ORIGINAL ARTICLE. Bone Marrow Transplantation (2015) 50, ; doi: /bmt ; published online 8 June 2015

Transcription

1 Bone Marrow Transplantation (2015) 50, Macmillan Publishers Limited All rights reserved /15 ORIGINAL ARTICLE High-resolution HLA matching in unrelated donor transplantation in Switzerland: differential impact of class I and class II mismatches may reflect selection of nonimmunogenic or weakly immunogenic DRB1/DQB1 disparities JR Passweg 1, U Schanz 2, Y Chalandon 3, T Güngör 4, H Baldomero 5, D Heim 1, G Nair 2, M Medinger 1, S Masouridi-Levrat 3, GN de Faveri 6 and J-M Tiercy 7 for the Swiss Blood Stem Cell Transplantation Group (SBST) Unrelated donor searches in Switzerland require high-resolution HLA typing for HLA-A/B/C/DRB1/DRB3,4/DQB1 loci. We evaluated this strategy accepting donors with 9/10 match. Of 802 unrelated donor transplants in , 570 were 10/10 matched, 31 were DRB3/4 mismatched, 261 were single-allele mismatched and 13 had 2 allele mismatches. Of the 261 single-allele disparities, 60 concerned HLA-A/-B, 55 HLA-C and 73 HLA-DRB1/-DQB1 loci. Transplants were reduced intensity conditioning (289, 36%), marrow (187, 23%), EBMT risk score was low in 39, intermediate I in 331, intermediate II in 333 and high in 99 patients. Five-year survival was 48 ± 4%. HLA affected survival in the multivariate model adjusted for risk score. HLA-A/-B and HLA-C mismatches had twice the mortality risks, whereas HLA-DRB1/-DQB1 mismatches were similar to matched transplants. HLA-DRB3/4 mismatches were associated with a nonsignificant increased mortality risk. HLA-DRB3/4 mismatches had higher graft-versus-host disease and transplant-related mortality risks and lower relapse rates compared with matched transplants. We show significant effects of HLA class I, but not HLA class II, mismatches. The lack of impact of DRB1 disparities may be related to the lower immunogenicity of the DRB1*11:01/11:04 and DRB1*14:01/14:54 mismatches, representing 46% of DRB1 incompatibilities. These results support a matching algorithm that prioritizes mismatches considered as more permissive. Bone Marrow Transplantation (2015) 50, ; doi: /bmt ; published online 8 June 2015 INTRODUCTION With the increasing number of HLA-typed volunteer donors in the many donor registries worldwide, identification of a matched unrelated donor has become reality for the majority of patients with a European genetic background and in need for a hematopoietic stem cell transplant (HSCT). 1,2 As a consequence and owing to improved outcome, 3 the number of unrelated donor transplants has steadily increased, and since 2009 it exceeds that of HLA-identical sibling donor transplants in Europe. 4 Nevertheless, even a well-matched unrelated donor HSCT remains associated with significant acute or chronic graft-versus-host disease (GVHD) and transplant-related mortality risks, and the best unrelated donor selection remains a matter of debate. 5 7 The implementation of HLA molecular typing in the donor search process has clearly contributed to improving the selection of optimally matched donors. 1 For many groups, a HLA-A/B/C/ DRB1/DQB1-compatible (that is, 5 loci, 10 alleles) donor is considered optimal with outcomes comparable to HSCTs from a HLA identical sibling donor. 8,9 Transplant-related mortality (TRM) is clearly linked to the level of HLA matching, but to a variable degree in different populations. 10 The impact of single-allele mismatches may also vary throughout time in the same centers. 11 Data on additional matching for HLA-DPB1 have led to controversial results An analysis of patients with a myeloablative HSCT within the framework of the 14th international histocompatibility workshop (IHWS) showed that DPB1 incompatibilities correlated with an increased risk of agvhd and a decreased disease relapse rate without any significant impact on the probability of overall survival. 