Hemophagocytic lymphohistiocytosis-like toxicity (carHLH) after CD19-specific CAR T-cell therapy

Abstract

Chimeric antigen receptor T-cell (CAR T-cell) therapy is associated with significant toxicities secondary to immune activation, including a rare but increasingly recognised severe toxicity resembling haemophagocytic lymphohistiocytosis (carHLH). We report the development of carHLH in 14·8% of paediatric patients and young adults treated with CD19-specific CAR T-cell therapy with carHLH, occurring most commonly in those with high disease burden. The diagnosis and treatment of carHLH required a high index of suspicion and included multidrug immunomodulation with variable response to therapies. Compared to patients without carHLH, patients with carHLH had both reduced response to CAR T-cell therapy (P-value = 0·018) and overall survival (P-value = < 0·0001).

Keywords: chimeric antigen receptor T-cell therapy; cytokine release syndrome; haemophagocytic lymphohistiocytosis; refractory acute B-cell lymphoblastic leukaemia.

Figure 1.. Clinical course of patients with carHLH after CAR T-cell therapy.

Graphical representation of clinical course of patients (n=4) who developed carHLH after receipt of CD19-CAR T-cell therapy, with each panel (A-D) representing a unique patient/infusion. Temperature and laboratory markers of inflammation and organ function are displayed temporally from CAR T-cell infusion until 30-days post-infusion (or until death, whichever was sooner), with corresponding timing of ICU admission (if applicable) and therapeutics administered for CRS and/or carHLH. Temperature (black), CRP (C-reactive protein; blue) and ferritin (red) are shown on top graphs for each patient. Total bilirubin (grey), creatinine (green) and ALT (alanine aminotransferase; yellow) are shown on the lower graphs for each patient (A-D). Vertical lines are shown to indicate start of CRS, day of peak CRS grade, and day of carHLH diagnosis (clinically and by Shah (6) criteria). Panel E depicts comparison of available serum cytokine levels between low grade CRS (red, downward triangle; n=2; Grade 1), high grade CRS (red, upward triangle n=2; Grade 3) and carHLH (n=3) patients. Bar represents median values with range. Cytokine analysis (ARUP Laboratories, Salt Lake City, UT) were obtained +/−3 days from carHLH/CRS diagnosis.