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AuthorTsamadou, Chrysanthidc.contributor.author
Date of accession2020-10-07T10:52:27Zdc.date.accessioned
Available in OPARU since2020-10-07T10:52:27Zdc.date.available
Year of creation2019dc.date.created
Date of first publication2020-10-07dc.date.issued
AbstractMore than 50 years after its first implementation for the treatment of acute leukemia, allogeneic hematopoietic stem cell transplantation (HSCT) is still considered the only therapeutic option with life-long curative potential. Despite the undeniable progress made, HSCT remains a high risk treatment even in the optimal setting of 10/10 Human Leukocyte Antigen (HLA) compatibility between recipient and donor. In the search of immunogenetic factors beyond classical HLA antigens possibly impacting HSCT outcome, a limited number of studies have investigated the role of HLA-E in HSCT outcome. HLA-E is a ubiquitously transcribed, non-classical Major Histocompatibility Complex (MHC) Ib molecule with a multifaceted yet not fully understood role in both innate and adaptive immunity. Aim of this study was to investigate for the first time on such a large scale the effect of HLA-E polymorphism on HSCT outcome in a 10/10 HLA matched unrelated acute leukemia setting analyzing data from two large independent cohorts. The two cohorts (German cohort n=509, CIBMTR (Center for International Blood and Marrow Transplant Research) cohort n=1840) analyzed within this study consisted of adult acute leukemia patients receiving their first 10/10 HLA matched unrelated graft between 2000 and 2015. Both recipients and donors were HLA-E genotyped by Sanger and Next Generation Sequencing (NGS) using in-house kits in our laboratory in Ulm. Overall survival (OS), disease free survival (DFS), relapse (RI), transplant-related mortality (TRM), acute GvHD (aGvHD) and chronic GvHD (cGvHD) were evaluated; p<0.05 and p< 0.01 were considered significant in the German and CIBMTR cohort analysis, respectively. The effect of patient and donor HLA-E genotype as well as of patient/donor HLA-E match grade were assessed using univariate Kaplan-Meier (KM), multivariate Cox regression, and competing risks analyses in both cohorts. In the CIBMTR cohort the joint effect of donor/recipient (D/R) HLA-E genotype was additionally explored through a 4-level analysis of D/R HLA-E*01:03 homozygous vs other. The HLA-E allele frequencies as well as the relatively high rate of HLA-E discrepant transplant pairs (>32%) observed in both cohorts were in accordance with previously reported data. Regarding the effect of HLA-E polymorphism on HSCT outcome, the German cohort analysis revealed a significant correlation between HLA-E mismatch and improved HSCT outcome mainly in advanced disease patients. Specifically, patients transplanted by HLA-E mismatched donors exhibited significantly better OS and DFS rates due to lower TRM. The CIBMTR cohort analysis did not confirm this favorable effect, as HLA-E match status between recipient and donor did not have any impact on any outcome endpoint. With respect to the effect of recipient and/or donor HLA-E genotype on HSCT outcome, both cohort analyses identified the HLA-E*01:03/01:03 as an unfavorable prognostic factor. The results of the CIBMTR analysis as to this finding were significantly more enlightening indicating that the HLA-E*01:03/01:03 negative effect is mainly donor driven, with the patient HLA-E genotype effect being only weakly synergistic. Specifically, donor HLA-E*01:03/01:03 genotype was found to associate with significantly lower DFS, apparently due to higher relapse incidence rate. This study is the largest to date investigating the effect of HLA-E polymorphism on HSCT outcome. The main conclusions drawn are that: HLA-E matching between patients and donors in the setting of unrelated HSCT for acute leukemia confers no advantage to outcome; HLA-E incompatibility between patients and donors may improve unrelated HSCT outcome in a subset of advanced disease patients receiving anti-thymocyte globulin and; avoidance of HLA-E*01:03/01:03 donors may improve DFS prognostics in patients in complete remission undergoing first matched unrelated HSCT for acute leukemia. Although no definitive conclusions can be drawn before molecular-based studies shed light on the mechanisms implicated, these observations certainly set the basis for future consideration of HLA-E as relevant clinical prognostic factor in a matched unrelated HSCT setting for acute leukemia patients.dc.description.abstract
Languageen_USdc.language.iso
PublisherUniversität Ulmdc.publisher
LicenseCC BY 4.0 Internationaldc.rights
Link to license texthttps://creativecommons.org/licenses/by/4.0/dc.rights.uri
KeywordHLA-Edc.subject
KeywordAcute Leukemiadc.subject
KeywordMatched unrelated HSCTdc.subject
Dewey Decimal GroupDDC 610 / Medicine & healthdc.subject.ddc
MeSHHLA antigensdc.subject.mesh
MeSHHematopoietic stem cell transplantationdc.subject.mesh
TitleThe role of HLA-E polymorphism in the outcome of unrelated hematopoietic stem cell transplantation : retrospective analysis of two large independent acute leukemia cohortsdc.title
Resource typeDissertationdc.type
Date of acceptance2020-07-31dcterms.dateAccepted
RefereeSchrezenmeier, Hubertdc.contributor.referee
RefereeBunjes, Donalddc.contributor.referee
DOIhttp://dx.doi.org/10.18725/OPARU-33228dc.identifier.doi
PPN1735241288dc.identifier.ppn
URNhttp://nbn-resolving.de/urn:nbn:de:bsz:289-oparu-33290-6dc.identifier.urn
GNDAkute Leukämiedc.subject.gnd
GNDPeriphere Stammzellentransplantationdc.subject.gnd
FacultyMedizinische Fakultätuulm.affiliationGeneral
InstitutionUKU. Institut für Transfusionsmedizinuulm.affiliationSpecific
InstitutionUKU. Klinik für Innere Medizin IIIuulm.affiliationSpecific
Grantor of degreeMedizinische Fakultätuulm.thesisGrantor
DCMI TypeTextuulm.typeDCMI
CategoryPublikationenuulm.category
Bibliographyuulmuulm.bibliographie


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