17 The large NMDP (National Marrow Donor Program) study was also unable to disclose an impact on survival. 18 Because of weak linkage disequilibrium, only 12% of donor recipient pairs that matched for 10/10 alleles in Switzerland are HLA-DPB1-matched, 21 a ratio comparable to that shown in several European studies (reviewed in Bettens et al. 21 ). Matching for DRB3/4 loci that are variably expressed is usually not considered, as some studies have shown these loci not to be associated with outcome. 22,23 Impact of such mismatches, if present, may be explained by immunogenicity, but it may also hint toward MHC haplotype differences. Separating the 2 haplotypes by microarray hybridization with HLA-B allele-specific probes 24 has shown that patient/donor haplotype mismatching, that is, with HLA alleles not segregating on the same 1 Division of Hematology, University Hospital Basel, Basel, Switzerland; 2 Division of Hematology, University Hospital, Zürich, Switzerland; 3 Service d Hématologie, Hôpitaux Universitaires de Genève, Geneva, Switzerland; 4 Division of Immunology, University Children s Hospital, Zürich, Switzerland; 5 SBST Data Office, University Hospital Basel, Basel, Switzerland; 6 Donor Registry, Swiss Transfusion SRC, Bern, Switzerland and 7 National Reference Laboratory for Histocompatibility (LNRH), Hôpitaux Universitaires de Genève, Geneva, Switzerland. Correspondence: Professor JR Passweg, Division of Hematology, University Hospital Basel, Petersgraben 4, Basel 4031, Switzerland. jakob.passweg@usb.ch Received 5 January 2015; revised 24 April 2015; accepted 28 April 2015; published online 8 June 2015

2 1202 chromosome, was associated with an increased incidence of agvhd. Similarly, a recent study in Germany showed survival differences among 10/10 allele-matched donor recipient pairs when the donor was from the same population group, as opposed to international donors. 25 A standardized donor search algorithm by the Swiss Blood Stem Cell Transplantation Group (SBST) requests donor and recipient 5 loci, 10 allele HLA high-resolution typing, that is, HLA-A/B/C/DRB1/ DRB3,B4/DQB1 for unrelated donor searches. Donors with a 9/10 match grade were acceptable. HLA-A/B/C/DRB1/DQB1 allele or antigen mismatches were qualified as a mismatch (without any discrimination between allele and antigen mismatches), and HLA-DRB3/4 disparities were documented but not counted. We made use of the mandate that all unrelated donor transplants in Switzerland are facilitated by the foundation Swiss Blood Stem Cells, that all donor recipient pairs are retyped at a high-resolution level before transplant by the Swiss National Reference Laboratory for Histocompatibility (LNRH) and that all transplant centers in Switzerland are JACIE accredited and do report full data. 2 The goal of this study was to evaluate this donor search strategy. PATIENTS AND METHODS This was a retrospective analysis of a cohort of all 802 patients receiving unrelated donor transplants using the donor search strategy, as specified above, and transplanted since All 802 patient/donor pairs were matched at the second field level typing (high-resolution typing, previously referred to as 4-digit typing) for the HLA- A,B,C,DRB1/B3/B4,DQB1 loci by standard methods: PCR-SSO on microbeads arrays (Luminex Technology, LabType HD, OneLambda, Ingen, Chilly- Mazarin, France), PCR-SSP (Genovision, Milan Analytika AG, Rheinfelden, Switzerland) and SBT (Protrans, Endotell AG, Allschwil, Switzerland). 