Cytokine Release Syndrome After Chimeric Antigen Receptor T Cell Therapy for Acute Lymphoblastic Leukemia

Abstract

Objective: Initial success with chimeric antigen receptor-modified T cell therapy for relapsed/refractory acute lymphoblastic leukemia is leading to expanded use through multicenter trials. Cytokine release syndrome, the most severe toxicity, presents a novel critical illness syndrome with limited data regarding diagnosis, prognosis, and therapy. We sought to characterize the timing, severity, and intensive care management of cytokine release syndrome after chimeric antigen receptor-modified T cell therapy.

Design: Retrospective cohort study.

Setting: Academic children's hospital.

Patients: Thirty-nine subjects with relapsed/refractory acute lymphoblastic leukemia treated with chimeric antigen receptor-modified T cell therapy on a phase I/IIa clinical trial (ClinicalTrials.gov number NCT01626495).

Interventions: All subjects received chimeric antigen receptor-modified T cell therapy. Thirteen subjects with cardiovascular dysfunction were treated with the interleukin-6 receptor antibody tocilizumab.

Measurements and main results: Eighteen subjects (46%) developed grade 3-4 cytokine release syndrome, with prolonged fever (median, 6.5 d), hyperferritinemia (median peak ferritin, 60,214 ng/mL), and organ dysfunction. Fourteen (36%) developed cardiovascular dysfunction treated with vasoactive infusions a median of 5 days after T cell therapy. Six (15%) developed acute respiratory failure treated with invasive mechanical ventilation a median of 6 days after T cell therapy; five met criteria for acute respiratory distress syndrome. Encephalopathy, hepatic, and renal dysfunction manifested later than cardiovascular and respiratory dysfunction. Subjects had a median of 15 organ dysfunction days (interquartile range, 8-20). Treatment with tocilizumab in 13 subjects resulted in rapid defervescence (median, 4 hr) and clinical improvement.

Conclusions: Grade 3-4 cytokine release syndrome occurred in 46% of patients following T cell therapy for relapsed/refractory acute lymphoblastic leukemia. Clinicians should be aware of expanding use of this breakthrough therapy and implications for critical care units in cancer centers.

Figure 1

Laboratory trends after chimeric antigen receptor (CAR) cell administration in grade 3 and 4 cytokine release syndrome patients. Means and SD are presented. A, Ferritin (n = 17). B, Lactate dehydrogenase (LDH) (n = 18). C, C-reactive protein (CRP) (n = 16). D, Platelet count (n = 18). E, Fibrinogen (n = 16). F, Alanine aminotransferase (ALT) (n = 18). G, Creatinine (n = 18). H, International normalized ratio (INR) (n = 14). I, Lactate (n = 15). J, Central venous oxyhemoglobin saturation (n = 14).

Figure 2

Time course of organ dysfunction after chimeric antigen receptor (CAR) cell administration in grade 3 and 4 cytokine release syndrome patients. The number of patients with each organ dysfunction on each day after CAR cell administration is presented. A, Cardiovascular dysfunction—use of vasoactive drug to support hemodynamic status (dopamine > 5 μg/kg/min or any dobutamine, epinephrine, norepinephrine, vasopressin, or milrinone). B, Respiratory failure—invasive or noninvasive mechanical ventilation. C, Hepatic dysfunction—total bilirubin greater than or equal to 4 mg/dL or alanine aminotransferase greater than 2× upper limit of normal for age. D, Renal dysfunction—two-fold increase in baseline creatinine. E, Encephalopathy—altered mental status or seizure. F, Hematologic dysfunction—international normalized ratio greater than 2.

Figure 3

Changes in A, temperature; B, heart rate; C, systolic blood pressure; and D), inotrope score after tocilizumab administration (n = 14). p < 0.05 for all changes in heart rate and temperature compared to time 0 (tocilizumab administration).