ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2019) 63 P1015 | DOI: 10.1530/endoabs.63.P1015

Advanced glycation end-products and chronic inflammation in adult survivors of childhood leukemia treated with hematopoietic stem cell transplantation: possible role in the pathogenesis of cardiovascular late effects

Francesco Felicetti1,2, Alessia Sofia Cento3, Paolo Fornengo4, Maurizio Cassader2, Raffaella Mastrocola3, Fabrizio D’Ascenzo2,5, Fabio Settanni6, Andrea Benso2,6, Emanuela Arvat2,7, Massimo Collino8, Franca Fagioli9, Manuela Aragno3 & Enrico Brignardello1

1Transition Unit for Childhood Cancer Survivors, Città della Salute e della Scienza Hospital, Turin, Italy; 2Department of Medical Science, University of Turin, Turin, Italy; 3General Pathology Unit, Department of Clinical and Biological Sciences, University of Turin, Turin, Italy; 4Department of Medicine, Città della Salute e della Scienza Hospital, Turin, Italy; 5Division of Cardiology, Città della Salute e della Scienza Hospital, Turin, Italy; 6Division of Endocrinology, Diabetology and Metabolism, Città della Salute e della Scienza Hospital, Turin, Italy; 7Division of Oncological Endocrinology, Città della Salute e della Scienza Hospital, Turin, Italy; 8Department of Drug Science and Technology, University of Turin, Turin, Italy; 9Division of Paediatric Onco-Haematology, Stem Cell Transplantation and Cellular Therapy, Città della Salute e della Scienza Hospital, Turin, Italy.

Cardiovascular (CV) diseases significantly contribute to the mortality excess observed in survivors of pediatric acute lymphoblastic leukemia (ALL) who received hematopoietic stem cell transplantation (HSCT). The study explores advanced glycation end-products (AGEs) levels, inflammatory status and lipid profile in a cohort of ALL survivors, in order to investigate their potential role in the pathogenesis of CV late effects. Inclusion criteria were: a) previous diagnosis of ALL at age <18 years, treated with HSCT conditioned with total body irradiation (TBI), b) age >18 at the time of the enrollment; c) off-therapy for at least 5 years. Radiotherapy other than TBI, pre-existing heart disease, glucose metabolism impairment, body mass index >25, smoking or treatment with cholesterol lowering medications were exclusion criteria. Eighteen survivors were included and 30 age-matched healthy subjects worked as controls. Age at the time of the study was 27.5±4.8 years for ALL survivors and 26.7±3.2 years for controls (mean±S.D.). ALL survivors had higher levels of triglycerides (189.38±147.40 vs 84.97±37.28 mg/dl, P<0.01) and Apo B (105.80±20.47 vs 80.81±13.54 mg/dl, P=0.001). Also the total cholesterol (Chol)/HDL Chol (4.25–1.09 vs 3.17–0.45, P< 0.02) and Apo B/Apo A-1 (0.73–0.15 vs 0.48–0.09, P< 0.001) ratios were higher in survivors. High-sensitivity C-reactive protein levels (2.32–1.70 vs 0.88–1.09 mg/dl, P<0.05), IL-1β (7.04–1.52 vs 4.64–2.02 pg/ml, P=0.001) and IL-17 (37.44–3.51 vs 25.19–6.34 pg/ml, P=0.001) were higher in ALL survivors than in the control group. AGEs plasma levels in ALL survivors were markedly higher than in heathy subjects (2.15–2.21 vs 0.29–0.15 pg/ml, P<0.01). In ALL survivors an increased GSSG/GSH ratio (0.085–0.07 vs 0.041–0.036, P<0.05) was also observed. Despite slight alterations of the lipid profile, adult survivors of childhood ALL who received HSCT with TBI have very high levels of AGEs and evidence of chronic inflammation. It can be hypothesized that the oxidative stress induced by exposure to chemotherapy or radiotherapy leads to the formation and accumulation of AGEs, which in turn could induce inflammation, reduce antioxidant defenses and enhance the production of reactive oxygen species (ROS). By this way the oxidative stress might be self-perpetuated after the end of cancer therapies. These alterations could contribute to the increased risk of CV diseases that has been reported in transplanted ALL survivors.