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HLA-B leader and survivorship after HLA-mismatched unrelated donor transplantation.

Authors
  • Petersdorf, Effie W1, 2
  • Stevenson, Philip1
  • Bengtsson, Mats3
  • De Santis, Dianne4
  • Dubois, Valerie5
  • Gooley, Ted1
  • Horowitz, Mary6, 7
  • Hsu, Katharine8
  • Madrigal, J Alejandro9
  • Malkki, Mari1
  • McKallor, Caroline1
  • Morishima, Yasuo10
  • Oudshoorn, Machteld11, 12
  • Spellman, Stephen R13
  • Villard, Jean14
  • Carrington, Mary15, 16
  • 1 Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA.
  • 2 Department of Medicine, University of Washington, Seattle, WA.
  • 3 Department of Immunology, Genetics and Pathology, University of Uppsala, Uppsala, Sweden. , (Sweden)
  • 4 PathWest, Fiona Stanley Hospital, Perth, Australia. , (Australia)
  • 5 Etablissement Français du Sang Auvergne Rhône Alpes, Lyon, France. , (France)
  • 6 Center for International Blood and Marrow Transplant Research, Milwaukee, WI.
  • 7 Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, WI.
  • 8 Memorial Sloan Kettering Cancer Center, New York, NY.
  • 9 Anthony Nolan Research Institute, Royal Free Hospital, London, United Kingdom. , (United Kingdom)
  • 10 Aichi Medical University, Nagakute, Japan. , (Japan)
  • 11 Leiden University Medical Centre, Leiden, The Netherlands. , (Netherlands)
  • 12 Matchis Foundation, Leiden, The Netherlands. , (Netherlands)
  • 13 Center for International Blood and Marrow Transplant Research, Minneapolis, MN.
  • 14 University Hospital, Geneva, Switzerland. , (Switzerland)
  • 15 Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD; and.
  • 16 Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard, Cambridge, MA.
Type
Published Article
Journal
Blood
Publisher
American Society of Hematology
Publication Date
Jul 16, 2020
Volume
136
Issue
3
Pages
362–369
Identifiers
DOI: 10.1182/blood.2020005743
PMID: 32483623
Source
Medline
Language
English
License
Unknown

Abstract

Hematopoietic cell transplantation (HCT) from HLA-mismatched unrelated donors can cure life-threatening blood disorders, but its success is limited by graft-versus-host disease (GVHD). HLA-B leaders encode methionine (M) or threonine (T) at position 2 and give rise to TT, MT, or MM genotypes. The dimorphic HLA-B leader informs GVHD risk in HLA-B-mismatched HCT. If the leader influences outcome in other HLA-mismatched transplant settings, the success of HCT could be improved for future patients. We determined leader genotypes for 10 415 patients receiving a transplant between 1988 and 2016 from unrelated donors with one HLA-A, HLA-B, HLA-C, HLA-DRB1, or HLA-DQB1 mismatch. Multivariate regression methods were used to evaluate risks associated with patient leader genotype according to the mismatched HLA locus and with HLA-A, HLA-B, HLA-C, HLA-DRB1, or HLA-DQB1 mismatching according to patient leader genotype. The impact of the patient leader genotype on acute GVHD and mortality varied across different mismatched HLA loci. Nonrelapse mortality was higher among HLA-DQB1-mismatched MM patients compared with HLA-DQB1-mismatched TT patients (hazard ratio, 1.35; P = .01). Grades III to IV GVHD risk was higher among HLA-DRB1-mismatched MM or MT patients compared with HLA-DRB1-mismatched TT patients (odds ratio, 2.52 and 1.51, respectively). Patients tolerated a single HLA-DQB1 mismatch better than mismatches at other loci. Outcome after HLA-mismatched transplantation depends on the HLA-B leader dimorphism and the mismatched HLA locus. The patient's leader variant provides new information on the limits of HLA mismatching. The success of HLA-mismatched unrelated transplantation might be enhanced through the judicious selection of mismatched donors for a patient's leader genotype.

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