Abstract
Chronic graft versus host disease (cGVHD) is a common long-term complication after allogeneic hematopoietic stem cell transplantation. The objective of our study was to compare the metabolic profiles for allotransplant recipients and thereby identify metabolic characteristics of patients with treatment-requiring cGVHD. The study included 51 consecutive patients (29 men and 22 women; median age: 44 years, range: 15–66 years) transplanted with peripheral blood stem cells derived from human leukocyte antigen-matched family donors. All serum samples investigated by global metabolomic profiling were collected approximately 1 year posttransplant (median 358 days). Thirty-one of the 51 patients (61%) had cGVHD 1 year posttransplant. The affected organs were (number of patients) liver/bile duct (23), eyes (15), gastrointestinal tract (14), skin (13), mouth (10), lungs (3), and urogenital tract (1). We compared the metabolic profile for patients with and without cGVHD, and a Random Forrest Classification Analysis then resulted in 75% accuracy in differentiating the two groups. The 30 top-ranked metabolites from this comparison included increased levels of bile acids, several metabolites from the cytokine-responsive kynurenine pathway for tryptophan degradation, pro-inflammatory lipid metabolites, phenylalanine and tyrosine metabolites derived from the gut microbial flora, and metabolites reflecting increased oxidative stress. However, nine of these 30 top-ranked metabolites were probably altered due to cyclosporine or steroid treatment, and we therefore did a hierarchical clustering analysis including all 51 patients but only based on the other 21 cGVHD-specific metabolites. This analysis identified three patient subsets: one cluster included mainly patients without cGVHD and had generally low metabolite levels; another cluster included mainly patients with cGVHD (most patients with at least three affected organs) and high metabolite levels, and the last intermediate group including cGVHD patients with limited organ involvement. We conclude that allotransplant recipients with cGVHD have an altered metabolic profile caused both by the disease and its immunosuppressive treatment.
Highlights
Allogeneic hematopoietic stem cell transplantation is used in the treatment of severe bone marrow failure and aggressive hematological malignancies, including acute leukemia [1, 2]
Metabolic regulation is important for immunoregulation, and we have previously demonstrated that pretransplant cytokine profiles as well as the pretransplant metabolic status of allotransplant recipients is associated with a risk of later acute GVHD (aGVHD) [23,24,25]
31 of the 51 patients included in the study (61%) had signs of Chronic graft versus host disease (cGVHD) 1 year posttransplant; 29 of the 31 cGVHD patients required systemic immunosuppressive treatment either as prolonged or increased treatment with cyclosporine A (27 patients)
Summary
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is used in the treatment of severe bone marrow failure and aggressive hematological malignancies, including acute leukemia [1, 2]. Allo-HSCT is a potentially curative treatment, at the same time the treatment is associated with a relatively high risk of morbidity and mortality due to severe transplant-related complications [3]. Chronic graft versus host disease (cGVHD) is the most common cause of late non-relapse mortality [4,5,6]. Among the risk factors for cGVHD are older patient age, previous acute GVHD (aGVHD), reduced intensity conditioning, female donor to male recipient, peripheral blood stem cell (PBSC) grafts and human leukocyte antigen (HLA) mismatched donors [14,15,16,17,18,19]
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