single HLA-C mismatches were 82 and 257 in JMDP and non-JMDP populations, respectively.
associated with a significant increase in risk (HR ⫽ 1.08; .80 to 1.46; P ⫽ .61). In contrast, Japanese recipients had an increased risk of mortality associated with an HLA-A mismatch (HR ⫽ 1.53; 1.1 to 2.1; P ⫽ .01) and not with HLA-C mismatching (HR ⫽ 1.03; .73 to 1.46; P ⫽ .85). Single HLA-A and single HLA-C mismatches that were observed at greater than 4% frequency displayed major differences in the kind of mismatches between the Japanese and Caucasian datasets (Fig 5). At the HLA-A locus, the most frequently mismatched antigen group was HLA-A2; however, the Japanese and Caucasian patients differed with respect to the specific HLA-A alleles: HLA-A*0201/0206 in the Japanese population, and HLA-A*0201/0205 in the Caucasians were the most common mismatches. Mismatching between HLA-A26 alleles was represented in both Japanese and Caucasian pairs but at different frequencies. Caucasian pairs were mismatched for alleles within the HLA-A3, A29, and A30 antigen
Conclusions We have reviewed the HLA factors that constitute optimal donor selection for transplantation, with a focus on myeloablative conditioning regimens and use of donor peripheral blood stem cells or bone marrow. As detailed in the articles by Gluckman, Hsu, van Rood, and Kodera in this issue, clinicians and patients have several different potential sources of stem cells from which to chose–related or unrelated donor, cord blood or blood or marrow, matched or mismatched–as well as an armamentarium of transplant conditioning and immunosuppressive regimens. Factors of importance in allogeneic transplantation must include consideration of HLA, as well as the transplant procedures and regimens. Individualization of donor selection to best meet the need of the patient is becoming increasingly important with the identification of non-HLA factors that also affect transplant outcome.
Acknowledgment We wish to thank our colleagues participating in the International Histocompatibility Working Group in Hematopoietic Cell Transplantation for their outstanding contributions (www.ihwg.org).
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