National Marrow Donor Program HLA Matching Guidelines for Unrelated Adult Donor Hematopoietic Cell Transplants
2008; Elsevier BV; Volume: 14; Issue: 9 Linguagem: Inglês
10.1016/j.bbmt.2008.06.014
ISSN1523-6536
AutoresRobert A. Bray, Carolyn Katovich Hurley, Naynesh Kamani, Ann E. Woolfrey, Carlheinz Müller, Stephen R. Spellman, Michelle Setterholm, Dennis L. Confer,
Tópico(s)T-cell and B-cell Immunology
ResumoThis commentary, sponsored by the National Marrow Donor Program® (NMDP), provides updated guidelines for unrelated hematopoietic cell donor selection in the format of frequently asked questions (FAQ). These revisions to the guidelines, initially published in 2003 [1Hurley C.K. Baxter-Lowe L.A. Logan B. et al.National Marrow Donor Program HLA matching guidelines for unrelated marrow transplants.Biol Blood Marrow Transplant. 2003; 9: 610-615Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar], are based on current and relevant data that we believe represent optimal donor-recipient matching criteria. Since its inception in 1987, the NMDP has required evaluation of donor-recipient histocompatibility matching (HLA-A, -B, and -DR) prior to unrelated hematopoietic cell transplantation (HCT). The minimum acceptable match was originally defined by serologic splits (antigen level of resolution) at these 3 loci (6 possible antigens) and required at least 5 matches, that is, a 5 of 6 match. This requirement has changed little over the years. Currently, to request a donor for transplantation, the minimal acceptable level of matching remains a 5 of 6 match for HLA-A, -B, and -DRB1. Although only evaluated at antigen level of resolution for donor release, each of these 3 loci must be typed at high-resolution by DNA-based methods. High-resolution typing is defined as the identification of alleles based on differences in the antigen recognition site (ARS) domains (Exons 2 and 3 of Class I and exon 2 of Class II genes). Alleles that are identical in the ARS domain have not been shown to have immunologic differences, and the standard practice of many transplant centers is to accept these alleles as a match [2Cano P. Klitz W. Mack S.J. et al.Common and well-documented HLA alleles: report of the Ad-Hoc Committee of the American Society for Histocompatiblity and Immunogenetics.Hum Immunol. 2007; 68: 392-417Crossref PubMed Scopus (190) Google Scholar]. In 2005, a requirement for HLA-C typing was added. The most recent studies have clearly shown that transplant outcomes can be improved by matching strategies that increase the overall degree of HLA compatibility above the minimum (eg, high-resolution matching, matching for HLA-C, -DP, -DQ, and haplotypes) [3Petersdorf E.W. Immunogenetics of unrelated hematopoietic stem cell transplantation.Curr Opin Immunol. 2006; 18: 559-564Crossref PubMed Scopus (16) Google Scholar]. There are many studies that evaluate the role of HLA matching in outcome. Our initial recommendations were based on large, contemporary studies from 3 groups that have evaluated most of the HLA loci using DNA testing to resolve alleles [4Morishima Y. Sasazuki T. Inoki H. 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. 2002; 99: 4200-4206Crossref PubMed Scopus (374) Google Scholar, 5Petersdorf E.W. Gooley T.A. Anasetti C. et al.Optimizing outcome after unrelated marrow transplantation by comprehensive matching of HLA class I and II alleles in the donor and recipient.Blood. 1998; 92: 3515-3520PubMed Google Scholar, 6Petersdorf E.W. Gooley T. Malkki M. et al.The biological significance of HLA-DP gene variation in haematopoietic cell transplantation.Br J Haematol. 2001; 112: 988-994Crossref PubMed Scopus (128) Google Scholar, 7Petersdorf E.W. Hansen J.A. Martin P.J. et al.Major-histocompatibility-complex class I alleles and antigens in hematopoietic-cell transplantation.N Engl J Med. 2001; 345: 1794-1800Crossref PubMed Scopus (278) Google Scholar, 8Petersdorf E.W. Anasetti C. Martin P.J. et al.Limits of HLA mismatching in unrelated hematopoietic cell transplantation.Blood. 2004; 104: 2976-2980Crossref PubMed Scopus (235) Google Scholar, 9Flomenberg N. Baxter-Lowe L.A. Confer D. et al.Impact of HLA class I and class II high-resolution matching on outcomes of unrelated donor bone marrow transplantation: HLA-C mismatching is associated with a strong adverse effect on transplantation outcome.Blood. 