Killer Immunoglobulin-Like Receptor-Ligand Interactions Predict Clinical Outcomes following Unrelated Donor Transplantations

Krieger, Elizabeth; Sabo, Roy; Moezzi, Sanauz; Cain, Caitlin J.; Roberts, Catherine; Kimball, Pamela; Chesney, Alden; McCarty, John M.; Keating, Armand; Romee, Rizwan; Wiedl, Christina M.; Qayyum, Rehan; Toor, Amir A.

doi:10.1016/j.bbmt.2019.10.016

Cited by 13 publications

(27 citation statements)

References 43 publications

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“…The score proposed by Krieger et al. integrates information on potential inhibitory KIR-ligand interactions and activating KIR-ligand interactions ( 25 ). Neither the simple score nor the weighted score predicted the risk of relapse or EFS in our cohort.…”

Section: Resultsmentioning

confidence: 99%

“…The score developed by Krieger et al. integrates information on inhibitory and activating KIR-ligand interactions ( 25 ). Two versions exist, a non-weighted version which incorporates the inhibitory missing KIR-ligand Score (IM-KIR Score) with assigned scores per interaction, and a weighted version (w-KIR Score).…”

Section: Methodsmentioning

confidence: 99%

“…Two versions exist, a non-weighted version which incorporates the inhibitory missing KIR-ligand Score (IM-KIR Score) with assigned scores per interaction, and a weighted version (w-KIR Score). Both versions were calculated according to the original publication ( 25 ).…”

Section: Methodsmentioning

confidence: 99%

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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

et al. 2021

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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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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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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

et al. 2021

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“…Recently, Krieger et al developed a scoring system, in which interactions of multiple KIR genes and HLA ligands were quantitatively analyzed. This comprehensive method raised an improved strategy to select a donor and exhibited great potential in the future ( 146 ).…”

Section: Kir and Transplant Outcomesmentioning

confidence: 99%

Influence of KIR and NK Cell Reconstitution in the Outcomes of Hematopoietic Stem Cell Transplantation

Gao

et al. 2020

Front. Immunol.

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Natural killer (NK) cells play a significant role in immune tolerance and immune surveillance. Killer immunoglobin-like receptors (KIRs), which recognize human leukocyte antigen (HLA) class I molecules, are particularly important for NK cell functions. Previous studies have suggested that, in the setting of hematopoietic stem cell transplantation (HSCT), alloreactive NK cells from the donor could efficiently eliminate recipient tumor cells and the residual immune cells. Subsequently, several clinical models were established to determine the optimal donors who would exhibit a graft-vs. -leukemia (GVL) effect without developing graft-vs. -host disease (GVHD). In addition, hypotheses about specific beneficial receptor-ligand pairs and KIR genes have been raised and the favorable effects of alloreactive NK cells are being investigated. Moreover, with a deeper understanding of the process of NK cell reconstitution post-HSCT, new factors involved in this process and the defects of previous models have been observed. In this review, we summarize the most relevant literatures about the impact of NK cell alloreactivity on transplant outcomes and the factors affecting NK cell reconstitution.

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“…This disconnect between known in vitro effective GVL mediation and apparent lack thereof in vivo , may be overcome by accounting for the complexity encountered in NK cell alloreactivity which is determined by multiple KIR and KIRL interacting simultaneously. A novel mathematical approach to quantifying KIR-KIRL interactions has been published 24 , utilizing a system of matrix, vector-operator equations to account for all possible donor-recipient KIR-KIRL interactions. This analysis highlighted the previously unknown importance of donor inhibitory KIR (iKIR) interactions, which complement the known missing KIRL interactions (mKIR) in mediating GVL.…”

Section: Introductionmentioning

confidence: 99%

Inhibitory KIR-Ligand Interactions and Relapse Protection Following HLA Matched Allogeneic HCT for AML

Krieger

Qayyum

Toor

2020

Preprint

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Killer immunoglobulin-like receptor (KIR) and KIR-ligand (KIRL) interactions play an important role in natural killer cell mediated graft versus leukemia effect (GVL) after hematopoietic stem cell transplant (HCT) for AML. Mathematically accounting for KIR-KIRL interactions may identify donors with optimal NK cell mediated alloreactivity and GVL. In this retrospective study of 2359 donor recipient pairs (DRP) who underwent unrelated donor (URD) HCT for AML, KIR-KIRL interaction scores were determined. Relapse risk was significantly reduced in donor-recipient pairs (DRP) with higher inhibitory KIR-KIRL interaction and missing KIRL (mKIR) scores, with HR=0.86 (P=0.01) & HR=0.84 (P=0.02) respectively. This effect was not observed with activating KIR-KIRL interactions. The inhibitory KIR-KIRL (iKIR) interaction score components were summed to give an inhibitory-missing ligand (IM-KIR) score, which if it was 5 as opposed to <5, was also associated with a lower relapse risk, SHR 0.8 (P=0.004). Acute and chronic graft vs. host disease (GVHD), survival, GRFS and relapse free survival were not significantly different. However, TRM was increased among those with IM-KIR=5, HR, 1.32 (P=0.01). Among those with HLA matched DRP, anti-thymocyte globulin recipients with IM-KIR=5, had a lower relapse rate HR, 0.61 (p=0.001), however TRM was increased in these patients with a HR, 1.49 (p=0.034). This study demonstrates that unrelated DRPs with high inhibitory KIR content scores confer relapse protection, albeit with increased TRM. Clinical trials utilizing donors with a higher iKIR content in conjunction with novel strategies to reduce TRM should be considered for URD HCT recipients with AML to optimize clinical outcomes.

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Killer Immunoglobulin-Like Receptor-Ligand Interactions Predict Clinical Outcomes following Unrelated Donor Transplantations

Cited by 13 publications

References 43 publications

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

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

Influence of KIR and NK Cell Reconstitution in the Outcomes of Hematopoietic Stem Cell Transplantation

Inhibitory KIR-Ligand Interactions and Relapse Protection Following HLA Matched Allogeneic HCT for AML

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