A comparative reference study for the validation of <scp>HLA</scp>‐matching algorithms in the search for allogeneic hematopoietic stem cell donors and cord blood units

Bochtler, Werner; Gragert, Loren; Patel, Zeel; Robinson, James T.; Steiner, David; Hofmann, Jan A.; Pingel, Julia; Baouz, A.; Melis, A; Schneider, J; Eberhard, Hans-Peter; Oudshoorn, Machteld; Marsh, Steven G.E.; Maiers, Martin; Müller, Carlheinz

doi:10.1111/tan.12817

Cited by 30 publications

(23 citation statements)

References 27 publications

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“…Several studies have demonstrated the direct link between haplotype frequencies in different HSC registries and the probabilities of identifying matched donors which led to the development of various software programs computing the likelihoods to identify donors with suitable matching criteria . With the increasing diversity of HLA haplotypes across Europe, the need for continuing growth of small/intermediate size registries has become more obvious .…”

Section: Discussionmentioning

confidence: 99%

A study of selected hematopoietic stem cell donors provided by an intermediate size registry

Nicoloso

Kürsteiner

Bussmann

et al. 2019

European J of Haematology

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Objective Planning new hematopoietic stem cell (HSC) donor recruitment strategies requires a sound understanding of the factors underlying donor selection, especially considering HLA‐matching criteria. Method A total of 182 consecutive workups of Swiss donors performed from 2014 to 2017 were analyzed for HLA match level, locus disparities, number of potentially 10/10 matched donors in the international database, donor ranking on the lists, donor date of registration, age, ABO, CMV, gender matching, patient genotype frequency, and country performing the search. Results Matching status of the selected donors was 10/10 for 38.5%, 10‐12/12 for 35.1%, and 8‐9/10 for 26.4% donors, without differences in average donor age in the three categories. HLA‐A and ‐C mismatches were most frequent and ‐DRB1 very rare. 8.2% patients were matched for HLA‐DPB1 (12/12). ABO matching was 46.3%, and CMV matching was 59.1%. Based on “HaploStat”‐derived genotype frequencies, 50.3% patients belonged to the “good,” 38.5% to the “fair,” and 11.2% to the “poor” search prognosis categories. 37.9% of transplants were gender‐mismatched, and 42.3% of donors were female. Conclusion HLA typing quality (high resolution, all loci typed), great diversity of haplotypes and donor age are main factors impacting the selection of Swiss donors, while gender and ABO matching seem to be of secondary importance.

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Section: Discussionmentioning

confidence: 99%

A study of selected hematopoietic stem cell donors provided by an intermediate size registry

Nicoloso

Kürsteiner

Bussmann

et al. 2019

European J of Haematology

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“…The 6-locus HLA-A, -B, -C, -DRB1, -DQB1, -DPB1 high resolution haplotype frequencies were estimated using the German National Bone Marrow Registry haplotype frequency estimation algorithm, which is based on the Expectation-Maximization (EM) method, and has successfully completed the matching validation of the World Marrow Donor Association [37].…”

Section: Haplotype and Allele Frequency Estimationsmentioning

confidence: 99%

Extended HLA Haplotypes and Their Impact on DPB1 Matching of Unrelated Hematologic Stem Cell Transplant Donors