2004; 104: 1923-1930Crossref PubMed Scopus (589) Google Scholar]. The number of pairs evaluated through the NMDP network has now increased to 3857, and further analysis of outcome has been published by Lee et al. [10Lee S.J. Klein J. Haagenson M. et al.High-resolution donor-recipient HLA matching contributes to the success of unrelated donor marrow transplantation.Blood. 2007; 110: 4576-4583Crossref PubMed Scopus (1008) Google Scholar]. The outcome of primary importance is survival. However, it may be important to consider the effect of HLA matching on the incidence of acute and chronic graft-versus-host disease (aGVHD, cGVHD), treatment-related mortality (TRM), or graft rejection. Although the impact of HLA matching on survival is considered to be the primary determinant for donor selection, the impact on other outcome measures may be important in developing a specific risk-adapted treatment strategy for the recipient. Associations between HLA disparity and survival differ in the studies. The differences are detailed in Table 1, and are likely the result of differences in study design as described below.Table 1Effect of HLA Mismatching on SurvivalStudyABCDRB1JMDP 4Morishima Y. Sasazuki T. Inoki H. 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. 2002; 99: 4200-4206Crossref PubMed Scopus (374) Google Scholardecrease∗“Decrease” means a decrease in survival caused by an HLA locus mismatch. (merged A+B)no effect†“No effect” means no impact of a mismatch.no effect (merged DR+DQ)FHCRC 8Petersdorf E.W. Anasetti C. Martin P.J. et al.Limits of HLA mismatching in unrelated hematopoietic cell transplantation.Blood. 2004; 104: 2976-2980Crossref PubMed Scopus (235) Google Scholarno effectno effectdecreaseno effectNMDP 9Flomenberg N. Baxter-Lowe L.A. Confer D. et al.Impact of HLA class I and class II high-resolution matching on outcomes of unrelated donor bone marrow transplantation: HLA-C mismatching is associated with a strong adverse effect on transplantation outcome.Blood. 2004; 104: 1923-1930Crossref PubMed Scopus (589) Google ScholardecreasedecreasedecreasedecreaseNMDP 10Lee S.J. Klein J. Haagenson M. et al.High-resolution donor-recipient HLA matching contributes to the success of unrelated donor marrow transplantation.Blood. 2007; 110: 4576-4583Crossref PubMed Scopus (1008) Google Scholardecreaseno effectdecreasedecrease∗ “Decrease” means a decrease in survival caused by an HLA locus mismatch.† “No effect” means no impact of a mismatch. Open table in a new tab Differences in the study designs are summarized in Table 2. Sample size dictated how the mismatches were classified across the multiple loci, and different studies collapsed the loci differently. For example, Morishima et al [4Morishima Y. Sasazuki T. Inoki H. 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. 2002; 99: 4200-4206Crossref PubMed Scopus (374) Google Scholar] combined mismatches at HLA-A and -B, and at -DR and -DQ, to get a larger sample size to detect differences among groups. Petersdorf et al [5Petersdorf E.W. Gooley T.A. Anasetti C. et al.Optimizing outcome after unrelated marrow transplantation by comprehensive matching of HLA class I and II alleles in the donor and recipient.Blood. 1998; 92: 3515-3520PubMed Google Scholar, 6Petersdorf E.W. Gooley T. Malkki M. et al.The biological significance of HLA-DP gene variation in haematopoietic cell transplantation.Br J Haematol. 2001; 112: 988-994Crossref PubMed Scopus (128) Google Scholar, 7Petersdorf E.W. Hansen J.A. Martin P.J. et al.Major-histocompatibility-complex class I alleles and antigens in hematopoietic-cell transplantation.N Engl J Med. 2001; 345: 1794-1800Crossref PubMed Scopus (278) Google Scholar] collapsed mismatches based on class I versus class II loci. In the more recent NMDP studies, Flomenberg et al [9Flomenberg N. Baxter-Lowe L.A. Confer D. et al.Impact of HLA class I and class II high-resolution matching on outcomes of unrelated donor bone marrow transplantation: HLA-C mismatching is associated with a strong adverse effect on transplantation outcome.Blood. 