26 Among 802 patients, of whom 63% were male, with a median age of 44 years (range of 1 71 years), 395 (49%) were treated for acute leukemia, 155 (19%) were treated for MDS/MPN, 75 (9%) were treated for chronic leukemia, 63 (8%) were treated for lymphoma, 45 (6%) were treated for myeloma and 69 (9%) were treated for non-malignant disorders. The disease stage was early in 375 (47%) patients, intermediate in 243 (30%) patients or advanced in 184 (23%) patients (Table 1). Thirty-nine (5%) patients had a low pretransplant risk profile, as defined by the European group for blood and marrow transplantation (EBMT) risk score ( ), 331 (41%) patients had intermediate I, 333 (41%) patients had intermediate II and 99 (12%) patients had a high risk. 4 7 In 36% of patients, a low-intensity conditioning was applied; the stem cell source was marrow in 187 (23%) patients and peripheral blood in the remaining patients. Cord blood transplants were excluded from this analysis. In all, 367 (46%) transplants were performed in the four national transplant centers in and 435 (54%) transplants were performed in (Table 1). The 802 donor recipient pairs were HLA 10/10 matched in 570 (71%), or presentedwithhla-a,37(5%),hla-b,23(3%),hla-c,55(7%),hla-drb1,35 (4%),HLA-DQB1,38(5%),HLA-DRB3/4, 31 (4%, all of whom were otherwise 10/10matched),orwith2/10HLA-mismatches,13(2%).Mismatcheswere considered to be present irrespective of these being bidirectional or in graft versus host or host versus graft direction. With the exception of the DRB1*14:01/14:54 mismatch, all class I and II disparities included one or several amino acid differences in the antigen recognition site. One pair differed outside the antigen recognition site, but this difference resulted in a null allele, C*04:09 N. Out of all DRB1 mismatches, 60% concerned the DRB1*11 specificity. Of the C mismatches, 17% only were detected at the high-resolution level and included alleles within the C*03, C*07 and C*12 groups. The remaining 83% were detected already by low-resolution typing. For convenience of presentation and because of similar outcomes, HLA-A and HLA-B mismatches and HLA-DRB1 and DQB1 mismatches were pooled in order to compare HLA-A/B, HLA-C, HLA-DRB1/DQB1, HLA-DRB3/4 and multiple mismatches to the matched population. To verify the justification of this pooling, Table 1 showing baseline data and Table 2 showing the multivariate analysis also provide the data separately for each locus. To estimate acute and chronic GvHD, transplant-related mortality and relapse incidence in patients with malignant disease, the cumulative incidence function was used, with death from other causes as defining the competing risk. To calculate survival probabilities, the Kaplan Meier estimator was used with the log-rank test for comparisons among groups. The Cox regression model was used for multivariate analysis. For the Table 1. Baseline data N (%) Patients unrelated donor HSCT 802 HLA typing 10/10 matched 570 (71) HLA-A or HLA-B mismatch 60 (8) (A:37; B:23) HLA-C mismatch 55 (7) HLA DRB1 or DQB1 mismatch 73 (9) (DRB1:35; DQB1:38) 10/10 matched, HLA DRB3/4 mismatch 31 (4) 8/10 matched 13 (2) Year of HSCT (46) (54) Treatment center A 301 (37) B 206 (26) C 207 (26) D 88 (11) Disease Acute leukemia 395 (49) Chronic leukemia (CML, CLL) 75 (9) MDS/MPN 155 (19) Lymphoma 63 (8) Plasma cell myeloma 45 (6) Marrow failure 25 (3) Inherited disorders 44 (5) Disease stage Early 375 (47) Intermediate 243 (30) Advanced 184 (23) Patient age (18) (25) (39) (18) Stem cell source Peripheral blood 615 (77) Bone marrow 187 (23) Conditioning intensity Myeloablative 496 (62) Reduced intensity 289 (36) Other 17 (2) EBMT risk score a 1 39 (5) (41) (42) (12) Abbreviations: CLL = chronic lymphocytic leukemia; CML = chronic myeloids leukemia; EBMT = European group for blood and marrow transplantation; HSCT = hematopoietic stem cell transplants; MDS = myelodysplastic syndrome; MPN = myeloproliferative neoplasia. a EBMT Risk Score using patient age, disease stage, donor-recipient sex-mismatching, time interval from diagnosis to transplantation. clinical pretransplant risk factors, we used the EBMT risk score including patient age, disease stage, donor type, donor recipient sex-matching and time from diagnosis to transplant. 