Survivors of acute lymphoblastic leukemia show an increased cardio-immune-metabolic risk

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Background and aims: Acute lymphoblastic leukaemia (ALL) is the most common haematological cancer in children. In high-risk cases, treatment involves chemotherapy, radiation and stem cell transplantation. Despite high survival rates (up to 90%), increased cardiovascular and metabolic risk has been observed in survivors. This project aims to study post-transplant metabolic and inflammatory changes and their impact on mature immune cells derived from stem cells. Methods: 14 ALL survivors who underwent transplantation (11 males, 3 females) and 14 matched sibling donors (3 males, 11 females) were selected according to defined criteria. Each recipient-donor couple were profiled for medical anamnesis and clinical assessment and were subjected to a blood collection, for immunophenotyping, transcriptomic analysis and telomere length measurement. An ultrasound examination of the supra-aortic trunks was also performed to assess intima-media thickness (IMT). Results: No differences have been detected in anthropometric characteristics, however, signs of dyslipidaemia were observed in recipients (cholesterol: 157.5 SE9.194 vs 171.9 SE10.43; triglycerides 65.57 SE5.216 vs 105.0 SE11.31; hyperinsulinemia 8.457 SE1.870 vs 15.23 SE2.945 and an increase in the HOMA index (1.587 SE0.3653 vs 2.981 SE0.6225). Metabolic syndrome was diagnosed in 14.3% of recipients. Carotid IMT analysis showed accelerated thickening (0.0083 vs 0.0034). Plasma proteomic analysis revealed increased levels of pro-inflammatory proteins (CRP, SAAP) and proteins related to dyslipidaemia (APOB, APOC4-APOC2). This metabolic and inflammatory phenotype is associated with accelerated telomere shortening in circulating immune cells (slope -0.009 vs -0.0008), a reduction in CD34+ and an increase in circulating CD19+. RNA-seq confirmed inflammation and B-cell dysfunction. Plasma IgM immunoglobulins were decreased in recipients compared to donors (58.62 SE4.062 vs 49.23 SE3.188), while IgG levels were comparable (350.6 SE14.49 vs 329.7 SE16.43). Conclusions: These data suggest that TBI conditioning negatively impact on the immunometabolic profile of cALL survivors, contributing to an increased risk of long-term cardiovascular complications. Together this evidence suggests the need to optimize the clinical follow-up strategies to mitigate the increased cardiometabolic risk in cALL survivors.

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