A Critical Review of PET/CT Assessment After CAR-T Cell Therapy in Large B-Cell Lymphoma, Limitations of Current Criteria, Emerging Biomarkers, and a Framework for Standardised Evaluation.

Chimeric antigen receptor (CAR) T-cell therapy has fundamentally altered the management of relapsed or refractory Large B-Cell Lymphoma (LBCL). Despite remarkable clinical efficacy, the radiologic evaluation of therapeutic response remains highly problematic. Standard assessment frameworks, notably the Lugano classification and the Deauville Five-Point Scale (D5PS), were calibrated for cytotoxic chemoimmunotherapy and demonstrate profound inadequacies when applied to the unique biological kinetics of cellular immunotherapy. This review critically examines the limitations of standard 18F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography (18F-FDG PET/CT) in the CAR-T setting through a multidisciplinary lens, incorporating perspectives from hematology, nuclear medicine, neuroradiology, and molecular pathology. Pre-infusion quantitative parameters, including total metabolic tumour volume and spatial dissemination, operate as robust biomarkers for risk stratification and predicting immune-mediated toxicities. Post-infusion, conventional visual grading yields unacceptable false-positive rates. Phenomena including pseudoprogression, delayed complete responses, and systemic inflammation secondary to Cytokine Release Syndrome (CRS) routinely mimic active malignancy. Furthermore, Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) necessitates specialized neuroradiological evaluation. To resolve these diagnostic ambiguities, circulating tumour DNA (ctDNA) provides a precise, tumour-specific molecular signal capable of differentiating therapy-induced inflammation from genuine refractory disease. This review supports a structural transition from static visual scoring to a dynamic, multi-modal paradigm. Accordingly, the CAR-T Response Assessment Framework (CART-RAF), is proposed as an algorithmic approach that integrates continuous metabolic kinetics with serial molecular surveillance. Adoption of this multidisciplinary framework may reduce false-positive progression classifications, limit the premature discontinuation of effective cellular therapy, and improve clinical outcomes.