Journal
BLOOD ADVANCES
Volume 2, Issue 14, Pages 1773-1783Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/bloodadvances.2018019620
Keywords
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Categories
Funding
- Deutsche Jose Carreras Leukamie Stiftung [DJCLS R 15/02]
- Joseph Senker Stiftung
- Public Health Service [5U24-CA076518]
- National Institutes of Health National Cancer Institute
- National Institutes of Health National Heart, Lung and Blood Institute [5U10HL069294]
- Office of Naval Research [N00014-15-1-0848, N00014-16-1-2020]
- Alexion
- Amgen, Inc.
- 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
- Leukemia AMP
- Lymphoma Society
- Medac, GmbH
- MedImmune
- 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
- Wellpoint, Inc.
- National Cancer Institute [5U10HL069294]
- Health Resources and Services Administration (Department of Health and Human Services) [CHHSH250201200016C]
- National Institute of Allergy and Infectious Diseases
- National Heart, Lung and Blood Institute
- NATIONAL CANCER INSTITUTE [U24CA076518] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [U10HL069294] Funding Source: NIH RePORTER
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In silico prediction of high-risk donor-recipient HLA mismatches after unrelated donor (UD) hematopoietic cell transplantation (HCT) is an attractive, yet elusive, objective. Nonpermissive T-cell epitope (TCE) group mismatches were defined by alloreactive T-cell cross-reactivity for 52/80 HLA-DPB1 alleles (TCE-X). More recently, a numerical functional distance (FD) scoring system for in silico prediction of TCE groups based on the median impact of exon 2-encoded amino acid polymorphism on T-cell alloreactivity was developed for all DPB1 alleles (TCE-FD), including the 28/80 common alleles not assigned by TCE-X. We compared clinical outcome associations of nonpermissive DPB1 mismatches defined by TCE-X or TCE-FD in 8/8 HLA-matched UD-HCT for acute leukemia, myelodysplastic syndrome, and chronic myelogenous leukemia between 1999 and 2011 (N=2730). Concordance between the 2 models was 92.3%, with most differences arising from DPB1*06:01 and DPB1*19:01 being differently assigned by TCE-X and TCE-FD. In both models, nonpermissive mismatches were associated with reduced overall survival (hazard ratio [HR], 1.15, P<.006 and HR, 1.12, P<.03), increased transplant-related mortality (HR, 1.31, P<.001 and HR, 1.26, P<.001) as well as acute (HR, 1.16, P<.02 and HR, 1.22, P<.001) and chronic (HR, 1.20, P<.003 and HR, 1.22, P<.001) graft-versus-host disease (GVHD). We show that in silico prediction of nonpermissive DPB1 mismatches significantly associated with major transplant outcomes is feasible for any DPB1 allele with known exon 2 sequence based on experimentally elaborated FD scores. This proof-of-principle observation opens new avenues for developing HLA risk-prediction models in HCT and has practical implications for UD searches.
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