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
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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. / 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.
In: FRONT IMMUNOL, Vol. 11, 584520, 2020.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - 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
AU - Schetelig, Johannes
AU - Baldauf, Henning
AU - Koster, Linda
AU - Kuxhausen, Michelle
AU - Heidenreich, Falk
AU - de Wreede, Liesbeth C
AU - Spellman, Stephen
AU - van Gelder, Michel
AU - Bruno, Benedetto
AU - Onida, Francesco
AU - Lange, Vinzenz
AU - Massalski, Carolin
AU - Potter, Victoria
AU - Ljungman, Per
AU - Schaap, Nicolaas
AU - Hayden, Patrick
AU - Lee, Stephanie J
AU - Kröger, Nicolaus
AU - Hsu, Kathy
AU - Schmidt, Alexander H
AU - Yakoub-Agha, Ibrahim
AU - Robin, Marie
N1 - 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.
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
KW - Adolescent
KW - Adult
KW - Aged
KW - Aged, 80 and over
KW - Donor Selection/methods
KW - Female
KW - Genotype
KW - Graft vs Host Disease/genetics
KW - Haplotypes
KW - Hematopoietic Stem Cell Transplantation/methods
KW - Humans
KW - Leukemia, Myeloid, Acute/genetics
KW - Male
KW - Middle Aged
KW - Myelodysplastic Syndromes/genetics
KW - Receptors, KIR/genetics
KW - Transplantation Conditioning/methods
KW - Transplantation, Homologous/methods
KW - Unrelated Donors
KW - Young Adult
U2 - 10.3389/fimmu.2020.584520
DO - 10.3389/fimmu.2020.584520
M3 - SCORING: Journal article
C2 - 33542712
VL - 11
JO - FRONT IMMUNOL
JF - FRONT IMMUNOL
SN - 1664-3224
M1 - 584520
ER -