Proposed observational study protocol for early differentiation of cytokine release syndrome and sepsis in CAR-T recipients with haematological malignancies using the IL-6/PCT ratio: the DRACARYS study

Chimeric Antigen Receptor T-cell (CAR-T) therapy has revolutionised treatment for haematological malignancies, demonstrating remarkable efficacy in B-cell leukaemias, lymphomas, and multiple myeloma. However, severe toxicities-particularly Cytokine Release Syndrome (CRS) and sepsis-present significant clinical challenges. Both conditions share overlapping features, including fever, hypotension, and multi-organ dysfunction, making timely and accurate differentiation essential. CRS is driven by excessive cytokine release, predominantly IL-6, and is treated with IL-6 receptor blockade (tocilizumab) and corticosteroids. Sepsis, by contrast, results from a dysregulated immune response to infection and requires antibiotics, as well as supportive care. Due to diagnostic uncertainty, clinicians often treat both conditions empirically. This can lead to inappropriate therapies-immunosuppressives may worsen sepsis, while antibiotics in CRS contribute to antimicrobial resistance and unnecessary healthcare burden. Existing biomarkers, such as IFN-γ and IL-1β, have shown potential but are limited by cost, availability, and the lack of rapid bedside implementation. There is a pressing need for a clinically accessible and reliable biomarker to distinguish CRS from sepsis in CAR-T patients. We hypothesise that the IL-6/procalcitonin (PCT) ratio will improve diagnostic accuracy. IL-6 is elevated in both conditions, while PCT is more specific to bacterial infection. However, PCT alone may be unreliable in immunocompromised patients, such as those receiving CAR-T therapy. The IL-6/PCT ratio is expected to reduce inter-individual variability and address limitations inherent to each marker when used alone. In this multi-centre, observational, prospective study, we will evaluate the IL-6/PCT ratio in febrile CAR-T patients. The primary analysis will focus on relapsed/refractory B-cell lymphomas, with a prespecified expansion/validation across other CAR-T indications. Clinical adjudication will serve as the standard of reference. We will assess diagnostic performance using Receiver Operating Characteristic (ROC) analysis to determine sensitivity, specificity, and optimal cutoffs. This study, titled <i>DRACARYS</i> (Differentiating Reactions-CRS versus sepsis-After CAR-Ts), aims to enhance diagnostic precision, guide timely and appropriate treatment, and reduce complications and unnecessary healthcare utilisation in CAR-T recipients.