Recognition and management of early complications in CAR-T cell therapy and virus-specific T-lymphocyte therapy: a practical clinical reference.

Background: Cellular immunotherapies-including chimeric antigen receptor T-cell (CAR-T) therapies and adoptive transfer of virus-specific T lymphocytes (VSTs) - have transformed the treatment of refractory hematological malignancies and post-transplant infectious complications. Eight products are currently authorized by the European Medicines Agency, encompassing seven autologous CAR-T products targeting CD19 or BCMA and tabelecleucel (Ebvallo), the first approved allogeneic off-the-shelf EBV-specific T-cell product for EBV-positive post-transplant lymphoproliferative disease. Despite their clinical efficacy, both modalities carry distinct early toxicity profiles that differ from conventional cytotoxic chemotherapy. Objective: This review summarizes current recommendations for identifying, assessing, and treating early problems that can occur after CAR-T cell therapy and VST administration. Content: CAR-T-specific complications discussed include cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), immune effector cell-associated hematotoxicity (ICAHT), and immune effector cell-associated HLH-like syndrome (IEC-HS). CRS is graded by ASTCT consensus criteria and managed with tocilizumab as first-line pharmacological therapy; steroid-refractory ICANS is most commonly treated with high-dose intravenous anakinra (up to 12 mg/kg/day) which is currently the most studied second-line option, although the supporting evidence remains largely observational. ICAHT is classified using the validated EHA/EBMT grading framework, separating early (day 0-30) and late (post-day 30) neutropenia by depth and duration, with management escalating from prophylactic G-CSF through hematopoietic cell boost to allogeneic HSCT as the ultimate option. For VSTs, the principal early complications are tumor flare reaction (in approximately 20% of tabelecleucel recipients), GVHD (below 5% with enriched products), acute infusion reactions, and low-grade CRS-like cytokine release. We summarize a differential diagnosis of overlapping syndromes, pediatric-specific adaptations, ICU escalation criteria, and a clinical monitoring schedule. Conclusions: Internationally validated criteria grade the early complications of cellular immune effector therapies. Prompt recognition, early pharmacological intervention, and monitoring are essential to minimize non-relapse mortality. Expanding real-world experience and the integration of pre-treatment risk stratification tools will continue to refine evidence-based practice in this rapidly evolving field, ultimately leading to improved patient outcomes and reduced non-relapse mortality rates.