Linjama

Räther

Ritari

et al. 2019

Biology of Blood and Marrow Transplantation

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Although HLA-DPB1 has long been considered of lesser importance in the selection of an unrelated donor (URD) hematologic stem cell transplantation, currently in many instances the DPB1 type of the donor is relevant or even critical. At present, however, only a minority of registry donors are DPB1 typed. It is also unclear to what extent the DPB1 alleles are linked to the 5-locus HLA-A-, B-, C-, DRB1,-DQB1 haplotypes. We sought to study whether there is such a linkage by using donors in the Finnish Stem Cell Registry as the study population. The 6-locus HLA-A,-B,-C,-DRB1,-DQB1,-DPB1 haplotype frequencies were estimated from a group of 43,365 Finnish registry donors using the German National Bone Marrow Registry algorithm. Five-locus haplotype (HLA-A,-B,-C,-DRB1,-DQB1) and HLA-DPB1 allele frequencies were calculated as marginal frequencies of the estimated 6-locus haplotype frequencies. The Finnish average frequency of individual DPB1 alleles was compared with their respective frequencies in association with individual 5-locus HLA haplotypes (haplotype-specific frequencies). Finally, the probability of DPB1 matching in 10/10 matched URD transplants was assessed. Haplotype-specific DPB1 frequencies differed significantly from the average DPB1 frequencies in 81 of 100 most frequent Finnish 5-locus HLA haplotypes, including some infrequent DPB1 alleles that were associated almost exclusively with certain individual 5-locus haplotypes. Five-locus haplotypes that are enriched in Finland but rare among other Europeans carried stronger DPB1 associations than haplotypes that are frequent European-wide. Finally, 10/10 matched transplants from domestic registry donors were significantly more likely to also be DPB1 matched than those from foreign donors. The results indicate an extension of linkage disequilibrium in the MHC complex in the Finnish population. With continuing upfront DPB1 typing of registry donors, it will be possible to perform similar extended 6-locus haplotype frequency estimations also in other registries. The associations are likely to be population specific but may be weaker in more heterogeneous populations. In the future the results might be used to predict the probability of DPB1 match or permissive/ nonpermissive DPB1 mismatch for non-DPB1 typed donors in registry donor searches.

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“…HLA-DPB1 mismatches between alleles from different TCE groups (non-permissive TCE mismatches) elicit stronger alloreactive T-cell responses in vitro 13 and are associated with increased risks of adverse clinical outcome 8–10 than those between alleles from the same TCE group (permissive TCE mismatches). The TCE matching algorithm has recently been incorporated in unrelated donor search tools provided to clinicians by Stem Cell Donor Registries in the United States (HapLogic™; https://bethematch.org) and Germany (Optimatch®; www.zkrd.de) 14, 15 , and is also freely available through the IMGT/HLA database (www.ebi.ac.uk/ipd/imgt/hla) 16 . Non-permissive TCE mismatches in GvH or HvG direction have been consistently found to be associated with similar hazards of acute GvHD and mortality in independent studies 9–10 .…”

Section: Introductionmentioning

confidence: 99%

Directionality of non-permissive HLA-DPB1 T-cell epitope group mismatches does not improve clinical risk stratification in 8/8 matched unrelated donor hematopoietic cell transplantation

Fleischhauer

Ahn

Wang

et al. 2017

Bone Marrow Transplant

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In 8/8 HLA-matched unrelated donor (UD) hematopoietic cell transplantation (HCT), HLA-DPB1 mismatches between alleles from different T-cell epitope (TCE) groups (non-permissive mismatches) are associated with significantly higher risks of mortality compared to those between alleles from the same TCE group (permissive mismatches); however, the relevance of mismatch directionality (host vs graft [uni-directional HvG], graft vs host [uni-directional GvH] or both [bi-directional]) in the non-permissive setting is unknown. We show here significantly higher in vitro relative responses (RR) to bi-directional mismatches compared to uni-directional HvG or GvH mismatches in a total of 420 one-way mixed lymphocyte reactions between 10/10 matched pairs (RR 27.5 vs 7.5 vs 15.5, respectively, p<0.001). However, in 3281 8/8 matched UD HCT for leukemia or myelodysplastic syndrome, the hazards of transplant-related mortality (TRM) were similar for uni-directional HvG or GvH mismatches and bi-directional mismatches (HR 1.32, p=0.001 vs HR 1.28, p=0.005 and HR 1.34, p=0.046), compared to permissive mismatches. Similar results were observed for overall survival. No statistical differences between the uni- and the bi-directional non-permissive groups were detected in pairwise comparisons for any of the outcomes tested. We conclude that consideration of directionality does not improve risk stratification by non-permissive HLA-DPB1 TCE mismatches in UD searches.

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A comparative reference study for the validation of HLA‐matching algorithms in the search for allogeneic hematopoietic stem cell donors and cord blood units

Cited by 30 publications

References 27 publications

A study of selected hematopoietic stem cell donors provided by an intermediate size registry

A study of selected hematopoietic stem cell donors provided by an intermediate size registry

Extended HLA Haplotypes and Their Impact on DPB1 Matching of Unrelated Hematologic Stem Cell Transplant Donors

Directionality of non-permissive HLA-DPB1 T-cell epitope group mismatches does not improve clinical risk stratification in 8/8 matched unrelated donor hematopoietic cell transplantation

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