Investigation of the risk factors to predict cytokine release syndrome in relapsed or refractory B-cell acute lymphoblastic leukemia patients receiving IL-6 knocking down anti-CD19 chimeric antigen receptor T-cell therapy

• DOI: 10.3389/fimmu.2022.922212
• Publication Date: 2022-08-29T04:37:30Z
• Authors: Wen-Jie Gong; Yan Qiu; Ming-Hao Li; Li-Yun Chen; Yan-Yan Li; Jing-Qiu Yu; Li-Qing Kang; Ai-Ning Sun; De-Pei Wu; Lei Yu; Sheng-Li Xue
• Keywords: IL-6 knocking down; 0301 basic medicine; Receptors, Chimeric Antigen; Interleukin-6; Immunology; Antigens, CD19; Cell- and Tissue-Based Therapy; cytokine release syndrome; RC581-607; Precursor Cell Lymphoblastic Leukemia-Lymphoma; 3. Good health; 03 medical and health sciences; Risk Factors; risk factors; Humans; relapsed or refractory B-cell acute lymphoblastic leukemia; chimeric antigen receptor T-cell therapy; Immunologic diseases. Allergy; Cytokine Release Syndrome; Lymphoma, Follicular; Adaptor Proteins, Signal Transducing

CD19 chimeric antigen receptor-T (CAR-T) cell therapy has achieved remarkable results in patients with relapsed or refractory B-cell acute lymphoblastic leukemia (r/r B-ALL). However, the cytokine release syndrome (CRS) was presented in most patients as common toxicity and severe CRS (sCRS) characterized by the sharp increase in interleukin-6 (IL-6) could be life-threatening. We conducted a phase II clinical trial of ssCAR-T-19 cells, anti-CD19 CAR-T cells with shRNA targeting IL-6, in 61 patients with r/r B-ALL. This trial was registered at www.clinicaltrials.gov as #NCT03275493. Fifty-two patients achieved CR while nine patients were considered NR. The median duration of response (DOR) and overall survival (OS) were not reached (>50 months). CRS developed in 81.97% of patients, including 54.10% with grades 1 to 2 (grade 1, 31.15%; grade 2, 22.95%) and 27.87% with grades 3 to 4 (grade 3, 26.23%; grade 4, 1.64%). sCRS occurs earlier than mild CRS (mCRS). A multivariable analysis of baseline characteristics identified high bone marrow disease burden and poor genetic risk before infusion as independent risk factors for sCRS. After infusion, patients with sCRS exhibited larger expansion of ssCAR-T-19 cells, higher peak levels of IL-6, IL-10, and IFN-γ, and suffered more severe hematological and non-hematological toxicities compared with those with mCRS.