27 RESULTS Table 1 shows the baseline patient-, disease- and transplantspecific data for the cohort of 802 patients. Engraftment was Bone Marrow Transplantation (2015) Macmillan Publishers Limited

3 slower in patients with HLA-A or HLA-B mismatched donor; the percentage of patients with primary nonengraftment or late graft lost was 3% in the matched group and 2, 5, 10, 3 and 8% in the groups mismatched for HLA-A/B, HLA-C, HLA-DRB1/DQB1, HLA-DRB3/4 and with multiple mismatches, respectively. Overall, these numbers of events were small (possibly with the exception of HLA-DRB1/DQB1 mismatches), and no statistical tests were done. Table 3 shows overall survival at 5 years, as well as treatmentrelated mortality and relapse incidence, in patients with malignancy and the cumulative incidence of acute grade II IV GvHD by day 100 and the incidence of any grade of chronic GvHD by 5 years for the different HLA matching groups. Adjusted 5-year survival differences are shown in Figure 1. Whereas single class I mismatches, including HLA-A or -B and HLA-C, were associated with poorer survival and higher TRM in univariate analysis, the class II (HLA-DRB1, HLA-DQB1) mismatches were not. Of note, HLA-DRB3/4 mismatches were associated with lower survival, higher TRM and higher incidence of acute and chronic GvHD, although the survival differences were of borderline significance only. Donor recipient pairs with 8/10 matches, that is, 2 mismatches, did not perform poorly, but this was a selected group of 13 mainly younger patients only (70%oage 20 years). Table 2 shows the multivariate model of survival confirming these differences adjusting for disease and EBMT risk score and stratified on transplant center DISCUSSION The major finding of this study on 802 unrelated donor transplants performed in Switzerland was poorer outcome in 9/10 matched donor recipient pairs if the HLA mismatch was in any of the class I loci (A,B and C), but not in a class II locus (DRB1 or DQB1). Of note, a mismatch in the DRB3/4 loci, not usually considered a mismatch, was associated with poorer outcome, although this difference was of borderline significance only. The lack of detectable impact of class II mismatching in this cohort may be explained by lower immunogenicity of DQB1 mismatches and by the fact that DRB1 mismatches were enriched for the possibly nonimmunogenic or weakly immunogenic HLA-DRB1*11:01/11:04 28 (identified in 14 patient/donor pairs) and DRB1*14:01/14:54 disparities (in two patient/donor pairs), which altogether comprised 46% of all HLA-DRB1-mismatched donor recipient pairs. Of the 35 DRB1 mismatches, 4 only were accompanied by a DRB3 mismatch, with 2 of these including a DRB1*14:01/14:54 mismatch previously reported as permissive. 