细胞因子模型预测儿童B系淋巴细胞白血病嵌合抗原受体T细胞治疗后器官功能损伤的临床研究  

Clinical study of cytokine models to predict organ functional impairment after treatment with chimeric antigen receptor T cells in children with B-lineage lymphocytic leukemia

作　　者：闰珂珂 杨帆[2] 林晓晨 张玥 代云红 吴水燕[1] 方芳[3] 柏振江[1] 李莺[1] 卢俊[2] Run Keke;Yang Fan;Lin Xiaochen;Zhang Yue;Dai Yunhong;Wu Shuiyan;Fang Fang;Bo Zhenjiang;Li Ying;Lu Jun(Department of Critical Care Medicine,Children′s Hospital of Soochow University,Suzhou 215025,China;Department of Hematology,Children′s Hospital of Soochow University,Suzhou 215025,China;Institute of Pediatrics,Children′s Hospital of Soochow University,Suzhou 215025,China)

机构地区：[1]苏州大学附属儿童医院重症医学科,215025 [2]苏州大学附属儿童医院血液科,215025 [3]苏州大学附属儿童医院儿研所,215025

出　　处：《中国小儿急救医学》2023年第5期340-346,共7页Chinese Pediatric Emergency Medicine

基　　金：江苏省自然科学基金(BK20211077);江苏省卫生健康委员会重点项目(ZD2021006);姑苏卫生人才培养项目(GSWS2019050、GSWS2020044);苏州市"科教兴卫"青年科技项目(KJXW2021026)。

摘　　要：目的探讨外周血细胞因子模型对儿童B系淋巴细胞白血病嵌合抗原受体T(CAR-T)细胞治疗后发生器官功能损伤的预测价值。方法回顾性分析2018年9月至2020年10月苏州大学附属儿童医院接受CAR-T细胞治疗的44例儿童急性B系淋巴细胞白血病患儿的临床资料。接受CAR-T细胞治疗后14 d内,每天检测外周血细胞因子,包括白细胞介素(interleukin,IL)-2、IL-4、IL-6、IL-10、肿瘤坏死因子-α、γ-干扰素(interferon-γ,IFN-γ)和IL-17A。以CAR-T细胞治疗后14 d内各器官功能恢复或患儿死亡为终点,分析外周血细胞因子水平的变化趋势。采用受试者工作特征曲线建立数学预测模型,预测患儿各脏器损伤的发生情况。结果44例患儿中,男31例,女13例,中位年龄7.96(5.19,11.48)岁。95.5%(42/44)的患儿发生细胞因子释放综合征(cytokine release syndrome,CRS)反应,其中88.1%(37/42)发生CRS 1-3级反应,16.7%(7/42)发生严重的CRS 4-5级反应。以IL-6>3892.95 pg/mL为最佳截断值,预测急性呼吸衰竭的曲线下面积(area under the curve,AUC)为0.818,敏感度为0.8,特异度为0.735,而联合IFN-γ>414.4 pg/mL、IL-6>3892.95 pg/mL和IL-2>27.05 pg/mL三者为最佳截断值,预测急性呼吸衰竭的AUC为0.741,敏感度为0.6,特异度为0.912。以IFN-γ>1699.5 pg/mL为最佳截断值,预测休克发生的AUC为0.908,敏感度为0.722,特异度为1。以IL-6>4607.3 pg/mL为最佳截断值,预测肝脏损伤的AUC为0.964,敏感度为1,特异度为0.906;而联合IL-6>4607.3 pg/mL和IFN-γ>1446.2 pg/mL两者为最佳截断值,预测肝脏损伤的AUC为0.977,敏感度为1,特异度为0.906。联合IL-6>6972.2 pg/mL和IFN-γ>3981.5 pg/mL两者,预测CRS 4-5级反应的阳性预测值为62.5%,阴性预测值为94.4%,AUC为0.846,预测敏感度为0.714,特异度为0.838,且患儿均合并2个及2个以上的脏器功能损伤。结论儿童急性B系淋巴细胞白血病在接受CAR-T细胞治疗后,外周血细胞因子IFN-γ、IL-6及IL-2联合指标可用Objective To explore the predictive value of peripheral blood cytokine models on organ functional impairment after chimeric antigen receptor T(CAR-T)cell therapy in children with B-lineage lymphocytic leukemia.Methods The clinical data of 44 children with acute B-lineage lymphoblastic leukemia who received CAR-T cell therapy at Children′s Hospital of Soochow University from September 2018 to October 2020 were retrospectively analyzed.Peripheral blood cytokines,including interleukin(IL)-2,IL-4,IL-6,IL-10,tumor necrosis factor-α,interferon(IFN)-γand IL-17A,were measured daily for 14 days after receiving CAR-T cell therapy.The trend of peripheral blood cytokine levels was analyzed at the endpoint of organ function recovery or death within 14 days after CAR-T cell treatment.Receiver operating characteristic curve was used to establish a mathematical prediction model to predict the occurrence of organ damage in the children.Results Of the 44 children,31 cases were boys and 13 cases were girls,with a median age of 7.96(5.19,11.48)years.Cytokine release syndrome(CRS)response occurred in 95.5%(42/44)children,with 88.1%(37/42)had a grade 1-3 CRS response,and 16.7%(7/42)had a severe grade 4-5 CRS response.Using IL-6>3892.95 pg/mL as cut-off value,the area under the curve(AUC)for predicting acute respiratory failure was 0.818,with a sensitivity of 0.8 and a specificity of 0.735,while combining IFN-γ>414.4 pg/mL,IL-6>3892.95 pg/mL and IL-2>27.05 pg/mL were the three cut-off values,with an AUC of 0.741,sensitivity of 0.6 and specificity of 0.912 for predicting acute respiratory failure.Using IFN-γ>1699.5 pg/mL as cut-off value,the AUC for predicting shock was 0.908,with a sensitivity of 0.722 and a specificity of 1.With IL-6>4607.3 pg/mL as cut-off value,the AUC for predicting liver injury was 0.964,with a sensitivity of 1 and a specificity of 0.906,while combining both IL-6>4607.3 pg/mL and IFN-γ>1446.2 pg/mL as cut-off values,the AUC for predicting liver injury was 0.977,with a sensitivity of 1 and a specificity of 0

关 键 词：嵌合抗原受体T细胞 器官功能损伤 细胞因子释放综合征 临床预测模型 急性B淋巴细胞白血病 

分 类 号：R733.71[医药卫生—肿瘤]