Journal
FRONTIERS IN IMMUNOLOGY
Volume 11, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2020.584520
Keywords
KIR; KIR2DS1; KIR3DL1; hematopoietic stem cell transplantation; donor selection; unrelated donor
Categories
Funding
- DKMS gGmbH
- Public Health Service from the National Cancer Institute (NCI) [U24CA076518]
- National Heart, Lung and Blood Institute (NHLBI) [U24HL138660, OT3HL147741, R21HL140314, U01HL128568]
- National Institute of Allergy and Infectious Diseases (NIAID)
- NCI [U24HL138660]
- Health Resources and Services Administration (HRSA) [HHSH250201700006C, SC1MC31881-01-00, HHSH250201700007C]
- Office of Naval Research [N00014-18-1-2850, N00014-18-1-2888, N00014-20-1-2705]
- BARDA
- Be the Match Foundation
- Boston Children's Hospital
- Dana Farber
- Japan Hematopoietic Cell Transplantation Data Center
- St. Baldrick's Foundation
- National Marrow Donor Program
- Medical College of Wisconsin
- AbbVie
- Actinium Pharmaceuticals, Inc.
- Adaptive Biotechnologies
- Adienne SA
- Allovir, Inc.
- Amgen, Inc.
- Anthem, Inc.
- Astellas Pharma US
- AstraZeneca
- Atara Biotherapeutics, Inc.
- bluebird bio, Inc.
- Bristol Myers Squibb Co.
- Celgene Corp.
- Chimerix, Inc.
- CSL Behring
- CytoSen Therapeutics, Inc.
- Daiichi Sankyo Co., Ltd.
- Gamida-Cell, Ltd.
- Genzyme
- GlaxoSmithKline (GSK)
- HistoGenetics, Inc.
- Incyte Corporation
- Janssen Biotech, Inc.
- Janssen Pharmaceuticals, Inc.
- Janssen/Johnson Johnson
- Jazz Pharmaceuticals, Inc.
- Kiadis Pharma
- Kite Pharma
- Kyowa Kirin
- Legend Biotech
- Magenta Therapeutics
- Mallinckrodt LLC
- Medac GmbH
- Merck Company, Inc.
- Merck Sharp Dohme Corp.
- Mesoblast
- Millennium
- Takeda Oncology Co.
- Miltenyi Biotec, Inc.
- Novartis Oncology
- Novartis Pharmaceuticals Corporation
- Omeros Corporation
- Oncoimmune, Inc.
- Orca Biosystems, Inc.
- Pfizer, Inc.
- Phamacyclics, LLC
- Regeneron Pharmaceuticals, Inc.
- REGiMMUNE Corp.
- Sanofi Genzyme
- Seattle Genetics
- Sobi, Inc.
- Takeda Oncology
- Takeda Pharma
- Terumo BCT
- Viracor Eurofins
- Xenikos BV
- [P01CA111412]
- [R01CA152108]
- [R01CA215134]
- [R01CA218285]
- [R01CA231141]
- [R01HL126589]
- [R01AI128775]
- [R01HL129472]
- [R01HL130388]
- [R01HL131731]
- [U01AI069197]
- [U01AI126612]
Ask authors/readers for more resources
This study aimed to validate models using KIR genes for donor selection in MDS or sAML patients to reduce the risk of relapse after HCT, but the results show that current models cannot consistently predict overall survival and relapse rates. Further research integrating cutting edge knowledge on KIR genetics and NK-cell biology is warranted for future studies.
Results from registry studies suggest that harnessing Natural Killer (NK) cell reactivity mediated through Killer cell Immunoglobulin-like Receptors (KIR) could reduce the risk of relapse after allogeneic Hematopoietic Cell Transplantation (HCT). Several competing models have been developed to classify donors as KIR-advantageous or disadvantageous. Basically, these models differ by grouping donors based on distinct KIR-KIR-ligand combinations or by haplotype motif assignment. This study aimed to validate different models for unrelated donor selection for patients with Myelodysplatic Syndromes (MDS) or secondary Acute Myeloid Leukemia (sAML). In a joint retrospective study of the European Society for Blood and Marrow Transplantation (EBMT) and the Center for International Blood and Marrow Transplant Research (CIBMTR) registry data from 1704 patients with secondary AML or MDS were analysed. The cohort consisted mainly of older patients (median age 61 years) with high risk disease who had received chemotherapy-based reduced intensity conditioning and anti-thymocyte globulin prior to allogeneic HCT from well-matched unrelated stem cell donors. The impact of the predictors on Overall Survival (OS) and relapse incidence was tested in Cox regression models adjusted for patient age, a modified disease risk index, performance status, donor age, HLA-match, sex-match, CMV-match, conditioning intensity, type of T-cell depletion and graft type. KIR genes were typed using high-resolution amplicon-based next generation sequencing. In univariable and multivariable analyses none of the models predicted OS and the risk of relapse consistently. Our results do not support the hypothesis that optimizing NK-mediated alloreactivity is possible by KIR-genotype informed selection of HLA-matched unrelated donors. However, in the context of allogeneic transplantation, NK-cell biology is complex and only partly understood. KIR-genes are highly diverse and current assignment of haplotype motifs based on the presence or absence of selected KIR genes is over-simplistic. As a consequence, further research is highly warranted and should integrate cutting edge knowledge on KIR genetics, and NK-cell biology into future studies focused on homogeneous groups of patients and treatment modalities.
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