High pretreatment disease burden as a risk factor for infectious complications following CD19 chimeric antigen receptor T‐cell therapy for large B‐cell lymphoma

Infection has emerged as the chief cause of non-relapse mortality (NRM) post CD19-targeting chimeric antigen receptor T-cell therapy (CAR-T) therapy. Even though up to 50% of patients may remain infection-free, many suffer multiple severe, life-threatening, or fatal infectious events. The primary aim of this study was to explore severe and life-threatening infections post licensed CAR-T therapy in large B-cell lymphoma, with a focus on the role of disease burden and disease sites in assessing individual risk. We sought to understand the cohort of patients who experience ≥2 infections and those at the highest risk of infectious NRM. Our analysis identifies a higher disease burden after bridging therapy as associated with infection events. Those developing ≥2 infections emerged as a uniquely high-risk cohort, particularly if the second (or beyond) infection occurred during an episode of immune effector cell-associated neurotoxicity syndrome (ICANS) or while on steroids and/or anakinra for ICANS. Herein, we also describe the first reported cases of "CAR-T cold sepsis," a phenomenon characterized by the lack of an appreciable systemic inflammatory response at the time of detection of infection. We propose a risk-based strategy to encourage heightened clinician awareness of cold sepsis, with a view to reducing NRM.