2004; 104: 1923-1930Crossref PubMed Scopus (589) Google Scholar] and Lee et al [10Lee S.J. Klein J. Haagenson M. et al.High-resolution donor-recipient HLA matching contributes to the success of unrelated donor marrow transplantation.Blood. 2007; 110: 4576-4583Crossref PubMed Scopus (1008) Google Scholar] looked at each locus separately. The former analysis employed multivariate modeling to evaluate mismatches across all loci studied [9Flomenberg N. Baxter-Lowe L.A. Confer D. et al.Impact of HLA class I and class II high-resolution matching on outcomes of unrelated donor bone marrow transplantation: HLA-C mismatching is associated with a strong adverse effect on transplantation outcome.Blood. 2004; 104: 1923-1930Crossref PubMed Scopus (589) Google Scholar]. The more recent study used “subset analysis,” which means that in examining mismatches at a particular locus, all other loci were high-resolution matched [10Lee S.J. Klein J. Haagenson M. et al.High-resolution donor-recipient HLA matching contributes to the success of unrelated donor marrow transplantation.Blood. 2007; 110: 4576-4583Crossref PubMed Scopus (1008) Google Scholar]. Flomenberg et al [9Flomenberg N. Baxter-Lowe L.A. Confer D. et al.Impact of HLA class I and class II high-resolution matching on outcomes of unrelated donor bone marrow transplantation: HLA-C mismatching is associated with a strong adverse effect on transplantation outcome.Blood. 2004; 104: 1923-1930Crossref PubMed Scopus (589) Google Scholar] found a direct association between the number of mismatched HLA alleles and survival, but did not identify a locus-specific effect. In contrast, Morishima et al and Lee et al identified locus-specific effects, albeit with somewhat differing results. Morishima et al identified the combined A/B group as having a stronger effect on survival than the other loci. However, because this combined A/B group included single allelic mismatches for A or B as well as mismatches for both A and B, the observed effect may have been magnified by these multiple mismatches. Lee et al found that a single mismatch either at HLA-A or HLA-DRB1 had a more profound effect on survival compared to HLA-B or HLA-C. This study also found that a high-resolution mismatch had an effect similar to an antigen level mismatch. The differences between the findings of Morishima et al and Lee et al may be explained by the different study populations. The distribution of alleles in the U.S. and Japanese populations was quite different, with little overlap in the alleles and mismatches represented in the 2 populations. There may be other immunologic factors that vary among ethnic/racial groups and influence the relationship between HLA matching and transplant outcomes. Other patient-related factors appear to be important, particularly diagnosis and phase of disease. Both Petersdorf et al [8Petersdorf E.W. Anasetti C. Martin P.J. et al.Limits of HLA mismatching in unrelated hematopoietic cell transplantation.Blood. 2004; 104: 2976-2980Crossref PubMed Scopus (235) Google Scholar] and Lee et al found that the impact of HLA-mismatching was more pronounced among patients with “low-risk” disease (generally defined as chronic myelogenous leukemia (CML)-chronic phase and/or early-phase myelodysplastic syndromes (MDS) and/or acute leukemia in first remission). In contrast, for “high-risk” patients, the increase in overall mortality associated with advanced disease status appears to obfuscate the benefit of HLA matching.Table 2Similarities and Differences in Design of the StudiesJMDP Morishima et al. 4Morishima Y. Sasazuki T. Inoki H. 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. 2002; 99: 4200-4206Crossref PubMed Scopus (374) Google ScholarFHCRC Petersdorf et al. 8Petersdorf E.W. Anasetti C. Martin P.J. et al.Limits of HLA mismatching in unrelated hematopoietic cell transplantation.Blood. 2004; 104: 2976-2980Crossref PubMed Scopus (235) Google ScholarNMDP Flomenberg et al. 9Flomenberg N. Baxter-Lowe L.A. Confer D. et al.Impact of HLA class I and class II high-resolution matching on outcomes of unrelated donor bone marrow transplantation: HLA-C mismatching is associated with a strong adverse effect on transplantation outcome.Blood. 