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Interleukin-18 and outcome after allogeneic stem cell transplantation: A retrospective cohort study.

ABSTRACT: BACKGROUND:Interleukin-18 (IL-18) is involved in endothelial activation and dysfunction, and in the pathogenesis and severity of acute graft-versus-host disease (aGVHD). Its relevance for patient outcome after allogeneic stem cell transplantation (alloSCT) has not yet been comprehensively addressed. METHODS:Pre-transplant serum levels of free IL-18 were retrospectively assessed in a cohort of 589 patients (training cohort). Results were validated in 688 patients allografted in a different centre. The primary endpoint was overall survival (OS). Secondary endpoints included incidences of non-relapse mortality (NRM), relapse, and aGVHD. FINDINGS:In the training cohort, higher pre-transplant levels of free IL-18 were significantly associated with worse OS (hazard ratio [HR] per 1-log2 increase, 1.25, P?=?0.008) in multivariable models. This was due to a higher hazard of NRM (HR per 1-log2 increase, 1.39, P?=?0.001), rather than relapse. The associations of pre-transplant free IL-18 with higher NRM (HR per 1-log2 increase, 1.24, P?=?0.02) and shorter OS (HR per 1-log2 increase, 1.22, P?=?0.006) were confirmed in the validation cohort. In both cohorts, the correlations of higher pre-transplant free IL-18 serum levels with increased NRM and worse OS were mainly driven by fatal infectious complications. No associations with incidence of aGVHD were observed. INTERPRETATION:Higher pre-transplant levels of free IL-18 were associated with non-relapse and overall mortality after alloSCT. Our results may provide a rationale for prospective studies evaluating IL-18 status and inhibition of IL-18 activity in patients undergoing allografting.

SUBMITTER: Radujkovic A

PROVIDER: S-EPMC6945194 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Interleukin-18 and outcome after allogeneic stem cell transplantation: A retrospective cohort study.

Radujkovic Aleksandar A Kordelas Lambros L Dai Hao H Schult David D Majer-Lauterbach Joshua J Beelen Dietrich D Müller-Tidow Carsten C Dreger Peter P Luft Thomas T

EBioMedicine 20191101

<h4>Background</h4>Interleukin-18 (IL-18) is involved in endothelial activation and dysfunction, and in the pathogenesis and severity of acute graft-versus-host disease (aGVHD). Its relevance for patient outcome after allogeneic stem cell transplantation (alloSCT) has not yet been comprehensively addressed.<h4>Methods</h4>Pre-transplant serum levels of free IL-18 were retrospectively assessed in a cohort of 589 patients (training cohort). Results were validated in 688 patients allografted in a d ...[more]

PMID: 31680001

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Project description:PurposeThe success of allogeneic hematopoietic stem cell transplantation (HSCT) is compromised by complications such as infection, relapse, and graft-versus-host disease (GVHD). The investigation of non-HLA immunogenetics, particularly of cytokines, could identify predictors of an unfavorable outcome after allogeneic HSCT. In this study, we examined the impact of single nucleotide polymorphisms (SNPs) within the promoter region of interleukin 6 (IL6) on the development of GVHD after pediatric allogeneic HSCT.MethodsIn this retrospective analysis, we included 320 pediatric patients with a median age of 10 years who underwent an allogeneic HSCT and their respective donors. We used TaqMan real-time polymerase chain reaction to analyze the SNPs IL6-174 (G/C) and IL6-597 (G/A). The IL6-174 polymorphism was examined in 300 recipients and 295 donors. The IL6-597 polymorphism was analyzed in 299 recipients and 296 donors. We investigated the influence of the IL6-174 and IL6-597 polymorphisms on overall survival, event-free survival, relapse incidence, transplant-related mortality, and the occurrence of GVHD.ResultsG polymorphism at position 174 of the recipient IL6 gene was associated with a higher incidence of acute GVHD (GG vs. GC/CC; P = 0.024). Patients with IL6-597 GG genotype developed acute GVHD more frequently than individuals with an A allele (GG vs. GA vs. AA; P = 0.013). IL6-174 GG homozygous recipients had a more frequent occurrence of chronic GVHD (GG vs. GC/CC; P = 0.049). We observed a significant increased risk of chronic GVHD in recipients with IL6-597 GG genotype (GG vs. GA vs. AA; P = 0.043). Polymorphisms of donors did not affect the incidence of acute GVHD and chronic GVHD. In multivariate analysis, the IL6-174 and IL6-597 SNPs were independent significant risk factors for acute GVHD (P = 0.030; P = 0.007, respectively) as well as for chronic GVHD (P = 0.045; P = 0.015, respectively). In addition, older age at time of transplantation turned out to be a significant risk factor for chronic GVHD (P = 0.003).ConclusionOur study identified the IL6-174 and IL6-597 GG genotypes of pediatric allogeneic HSCT recipients as genetic risk factors for the development of acute GVHD and chronic GVHD. After evaluations in further studies, these findings could implicate the adjustment of prophylactic measures to reduce the occurrence of acute GVHD and chronic GVHD.

Dataset Information

Interleukin-18 and outcome after allogeneic stem cell transplantation: A retrospective cohort study.

Publications

Interleukin-18 and outcome after allogeneic stem cell transplantation: A retrospective cohort study.

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