29 Interestingly, 22% of the DQB1 incompatibilities consisted of the DQB1*03:01/03:02 mismatch that had been shown to be undetectable in mixed lymphocyte Table 2. Multivariate model of survival of 802 patients, adjusted for type of disease and EBMT risk score and stratified on transplant center RR (95% CI) P-value Cum survival HLA matching /10 matched including DRB3/4 1.0 HLA-A or HLA-B mismatch 2.10 ( ) HLA-A 2.2 ( ) HLA-B 1.9 ( ) HLA-C mismatch 2.12 ( ) HLA-DRB1/DQB1 mismatch 1.06 ( ) 0.75 HLA-DRB1 1.1 ( ) HLA-DQB1 1.0 ( ) HLA-DRB3/4 mismatch 1.62 ( ) /10 matched donor recipient pairs 1.39 ( ) 0.44 Abbreviations: CI = confidence interval; RR = relative risk Years Figure 1. Adjusted 5-year survival curve by degree of HLA matching. Blue, 10/10 HLA matched; purple, DRB1/DQB1 single-allele mismatch; red two allele mismatched; black, DRB3/4 mismatch; green, HLA-A or HLA-B single-allele mismatch; gray, HLA-C single-allele mismatch. Table 3. Univariate 5-year cumulative incidence of survival, treatment-related mortality, relapse/progression, chronic GvHD and 100-day cumulative incidence of acute GvHD; P-values are by log-rank test comparing with the fully matched group HLA Survival TRM Relapse agvhd cgvhd 10/10 matched 52 (±5) % 20 (16 24) % 36 (31 40) % 26 (23 31) % 45 (40 50) % HLA-A or HLA-B mismatch 41 (±14) % P = (19 44) % P = (26 54) % P = (17 45) % P = (21 50) % P = 0.73 HLA-C mismatch 32 (±14) % 42 (30 59) % 33 (22 50) % P = (24 57) % P = (32 64) % P = 0.43 HLA-DRB1/DQB1 mismatch 42 (±14) % P = (10 28) % P = (32 58) % P = (16 39) % P = (30 57) % P = 0.56 HLA-DRB3/4 mismatch 46 (±21) % P = (30 71) % 16 (7 40) % P = (29 72) % P = (54 99) % P = /10 matched donor recipient pairs 29 (±29) % P = (1 51) % P = (15 74) % P = (2 70) % P = (6 70) % P = 0.13 Abbreviations: agvhd = acute graft versus host disease; cgvhd = chronic graft versus host disease; GVHD = graft-versus-host disease; TRM = transplant-related mortality Macmillan Publishers Limited Bone Marrow Transplantation (2015)

4 1204 culture assays. 30 Altogether, the lack of a significant impact of single DRB1/DQB1 mismatches may reflect adequate selection of low-risk disparities that are associated with lower immunogenicity, most likely owing to very similar peptide binding repertoire between specific HLA alleles. The multivariate model confirms the possible impact of HLA-DRB3/4 mismatching. This model was adjusted for diagnosis and EBMT risk score and stratified on transplant center, as there were significant differences among centers in outcome. The study has limited power to detect the impact of class II mismatches on outcome, which may serve as an alternative explanation for the lack of impact of class II mismatches. This contrasts, however, with the strong impact of class I mismatches in groups of comparable size. Analyzing these center differences is not part of the present work. The possible impact of HLA-DRB3/4 mismatches may be explained by chance, by a small immunogenetic impact of these differences, by concomitant DPB1 mismatches (92.6% of the 27 donors retrospectively typed were indeed DPB1 incompatible), but also by less conserved haplotypes associated with unfavourable non-hla polymorphisms. 7,21 A recent study by the German registry 25 showed that HLA 10/10 matched unrelated donor transplants had better results if the donor was from Germany than if the donor was from abroad, highlighting the issue that conservation of whole MHC haplotypes may have a role in outcome of unrelated donor transplantation. In this respect, we had previously reported a beneficial impact of common and frequent haplotypes on outcome, 21 an observation that was subsequently confirmed by another laboratory. 