Correlation analysis between levels of inflammatory cytokine in peripheral blood and cytokine release syndrome in patients with B-ALL after CAR-T immunotherapy

Objective To explore the correlation between levels of inflammatory factor in peripheral blood and cytokine release syndrome (CRS) in patients with B cell acute lymphoblastic leukemia (B-ALL) after receiving chimeric antigen receptor T cells (CAR-T) immunotherapy. Methods From April 1, 2016 to September 30, 2018, a total of 38 patients with B-ALL who underwent CAR-T immunotherapy in the Department of Hematology, Affiliated Hospital of Xuzhou Medical University, and had complete clinical data, were selected as subjects. And 21 patients were male and 17 ones were female with median age of 16 years (8-35 years). All patients received the fludarabine combined with cyclophosphamide (FC) conditioning regimen before CAR-T immunotherapy. In this study, all of the 38 patients were treated with humanized CD19 CAR-T (hCART19s), and the total infused number of CAR-T in each patient was calculated as 1×106/kg. A retrospective research method was used to collect results of relevant clinical data, laboratory and auxiliary examination. The peak levels of ferritin, C-reactive protein (CRP) and interleukin (IL)-6 in peripheral blood were recorded on d0-30 after CAR-T immunotherapy. According to the clinical data of patients on d0-30 after CAR-T immunotherapy, the CRS of the patients was diagnosed and graded. Correlation analysis between CRS grades and peak levels of ferritin, CRP and IL-6 in peripheral blood was performed using Spearman rank correlation analysis. The Mann-Whitney U test was used to compare the peak levels of ferritin, CRP and IL-6 in peripheral blood between patients with grade 1-2 CRS and grade 3-5 CRS. The procedure followed in this study was in accordance with the ethical standards established by the Human Experimental Committee of the Affiliated Hospital of Xuzhou Medical University, and was approved by the committee (Approval No. XYFY2016-KL002-01). All subjects or their guardians signed an informed consent for this clinical research. Results ① Among the 38 patients with B-ALL in this study, there were 34 patients who developed CRS after CAR-T immunotherapy, and the incidence rate of CRS was 89.5% (34/38). There were 24 patients (63.2%) developed grade 1-2 CRS, and 10 cases (26.3%) developed grade 3-5 CRS. The main clinical manifestations of patients with CRS were fever, hypotension, liver or kidney dysfunction, coagulation abnormalities, central nervous system adverse reactions, etc.. ② The CRS grades of patients with B-ALL after CAR-T immunotherapy were positively correlated with peak levels of ferritin, CRP and IL-6 levels in peripheral blood (rs=0.779, P<0.001; rs=0.673, P<0.001; rs=0.612, P<0.001). ③ The median peak levels of peripheral blood ferritin, CRP and IL-6 in patients with grade 3-5 CRS were 33 080 ng/mL (2 352-69 614 ng/mL), 200.0 mg/L (151.4-203.5 mg/L) and 799.5 pg/mL (220.9-1 677.5 pg/mL) respectively, which were higher than those of 1 979 ng/mL (1 133-2 147 ng/mL), 86.1 mg/L (33.8-136.6 mg/L) and 70.7 pg/mL (18.8-265.2 pg/mL) in patients with grade 1-2 CRS, and the differences were statistically significant (U=210.000, P<0.001; U=192.000, P=0.005; U=201.000, P=0.001). Conclusions The incidence rate of CRS was high in patients with B-ALL after CAR-T immunotherapy. The severity of CRS was correlated with levels of ferritin, CRP and IL-6 in peripheral blood, and the levels of ferritin, CRP and IL-6 in peripheral blood were significant elevated in patients with severe CRS. Patients with B-ALL need to regularly monitor ferritin, CRP and IL-6 in peripheral blood after CAR-T immunotherapy. When the above inflammatory factors are elevated, it is necessary to be alert to the occurrence of severe CRS. Key words: Leukemia, B-cell; Cytokines; Ferritins; C-reactive protein; Interleukin-6; Chimeric antigen receptor T cell; Cytokine release syndrome