2004; 104: 1923-1930Crossref PubMed Scopus (589) Google ScholarNMDP Lee et al. 10Lee S.J. Klein J. Haagenson M. et al.High-resolution donor-recipient HLA matching contributes to the success of unrelated donor marrow transplantation.Blood. 2007; 110: 4576-4583Crossref PubMed Scopus (1008) Google ScholarTransplant sourceMulticenterSingle centerMulticenterMulticenterStem cell sourceMarrow90% MarrowMarrow94% MarrowPatient diseasesAML, ALL, CML, MDS, SAA, othersCML, AML, ALL, MDSCML, AML, ALL, MDS, SAA, othersCML, AML, ALL, MDSPatient ages0-51, median 231-62, median 350-66, median 300-65, median 33Patient raceJapanesePredominantly White from U. S.Predominantly White from U. S.Predominantly White from U.S.No pairs evaluated129894818743857HLA loci characterized∗[Brackets] indicate HLA loci grouped together for analysis.][A,B] [C] [DRB1, DQB1][A] [B] [C] [DRB1] [DQB1] [DPB1][A] [B] [C] [DRB1] [DQA1, DQB1] [DPA1, DPB1][A] [B] [C] [DRB1] [DQA1, DQB1] [DPA1, DPB1]Match criteria for patients entered into studyAntigen A, B, DR matched onlyAntigen matching at A, B, DR with Dw or DRB1 allele matching; mismatching allowed within guidelines described in 1998 studyAntigen matching at A, B and antigen or high resolution level at DRB1; 5 of 6 minimum matchAntigen matching at A, B and antigen or high resolution level at DRBI:5 of 6 minimum matchLevel of match investigatedHigh resolutionHigh resolution and antigen levelHigh resolution and antigen level for A, B, C, DRB1; any level for DQ and DPHigh resolution and antigen levelSAA indicates severe aplastic anemia.∗ [Brackets] indicate HLA loci grouped together for analysis.] Open table in a new tab SAA indicates severe aplastic anemia. Taken together, these studies support several general concepts in analyzing the effect of HLA mismatch on survival. First, there appears to be a direct association between the number of HLA mismatches and the risk for mortality. Second, mismatching between donor and recipient appears to have a greater impact on patients with “low-risk” disease. Finally, specific mismatches among the HLA-loci may be tolerated better within certain ethnic groups. The reports reviewed above show that high-resolution matching for HLA-A, -B, -C, and -DRB1 maximizes posttransplant survival (Table 3). Thus, whenever possible, donors who are high resolution matched at these 4 HLA loci should be sought. This does not imply that the unavailability of such a well-matched donor is a contraindication for transplant. If a mismatch is unavoidable, a single mismatched donor (-A, -B, -C, or -DRB1) should be sought. From the NMDP data reviewed above, it appears that high-resolution mismatches have a negative impact similar to antigen-level mismatches [10Lee S.J. Klein J. Haagenson M. et al.High-resolution donor-recipient HLA matching contributes to the success of unrelated donor marrow transplantation.Blood. 2007; 110: 4576-4583Crossref PubMed Scopus (1008) Google Scholar]. The sole exception may occur at HLA-C where high-resolution mismatches appear to be better tolerated; however, this particular aspect needs further study. In the NMDP data, mismatches at HLA-B and -C may be less detrimental than those at HLA-A and -DRB1, but this sense is tempered by limited numbers of transplants and by the lack of allele-specific mismatch analyses. That is, within the existing dataset, the distribution of “permissive” and “nonpermissive” mismatches at each locus may be nonuniform. For example, more permissive mismatches within the HLA-B locus mismatched dataset would diminish the negative impact of mismatching for HLA-B. Clearly, more research is needed in this area.Table 3Typing and Matching of Potential Donor and Patient HLA LociHLA LocusSearch StrategyMatchingResolution of TestingAYesRecommendedHighBYesRecommendedHighCYesRecommendedHighDRANoNoDRB1YesRecommendedHighDRB3, DRB4, DRB5Yes (DRB1 association)∗Certain alleles at one locus are preferentially associated with some but not other alleles at a second locus. Knowledge of the patient's HLA-DRB3/4/5 or DQB1 assignment provides a check on the patient's typing by association, can be used to select the best matched donor from potential donors equivalently matched at HLA-A, -B, -C, and -DRB1 and, for DQB1, permits HapLogic match