Chimeric antigen receptor T-cell therapies related to immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome: Diagnosis, high-risk factors, and management

ABSTRACT: Immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS) is a life-threatening complication of chimeric antigen receptor T cell (CAR-T) therapy. Despite its high mortality rate, IEC-HS remains underrecognized due to overlapping clinical and laboratory features with severe cytokine release syndrome (CRS), leading to delayed diagnosis and suboptimal management. This review systematically analyzes key strategies to distinguish IEC-HS from severe CRS in the literature. The analysis focuses on temporal patterns, such as the delayed onset of IEC-HS after CAR-T infusion. It also examines dynamic laboratory trends, including persistently elevated ferritin and lactate dehydrogenase levels and a slower decline in C-reactive protein (CRP). In addition, distinct cytokine profiles are discussed, such as prolonged interferon-gamma (IFN-γ) elevation and surges in chemokines and growth factors. We further identify high-risk factors for IEC-HS, including patient-specific factors (baseline inflammation, low natural killer [NK] cell counts), disease-related factors (high B-cell acute lymphoblastic leukemia [B-ALL] burden and prior high-grade CRS), and CAR-T-related factors (CD22 target, CD28 costimulation, T-cell selection, high CAR-T cell dose, excessive CAR-T cell expansion, and TET2 gene mutation). For management, we evaluate conventional therapies (corticosteroids, etoposide) and emerging immunomodulatory agents (anakinra, ruxolitinib, emapalumab), emphasizing the 2023 treatment regimen by the American Society of Transplantation and Cellular Therapy (ASTCT). By integrating risk stratification, early diagnostic criteria, and tailored therapeutic approaches, this review aims to improve clinical outcomes for IEC-HS patients.