Severe cytokine release syndrome is associated with hematologic toxicity following CD19 CAR T-cell therapy.

Abstract

CD19-targeted chimeric antigen receptor (CAR) T-cell therapy has demonstrated remarkable efficacy in patients with relapsed/refractory B-cell malignancies, however, is associated with toxicities including cytokine release syndrome (CRS), neurotoxicity, and impaired hematopoietic recovery. The latter is associated with high grade cytopenias requiring extended growth factor or transfusional support, potentially leading to additional complications such as infection or hemorrhage. To date, the factors independently associated with hematologic toxicity have not been well characterized. To address this, we retrospectively analyzed 173 patients who received defined-composition CD19 CAR T-cell therapy on a phase I/II clinical trial (NCT01865617), with primary endpoints of absolute neutrophil count (ANC) and platelet count at day-28 following CAR T-cell infusion. We observed cumulative incidences of neutrophil and platelet recovery of 81% and 75% respectively, at 28 days post-CAR T-cell infusion. Hematologic toxicity was noted in a significant subset of patients with persistent neutropenia in 9% and thrombocytopenia in 14% at last follow-up. Utilizing debiased LASSO regression analysis for high-dimensional modeling and considering patient-, disease-, and treatment-related variables, we identified increased CRS severity as an independent predictor for decreased platelet count and lower pre-lymphodepletion platelet count as independent predictors for both decreased neutrophil and platelet counts following CD19 CAR T-cell infusion. Furthermore, multivariable models including CRS-related cytokines identified associations between higher peak serum concentrations of IL-6 and lower day-28 counts; in contrast, higher serum concentrations of TGF-β were associated with higher counts. Our findings suggest that patient selection and improved CRS management may improve hematopoietic recovery following CD19 CAR T-cell therapy.