Rationale and Design of the CARdio-Tox Study: A Prospective Evaluation of Cardiovascular Toxicity in Patients Receiving Chimeric Antigen Receptor-T (CAR-T) Cell Therapy

Chimeric Antigen Receptor (CAR)-T cell therapy has emerged as an innovative treatment of haematologic malignancies; however, its use is frequently complicated by Cytokine Release Syndrome (CRS), an increasingly recognized driver of cancer therapy-related cardiovascular toxicity (CTR-CVT) able to provoke a wide spectrum of manifestations, from paucysimptomatic and reversible effects to potentially fatal cardiovascular damage. The 2022 European Society of Cardiology (ESC) guidelines on cardio-oncology highlighted the need for systematic cardiovascular assessment in patients receiving CAR-T therapy, yet specific monitoring protocols are lacking at this point in time. The CARdio-Tox study was conceived to address this surveillance gap, testing the hypothesis that acute systemic inflammation, particularly mediated by high levels of interleukin (IL)-1 and IL-6 pathways, might represent the key determinant of early myocardial dysfunction. The primary endpoint of this protocol is to assess the incidence of acute CTR-cardiac dysfunction (CTRCD) occurring within 7 and 30 days after CAR-T cell infusion. Key secondary endpoints include the assessment of the relationship between CTRCD occurrence and CRS diagnosis and grade, as well as the association of inflammatory biomarkers increase with cardiac imaging and/or serum biomarker abnormalities. Data collection will continue over 30 days to assess middle and long-term cardiovascular toxicity. Despite its single-center design, the CARdio-Tox results might provide clinically relevant insights into early cardiovascular effects of CAR-T cell administration, identify key risk factors for CTR-CVT and support more tailored, pathophysiology-driven monitoring strategies in this rapidly evolving field.