evaluation and prediction.Unknown†Unknown indicates that the impact of matching has not been evaluated.DQA1NoNoDQB1Yes (DRB1 association)∗Certain alleles at one locus are preferentially associated with some but not other alleles at a second locus. Knowledge of the patient's HLA-DRB3/4/5 or DQB1 assignment provides a check on the patient's typing by association, can be used to select the best matched donor from potential donors equivalently matched at HLA-A, -B, -C, and -DRB1 and, for DQB1, permits HapLogic match evaluation and prediction.Uncertain‡Uncertian indicates that studies as to the importance of these loci in matching. Matching may be necessary if patient possesses anti-HLA antibodies to the mismatched antigens.DPA1NoNoDPB1NoUncertain∗ Certain alleles at one locus are preferentially associated with some but not other alleles at a second locus. Knowledge of the patient's HLA-DRB3/4/5 or DQB1 assignment provides a check on the patient's typing by association, can be used to select the best matched donor from potential donors equivalently matched at HLA-A, -B, -C, and -DRB1 and, for DQB1, permits HapLogic match evaluation and prediction.† Unknown indicates that the impact of matching has not been evaluated.‡ Uncertian indicates that studies as to the importance of these loci in matching. Matching may be necessary if patient possesses anti-HLA antibodies to the mismatched antigens. Open table in a new tab Of importance is the observation in the NMDP data that mismatches at HLA-DQ do not show the same overall negative impact as those at the 4 other HLA loci [10Lee S.J. Klein J. Haagenson M. et al.High-resolution donor-recipient HLA matching contributes to the success of unrelated donor marrow transplantation.Blood. 2007; 110: 4576-4583Crossref PubMed Scopus (1008) Google Scholar], but DQ mismatches may be important in certain disease subsets or when coupled with mismatches at other loci [3Petersdorf E.W. Immunogenetics of unrelated hematopoietic stem cell transplantation.Curr Opin Immunol. 2006; 18: 559-564Crossref PubMed Scopus (16) Google Scholar, 8Petersdorf E.W. Anasetti C. Martin P.J. et al.Limits of HLA mismatching in unrelated hematopoietic cell transplantation.Blood. 2004; 104: 2976-2980Crossref PubMed Scopus (235) Google Scholar]. Similar to HLA-DQ, mismatches at HLA-DP do not seem to play a role in overall mortality. In the Lee et al. [10Lee S.J. Klein J. Haagenson M. et al.High-resolution donor-recipient HLA matching contributes to the success of unrelated donor marrow transplantation.Blood. 2007; 110: 4576-4583Crossref PubMed Scopus (1008) Google Scholar] study, HLA-DP mismatching was associated with an increased risk for aGVHD; however, there was no impact on overall survival (OS), and only a suggestion of an association with increased risk of treatment-related mortality. In addition, Shaw et al [11Shaw B. Gooley T. Malkki M. et al.The importance of HLA-DPB1 in unrelated donor hematopoietic cell transplantation.Blood. 2007; 110: 4560-4566Crossref PubMed Scopus (152) Google Scholar] showed a similar association between HLA-DP mismatches and an increased risk for aGVHD; however, this negative impact may be offset by a decreased risk for disease relapse. A recent Center for International Blood and Marrow Transplant Research (CIBMTR) analysis of unrelated donor transplantation comparing bone marrow to peripheral blood stem cells (PBSCs) as hematopoietic cell sources in adults with leukemia and myelodysplastic syndrome showed a significantly higher risk of grades II-IV aGVHD and cGVHD following unrelated donor PBSC transplantation with no survival benefit for PBSC recipients [12Eapen M. Logan B.R. Confer D.L. et al.Peripheral blood grafts from unrelated donors are associated with increased acute and chronic graft-versus-host disease without improved survival.Biol Blood Marrow Transplant. 