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]4 However, it causes a unique set of toxicities, the foremost of which is cytokine release syndrome (CRS). 5,6The pathophysiology of CRS remains poorly defined, but appears to result from the hyper-activation of CARTs strongly stimulated by the malignant cells, leading to massive production of several cytokines, including interleukin-6. 2,3,6,7This results in capillary leak and profound hypotension in the most severe cases. 8,9To understand the mechanisms of CART-induced CRS, we performed a comprehensive morphologic, immunophenotypic, and molecular analysis of tissues from a patient who succumbed to the syndrome.Detailed methods are described in the supplemental Appendix, available on the Blood Web site.The patient was a 63-year-old man with CD19 1 /CD34 1 /CD10 1 /TdT 1 B-cell acute lymphoblastic leukemia (B-ALL).Within 12 hours after infusion of CD19-directed CARTs (CTL019) 1-3 he developed fever, mental status changes, multiorgan dysfunction, and hemodynamic instability.Cytokine serum concentrations, as assessed by multiplex bead assay, rose precipitously postinfusion with the overall profile (supplemental Figure 1A, supplemental Table 1) recapitulating CRS seen in CART-treated B-ALL patients. 7Accordingly, on day 3 postinfusion, his serum interleukin-6 (IL-6) concentration had markedly increased.However, the concentrations of the natural buffers of circulating IL-6, soluble IL-6 receptor and soluble glycoprotein 130, 10 had decreased and increased very mildly, respectively.This discrepancy in cytokine vs cytokine receptor concentrations presumably led to higher amount of "unbuffered" IL-6 and possibly contributed to the patient's demise.He was administered
Obstfeld et al. (Thu,) studied this question.