Hemophagocytic lymphohistiocytosis‐like syndrome after CD19‐directed CAR T‐cells for B‐cell lymphoma and B‐cell acute lymphoblastic leukemia: A LYSA, SFCE, and GRAALL study from the DESCAR‐T registry

While cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS) are well‐recognized toxicities of CAR T‐cell therapy, immune effector cell‐associated hemophagocytic lymphohistiocytosis‐like syndrome (IEC‐HS) remains poorly characterized. We aimed to describe the incidence, clinical features, management, and outcomes of IEC‐HS using real‐world data from the DESCAR‐T registry (NCT04328298). We conducted a multicenter retrospective study of patients registered in DESCAR‐T who received standard‐of‐care CD19 CAR T‐cell therapy for relapsed or refractory B‐cell non‐Hodgkin lymphoma (B‐NHL) or B‐cell acute lymphoblastic leukemia (B‐ALL) and fulfilled ASTCT criteria for IEC‐HS. We analyzed 42 patients who developed IEC‐HS. Most had a high CAR‐HEMATOTOX score (≥2, n = 36) and prior high‐grade CRS (grade ≥3, n = 20). IEC‐HS was characterized by marked hyperinflammation, with high median ferritin (18,561 µg/L), lactate dehydrogenase (825 IU/L), and triglycerides (4.5 g/L), and low fibrinogen (0.9 g/L). Median time to IEC‐HS onset was 9 days (IQR 6–21). Patients received a median of two treatment lines. Observed response rates were 77% with etoposide, 70% with corticosteroids, 70% with corticosteroids plus anakinra, and 50% with tocilizumab, with combination therapy more frequently used in severe cases. After a median follow‐up of 24.1 months, overall mortality was 81%. One‐year overall survival was 15.6% for B‐NHL and 47.1% for B‐ALL. In this real‐world cohort, IEC‐HS was a rare but life‐threatening complication of CD19 CAR T‐cell therapy, often occurring after severe CRS and associated with poor outcomes. Despite initial inflammatory control, mortality remained high, underscoring the need for improved risk stratification and management strategies.