2007; 13: 1461-1468Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar]. The data currently available regarding the role of HLA mismatch in transplant outcome are generated from series using bone marrow as a stem cell source. Additional analyses of transplants using PBSCs as a stem cell source are needed to determine if the same principles apply. One alternative stem cell source for cases without a suitable donor is the use of umbilical cord blood. Recent studies have established the utility of umbilical cord blood, particularly as a treatment for childhood leukemia [13Eapen M. Rubinstein P. Zhang M.J. et al.Outcomes of transplantation of unrelated donor umbilical cord blood and bone marrow in children with acute leukaemia: a comparison study.Lancet. 2007; 369: 1947-1954Abstract Full Text Full Text PDF PubMed Scopus (662) Google Scholar]. The impact of HLA matching on outcomes following unrelated donor umbilical cord blood transplantation was recently summarized by the NMDP [14Kamani N. Spellman S. Hurley C.K. et al.State of the art review: HLA matching and outcome of unrelated donor umbilical cord blood transplants.Biol Blood Marrow Transplant. 2008; 14: 1-6Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar]. Other non-HLA factors are often considered when selecting donors including CMV negative serology (for CMV-negative patients), male sex, younger age, ABO compatibility, larger body weight, and matched race. In the recent NMDP analysis by Lee et al [10Lee S.J. Klein J. Haagenson M. et al.High-resolution donor-recipient HLA matching contributes to the success of unrelated donor marrow transplantation.Blood. 2007; 110: 4576-4583Crossref PubMed Scopus (1008) Google Scholar], none of these factors were important when compared to HLA matching. This finding contrasted with another NMDP study by Kollman et al [15Kollman C. Howe C.W. Anasetti C. et al.Donor characteristics as risk factors in recipients after transplantation of bone marrow from unrelated donors: the effect of donor age.Blood. 2001; 98: 2043-2051Crossref PubMed Scopus (541) Google Scholar], which found that, in addition to HLA matching, younger donor age was associated with better survival. In the Kollman study, there was also no significant association of donor CMV serology, sex, parity, race, or ABO matching and recipient survival. Female donors with multiple pregnancies were associated with a higher risk of cGVHD, but there was no impact on survival. Several variables likely explain the different findings in these 2 studies including the absolute patient numbers, the definitions of HLA matching, duration of follow-up, and the consideration of center effects. Each search should be initiated based on high-resolution HLA assignments of the patient. HLA-A, -B, -C, and -DRB1 loci should be characterized because they are important in matching; others assist in designing an efficient search strategy for the patient (Table 3). The search report received from the NMDP now contains information that indicates the likelihood of each potential donor carrying the same alleles as the searching patient. This is especially helpful when faced with a long list of potential adult or cord blood donors but only sufficient resources and/or time to type a few of the potential donors at higher resolution. The NMDP search algorithm HapLogicSM uses data on the frequencies of alleles and haplotypes in human populations to predict the probability of high-resolution matches at individual HLA loci and at all key loci simultaneously (Figure 1). The optimal number of potential donors to select from the search report should be individualized for each patient because many factors influence the likelihood of finding a compatible donor. Factors to be considered include the patient's alleles and haplotypes (ie, rare versus common), as well as clinical urgency. For patients with potential donors with a high probability of high-resolution matches as determined by HapLogic, high-resolution typing of a small number (eg, 3-5) of donors is usually sufficient. However, more than 1 donor should be selected because donors may be unavailable, mistyped, or not matched once high-resolution testing is complete. For patients with rare alleles and haplotypes where the likelihood of matching is low, 10 or more donors may be required to find the best match. In the latter situation, help should be immediately sought from in-house or NMDP histocompatibility experts to design an effective search strategy that may include evaluation of worldwide donor registries. Similarly, for a patient with clinical urgency, multiple