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Haplotype Motif-Based Models for KIR-Genotype Informed Selection of Hematopoietic Cell Donors Fail to Predict Outcome of Patients With Myelodysplastic Syndromes or Secondary Acute Myeloid Leukemia

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 class...

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Autores principales: Schetelig, Johannes, Baldauf, Henning, Koster, Linda, Kuxhausen, Michelle, Heidenreich, Falk, de Wreede, Liesbeth C., Spellman, Stephen, van Gelder, Michel, Bruno, Benedetto, Onida, Francesco, Lange, Vinzenz, Massalski, Carolin, Potter, Victoria, Ljungman, Per, Schaap, Nicolaas, Hayden, Patrick, Lee, Stephanie J., Kröger, Nicolaus, Hsu, Kathy, Schmidt, Alexander H., Yakoub-Agha, Ibrahim, Robin, Marie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851088/
https://www.ncbi.nlm.nih.gov/pubmed/33542712
http://dx.doi.org/10.3389/fimmu.2020.584520
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author Schetelig, Johannes
Baldauf, Henning
Koster, Linda
Kuxhausen, Michelle
Heidenreich, Falk
de Wreede, Liesbeth C.
Spellman, Stephen
van Gelder, Michel
Bruno, Benedetto
Onida, Francesco
Lange, Vinzenz
Massalski, Carolin
Potter, Victoria
Ljungman, Per
Schaap, Nicolaas
Hayden, Patrick
Lee, Stephanie J.
Kröger, Nicolaus
Hsu, Kathy
Schmidt, Alexander H.
Yakoub-Agha, Ibrahim
Robin, Marie
author_facet Schetelig, Johannes
Baldauf, Henning
Koster, Linda
Kuxhausen, Michelle
Heidenreich, Falk
de Wreede, Liesbeth C.
Spellman, Stephen
van Gelder, Michel
Bruno, Benedetto
Onida, Francesco
Lange, Vinzenz
Massalski, Carolin
Potter, Victoria
Ljungman, Per
Schaap, Nicolaas
Hayden, Patrick
Lee, Stephanie J.
Kröger, Nicolaus
Hsu, Kathy
Schmidt, Alexander H.
Yakoub-Agha, Ibrahim
Robin, Marie
author_sort Schetelig, Johannes
collection PubMed
description 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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spelling pubmed-78510882021-02-03 Haplotype Motif-Based Models for KIR-Genotype Informed Selection of Hematopoietic Cell Donors Fail to Predict Outcome of Patients With Myelodysplastic Syndromes or Secondary Acute Myeloid Leukemia Schetelig, Johannes Baldauf, Henning Koster, Linda Kuxhausen, Michelle Heidenreich, Falk de Wreede, Liesbeth C. Spellman, Stephen van Gelder, Michel Bruno, Benedetto Onida, Francesco Lange, Vinzenz Massalski, Carolin Potter, Victoria Ljungman, Per Schaap, Nicolaas Hayden, Patrick Lee, Stephanie J. Kröger, Nicolaus Hsu, Kathy Schmidt, Alexander H. Yakoub-Agha, Ibrahim Robin, Marie Front Immunol Immunology 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. Frontiers Media S.A. 2021-01-19 /pmc/articles/PMC7851088/ /pubmed/33542712 http://dx.doi.org/10.3389/fimmu.2020.584520 Text en Copyright © 2021 Schetelig, Baldauf, Koster, Kuxhausen, Heidenreich, de Wreede, Spellman, van Gelder, Bruno, Onida, Lange, Massalski, Potter, Ljungman, Schaap, Hayden, Lee, Kröger, Hsu, Schmidt, Yakoub-Agha and Robin https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Schetelig, Johannes
Baldauf, Henning
Koster, Linda
Kuxhausen, Michelle
Heidenreich, Falk
de Wreede, Liesbeth C.
Spellman, Stephen
van Gelder, Michel
Bruno, Benedetto
Onida, Francesco
Lange, Vinzenz
Massalski, Carolin
Potter, Victoria
Ljungman, Per
Schaap, Nicolaas
Hayden, Patrick
Lee, Stephanie J.
Kröger, Nicolaus
Hsu, Kathy
Schmidt, Alexander H.
Yakoub-Agha, Ibrahim
Robin, Marie
Haplotype Motif-Based Models for KIR-Genotype Informed Selection of Hematopoietic Cell Donors Fail to Predict Outcome of Patients With Myelodysplastic Syndromes or Secondary Acute Myeloid Leukemia
title Haplotype Motif-Based Models for KIR-Genotype Informed Selection of Hematopoietic Cell Donors Fail to Predict Outcome of Patients With Myelodysplastic Syndromes or Secondary Acute Myeloid Leukemia
title_full Haplotype Motif-Based Models for KIR-Genotype Informed Selection of Hematopoietic Cell Donors Fail to Predict Outcome of Patients With Myelodysplastic Syndromes or Secondary Acute Myeloid Leukemia
title_fullStr Haplotype Motif-Based Models for KIR-Genotype Informed Selection of Hematopoietic Cell Donors Fail to Predict Outcome of Patients With Myelodysplastic Syndromes or Secondary Acute Myeloid Leukemia
title_full_unstemmed Haplotype Motif-Based Models for KIR-Genotype Informed Selection of Hematopoietic Cell Donors Fail to Predict Outcome of Patients With Myelodysplastic Syndromes or Secondary Acute Myeloid Leukemia
title_short Haplotype Motif-Based Models for KIR-Genotype Informed Selection of Hematopoietic Cell Donors Fail to Predict Outcome of Patients With Myelodysplastic Syndromes or Secondary Acute Myeloid Leukemia
title_sort haplotype motif-based models for kir-genotype informed selection of hematopoietic cell donors fail to predict outcome of patients with myelodysplastic syndromes or secondary acute myeloid leukemia
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851088/
https://www.ncbi.nlm.nih.gov/pubmed/33542712
http://dx.doi.org/10.3389/fimmu.2020.584520
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