31 Although our experience of transplants with more than one mismatch is too limited to draw any conclusions, the current strategy of SBST to accept HLA 10/10 matched donors and singleallele or antigen mismatches for unrelated transplantation appears reasonable. HLA class I mismatches, whether HLA-A, HLA-B or HLA-C, are doubling mortality risks, and this has to be taken into account. Our data do not allow the conclusion that class II mismatches are without consequences because of nonrandomly accepted mismatches, but they reveal that the strategy to favor mismatches considered as nonimmunogenic has to be pursued and analyzed further. The finding of a possible impact of HLA-DRB3/4 mismatches strengthens our strategy to systematically include DRB3/4 typing in the algorithm and to favor DRB3/4-matched donors whenever a choice is possible. CONFLICT OF INTEREST The authors declare no conflict of interest. ACKNOWLEDGEMENTS This work was supported by grant number from the Swiss National Science Foundation. AUTHOR CONTRIBUTIONS JRP and JMT were responsible for the analysis. HB was responsible for the data management. US, YC, TG, DH, GN, MM, SM and GN contributed to writing and analysis. REFERENCES 1 Petersdorf EW. Optimal HLA matching in haematopoietic stem cell transplantation. Curr Opin Immunol 2008; 20: Tiercy J-M, Nicoloso de Faveri G, Passweg J, Schanz U, Seger R, Chalandon Y et al. The probability to identify a 10/10 HLA allele-matched unrelated donor is highly predictable. Bone Marrow Transplant 2007; 40: Gooley TA, Chien JW, Pergam SA, Hingorani S, Sorror ML, Boeckh M et al. Reduced mortality after allogeneic hematopoietic-cell transplantation. New Engl J Med 2010; 363: Gratwohl A, Baldomero H, Schwendener A, Rocha V, Apperley J, Frauendorfer K et al. The EBMT activity survey 2007 with focus on allogeneic HSCT for AML and novel cellular therapies. Bone Marrow Transplant 2009; 43: Hambach L, Spierings E, Goulmy E. Risk assessment in hematopoietic stem cell transplantation: minor histocompatibility antigens. Best Pract Res Clin Haematol 2007; 20: Dickinson AM. Non-HLA genetics and predicting outcome in HSCT. Int J Immunogenet 2008; 35: Petersdorf EW, Malkki M, Horowitz MM, Spellman SR, Haagenson MD, Wang T. Mapping MHC haplotype effects in unrelated donor hematopoietic cell transplantation. Blood 2013; 121: Shaw BE, Arguello R, Garcia-Sepulveda CA, Madrigal JA. The impact of HLA genotyping on survival following unrelated donor haematopoietic stem cell transplantation. Br J Haematol 2010; 150: Schlenk RF, Döhner K, Mack S, Stoppel M, Király F, Götze K et al. Prospective evaluation of allogeneic hematopoietic stem-cell transplantation from matched related and matched unrelated donors in younger adults with high-risk acute myeloid leukemia: German-Austrian trial AMLHD98A. J Clin Oncol 2010; 28: Sasazuki T, Juji T, Morishima Y, Kinukawa N, Kashiwabara H, Inoko H et al. Effect of matching of HLA class I HLA alleles on clinical outcome after transplantation of hematopoietic stem cells from an unrelated donor. New Engl J Med 1998; 339: Kanda Y, Kanda J, Atsuta Y, Kinukawa N, Kashiwabara H, Inoko H et al. Impact of a single human leucocyte antigen (HLA) allele mismatch on the outcome of unrelated bone marrow transplantation over two time periods. A retrospective analysis of 3003 patients from the HLA Working Group of the Japan Society for Blood and Marrow Transplantation. Br J Haematol 2013; 161: Fleischhauer K, Shaw BE, Gooley T, Malkki M, Bardy P, Bignon JD et al. International Histocompatibility Working Group in Hematopoietic Cell Transplantation. Effect of T-cell-epitope matching at HLA-DPB1 in recipients of unrelated-donor haemopoietic-cell transplantation: a retrospective study. Lancet Oncol 2012; 13: Flomenberg N, Baxter-Lowe LA, Confer D, Fernandez-Vina M, Filipovich A, Horowitz M 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: Loiseau P, Busson M, Balere ML, Dormoy A, Bignon JD, Gagne K et al. HLA association with hematopoietic stem cell transplantation outcome: the number of mismatches at HLA-A, -B, -C, -DRB1 or -DQB1 is strongly associated with overall survival. Biol Blood Marrow Transplant 2007; 13: Ludajic K, Balavarca Y, Bickeböller H, Pohlreich D, Kouba M, Dobrovolna M et al. Impact