donors should be simultaneously evaluated and typed. The NMDP donor file includes volunteers from the U.S. as well as Norway, Sweden, Germany, and Israel. The NMDP also provides a general search of Bone Marrow Donors Worldwide (BMDW) as well as an automatic detailed search of certain international registries using the EMDIS (European Marrow Donor Information System) network that are readily accessible through NMDP software or by written request. The BMDW report is particularly helpful to set an optimal, but realistic, target for the donor search in relation to the number and details of the potential donors and the time and resources available for a particular patient. However, the decision on the overall search strategy and the usefulness of an extended international search must also take into account the variation of allele and haplotype frequencies in different geographic, racial, or ethnic groups. Whenever deemed useful, the NMDP can be asked to request search reports from additional registries and/or with relaxed matching criteria for difficult cases or specifically filtered match lists for searches with many donor candidates. For patients with common haplotypes, a suitably matched donor can usually be identified on the first match run. For patients with uncommon haplotypes, a well-matched donor may not be readily apparent on the initial match run. For these patients, we recommend that one request help from a local HLA laboratory or NMDP consultant to assist in identifying the best potential match. If one is not able to identify an available, acceptably matched donor within the current NMDP Registry, it is very unlikely that newly recruited donors will match the patient in a useful time frame. The NMDP donor file contains nearly 7 million donors (∼78% typed for HLA-A, -B, and -DR) and the NMDP search also provides a match report of an additional ∼5 million donors listed in BMDW, so patients who are not able to find a suitably matched donor in this pool most likely have haplotypes that are infrequently represented. The NMDP adds an average of 30,000 new donors to the file monthly. The likelihood that a patient's type will be represented in those new recruits when it did not appear in the initial file of ∼12 million is low. Therefore, it is recommended that one reevaluate the alternative treatment options for those patients and decide whether to reduce the matching requirements or select another therapy (eg, unrelated cord blood transplantation, a partially matched related donor transplantation, or nontransplant therapy). However, it should be recognized that search strategies can be significantly affected by the lack of financial resources. For some individuals, enlisting the assistance of an HLA expert can help maximize available resources by optimizing potential donor screening. The clinical status of the patient will influence donor selection. Patients with a relatively stable disease such as low-risk MDS or a non-SCID primary immune deficiency are less likely to deteriorate quickly, thus giving their physician time to search and identify the best matched unrelated donor. In contrast, patients with acute leukemia may have only a brief remission time in which transplant is feasible. A prolonged search time exposes patients to additional toxic chemotherapy, an increased risk of infection and risk of relapse. For these patients, a short search time and ongoing consideration of alternatives (such as using an unrelated cord blood unit, a mismatched unrelated donor, a haploidentical donor, or an investigational therapy) should be entertained. The risk from the underlying disease and the availability of therapeutic alternatives also influences the degree of mismatch considered acceptable by the physician and patient. Besides considering differences in life expectancy, the quality of life associated with transplantation from the best available unrelated donor should be compared to the quality of life associated with alternative therapies. Donors identified on the NMDP search report with the highest likelihood of matching the patient should undergo complete high-resolution testing to select the best HLA
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