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Histocompatibility and Donor Selection Issues

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

Bone Marrow Transplantation volume 52, pages 1280–1287 (2017)Cite this article

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Abstract

In 8/8 HLA-matched unrelated donor (UD) hematopoietic cell transplants (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 with those between alleles from the same TCE group (permissive mismatches); however, the relevance of mismatch directionality, that is (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 with 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 (hazard ratio (HR) 1.32, P=0.001 vs HR 1.28, P=0.005 and HR 1.34, P=0.046), compared with 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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Acknowledgements

This work was supported by grants from the Deutsche José Carreras Leukämie Stiftung (DJCLS R 15/02) and from the Joseph Senker Stiftung to K.F. The CIBMTR is supported by Public Health Service Grant/Cooperative Agreement 5U24-CA076518 from the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI) and the National Institute of Allergy and Infectious Diseases (NIAID); a Grant/Cooperative Agreement 5U10HL069294 from NHLBI and NCI; a contract HHSH250201200016C with Health Resources and Services Administration (HRSA/DHHS); two Grants N00014-15-1-0848 and N00014-16-1-2020 from the Office of Naval Research; and grants from Alexion; *Amgen, Inc.; Anonymous donation to the Medical College of Wisconsin; Astellas Pharma US; AstraZeneca; Be the Match Foundation; *Bluebird Bio, Inc.; *Bristol Myers Squibb Oncology; *Celgene Corporation; Cellular Dynamics International, Inc.; *Chimerix, Inc.; Fred Hutchinson Cancer Research Center; Gamida Cell Ltd.; Genentech, Inc.; Genzyme Corporation; *Gilead Sciences, Inc.; Health Research, Inc. Roswell Park Cancer Institute; HistoGenetics, Inc.; Incyte Corporation; Janssen Scientific Affairs, LLC; *Jazz Pharmaceuticals, Inc.; Jeff Gordon Children’s Foundation; The Leukemia & Lymphoma Society; Medac, GmbH; MedImmune; The Medical College of Wisconsin; *Merck & Co, Inc.; Mesoblast; MesoScale Diagnostics, Inc.; *Miltenyi Biotec, Inc.; National Marrow Donor Program; Neovii Biotech NA, Inc.; Novartis Pharmaceuticals Corporation; Onyx Pharmaceuticals; Optum Healthcare Solutions, Inc.; Otsuka America Pharmaceutical, Inc.; Otsuka Pharmaceutical Co, Ltd.–Japan; PCORI; Perkin Elmer, Inc.; Pfizer, Inc; *Sanofi US; *Seattle Genetics; *Spectrum Pharmaceuticals, Inc.; St. Baldrick’s Foundation; *Sunesis Pharmaceuticals, Inc.; Swedish Orphan Biovitrum, Inc.; Takeda Oncology; Telomere Diagnostics, Inc.; University of Minnesota; and *Wellpoint, Inc. The views expressed in this article do not reflect the official policy or position of the National Institute of Health, the Department of the Navy, the Department of Defense, Health Resources and Services Administration (HRSA) or any other agency of the U.S. Government (*Corporate Members).

Author contributions

KF designed and supervised the study and wrote the manuscript. LZ performed the analysis of experimental data. PC supervised the analysis of experimental data and the HLA-DPB1 assignments of clinical data. MO performed and provided the experimental data. KWA and HW performed statistical analyses. KF, SRS, SJL and KWA interpreted the statistical analysis results. KF, KWA, HW, LZ, PC, CM, MV, BES, JP, MO, SJL and SRS participated in the writing and editing of the manuscript.

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Authors and Affiliations

  1. Institute for Experimental Cellular Therapy, University Hospital, Essen, Essen, Germany

    K Fleischhauer & P Crivello

  2. Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, Milwaukee, WI, USA

    K W Ahn, H L Wang, B E Shaw & S J Lee

  3. Unit of Immunogenetics, Leukemia Genomics and Immunobiology, San Raffaele Scientific Institute, Milan, Italy

    L Zito

  4. ZKRD-Zentrales Knochenmarkspender-Register Deutschland, Ulm, Germany

    C Müller

  5. Pediatric BMT, University of Minnesota, Minneapolis, MN, USA

    M Verneris

  6. Department of Blood and Marrow Transplantation, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA

    J Pidala

  7. Department of Immunohematology and Blood Transfusion, Matchis Foundation, Leiden University Medical Center, Leiden, The Netherlands

    M Oudshorn

  8. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    S J Lee

  9. CIBMTR (Center for International Blood and Marrow Transplant Research) National Marrow Donor Program/Be the Match, Minneapolis, MN, USA

    S R Spellman

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Correspondence to K Fleischhauer.

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Fleischhauer, K., Ahn, K., Wang, H. et al. 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. Bone Marrow Transplant 52, 1280–1287 (2017). https://doi.org/10.1038/bmt.2017.96

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