of HLA-DPB1 allelic and single amino acid mismatches on HSCT. Br J Haematol 2008; 142: Shaw BE, Marsh SG, Mayor NP, Russell NH, Madrigal JA. HLA-DPB1 matching status has significant implications for recipients of unrelated donor stem cell transplants. Blood 2006; 107: Shaw BE, Gooley TA, Malkki M, Madrigal JA, Begovich AB, Horowitz MM et al. The importance of HLA-DPB1 in unrelated donor hematopoietic cell transplantation. Blood 2007; 110: Lee SJ, Klein J, Haagenson M, Baxter-Lowe LA, Confer DL, Eapen M et al. High resolution donor-recipient HLA matching contributes to the success of unrelated donor marrow transplantation. Blood 2007; 110: Kawase T, Matsuo K, Kashiwase K, Inoko H, Saji H, Ogawa S et al. HLA mismatch combinations associated with decreased risk of relapse: implications for the molecular mechanisms. Blood 2009; 113: Shaw BE, Mayor NP, Russell NH, Apperley JF, Clark RE, Cornish J et al. Diverging effects of HLA-DPB1 matching status on outcome following unrelated donor transplantation depending on disease stage and the degree of matching for other HLA alleles. Leukemia 2010; 24: Bettens F, Passweg J, Schanz U, Chalandon Y, Heim D, Güngör T et al. Impact of HLA-DPB1 haplotypes on outcome of 10/10 matched unrelated hematopoietic stem cell donor transplants depends on MHC-linked microsatellite polymorphisms. Biol Blood Marrow Transplant 2012; 18: Fernández-Viña MA, Klein JP, Haagenson M, Spellman SR, Anasetti C, Noreen H et al. Multiple mismatches at the low expression HLA loci DP, DQ, and DRB3/4/5 associate with adverse outcomes in hematopoietic stem cell transplantation. Blood 2013; 121: Chalandon Y, Tiercy JM, Schanz U, Gungor T, Seger R, Halter J et al. Swiss Transplant Working Group for Blood and Marrow Transplantation (STABMT); Swiss National Donor Registry. Impact of high-resolution matching in allogeneic unrelated donor stem cell transplantation in Switzerland. Bone Marrow Transplant 2006; 37: Petersdorf EW, Malkki M, Gooley TA, Martin PJ, Guo Z. MHC haplotype matching for unrelated hematopoietic cell transplantation. PLoS Med 2007; 4: e8. Bone Marrow Transplantation (2015) Macmillan Publishers Limited

5 25 Fürst D, Müller C, Vucinic V, Bunjes D, Herr W, Gramatzki M et al. High-resolution HLA matching in hematopoietic stem cell transplantation: a retrospective collaborative analysis. Blood 2013; 122: Tiercy JM. Unrelated hematopoietic stem cell donor matching probability and search algorithm. Bone Marrow Res 2012; 2012: Gratwohl A, Stern M, Brand R, Apperley J, Baldomero H, de Witte T et al. The European Group for Blood and Marrow Transplantation and the European Leukemia Net. Risk score for outcome after allogeneic hematopoietic stem cell transplantation: a retrospective analysis. Cancer 2009; 115: Demotz S, Barbey C, Corradin G, Amoroso A, Lanzavecchia A. The set of naturally processed peptides displayed by DR molecules is tuned by polymorphism of residue 86. Eur J Immunol 1993; 23: Pasi A, Crocchiolo R, Bontempelli M, Carcassi C, Carella G, Crespiatico L et al. The conundrum of HLA-DRB1*14:01/*14:54 and HLA-DRB3*02:01/*02:02 mismatches in unrelated hematopoietic SCT. Bone Marrow Transplant 2011; 46: Tiercy JM, Morel C, Freidel AC, Zwahlen F, Gebuhrer L, Bétuel H et al. Selection of unrelated donors for bone marrow transplantation is improved by HLA class II genotyping with oligonucleotide hybridization. Proc Natl Acad Sci USA 1991; 88: Jöris MM, Lankester AC, von dem Borne PA, Kuball J, Bierings M, Cornelissen JJ et al. The impact of frequent HLA haplotypes in high linkage disequilibrium on donor search and clinical outcome after unrelated haematopoietic SCT. Bone Marrow Transplant 2013; 48: Macmillan Publishers Limited Bone Marrow Transplantation (2015)