Cytokine Release Syndrome After Chimeric Antigen Receptor T Cell Therapy for Acute Lymphoblastic Leukemia.
Cytokine Release Syndrome After Chimeric Antigen Receptor T Cell Therapy for Acute Lymphoblastic Leukemia.
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DOI：
10.1097/ccm.0000000000002053
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发表时间：
2017-02
影响因子：
8.8
通讯作者：
Teachey DT
中科院分区：
文献类型：
--
作者：
Fitzgerald JC;Weiss SL;Maude SL;Barrett DM;Lacey SF;Melenhorst JJ;Shaw P;Berg RA;June CH;Porter DL;Frey NV;Grupp SA;Teachey DT
嵌合抗原受体修饰的T细胞治疗复发性/难治性急性淋巴细胞白血病的初步成功正在通过多中心试验扩大使用。细胞因子释放综合征是最严重的毒性，是一种新型的危重病综合征，其诊断、预后和治疗方面的数据有限。我们试图描述嵌合抗原受体修饰的T细胞治疗后细胞因子释放综合征的时间、严重程度和重症监护管理。回顾性队列研究。学术儿童医院。在一项I/IIa期临床试验（ClinicalTrials.gov编号NCT 01626495）中接受嵌合抗原受体修饰的T细胞疗法治疗的39例复发性/难治性急性淋巴细胞白血病受试者。所有受试者均接受嵌合抗原受体修饰的T细胞治疗。13名心血管功能障碍受试者接受了白细胞介素-6受体抗体托珠单抗治疗。18例受试者（46%）发生3-4级细胞因子释放综合征，伴长期发热（中位数，6.5天）、高铁蛋白血症（中位数峰值铁蛋白，60，214 ng/mL）和器官功能障碍。14例（36%）患者在T细胞治疗后中位5天接受血管活性物质输注治疗，发生心血管功能障碍。6例（15%）患者在T细胞治疗后6天（中位数）发生急性呼吸衰竭，接受有创机械通气治疗; 5例符合急性呼吸窘迫综合征的标准。脑病、肝、肾功能不全的出现晚于心血管和呼吸功能不全。受试者的中位器官功能障碍天数为15天（四分位距，8-20）。13例受试者接受托珠单抗治疗后迅速退热（中位数，4小时）和临床改善。复发/难治性急性淋巴细胞白血病T细胞治疗后，46%的患者发生3-4级细胞因子释放综合征。临床医生应该意识到这种突破性疗法的扩大使用以及对癌症中心重症监护室的影响。
Initial success with chimeric antigen receptor–modified T cell therapy for relapsed/refractory acute lymphoblastic leukemia is leading to expanded use through multicenter trials. Cytokine release syndrome, the most severe toxicity, presents a novel critical illness syndrome with limited data regarding diagnosis, prognosis, and therapy. We sought to characterize the timing, severity, and intensive care management of cytokine release syndrome after chimeric antigen receptor–modified T cell therapy. Retrospective cohort study. Academic children’s hospital. Thirty-nine subjects with relapsed/refractory acute lymphoblastic leukemia treated with chimeric antigen receptor–modified T cell therapy on a phase I/IIa clinical trial (ClinicalTrials.gov number NCT01626495). All subjects received chimeric antigen receptor–modified T cell therapy. Thirteen subjects with cardiovascular dysfunction were treated with the interleukin-6 receptor antibody tocilizumab. Eighteen subjects (46%) developed grade 3–4 cytokine release syndrome, with prolonged fever (median, 6.5 d), hyperferritinemia (median peak ferritin, 60,214 ng/mL), and organ dysfunction. Fourteen (36%) developed cardiovascular dysfunction treated with vasoactive infusions a median of 5 days after T cell therapy. Six (15%) developed acute respiratory failure treated with invasive mechanical ventilation a median of 6 days after T cell therapy; five met criteria for acute respiratory distress syndrome. Encephalopathy, hepatic, and renal dysfunction manifested later than cardiovascular and respiratory dysfunction. Subjects had a median of 15 organ dysfunction days (interquartile range, 8–20). Treatment with tocilizumab in 13 subjects resulted in rapid defervescence (median, 4 hr) and clinical improvement. Grade 3–4 cytokine release syndrome occurred in 46% of patients following T cell therapy for relapsed/refractory acute lymphoblastic leukemia. Clinicians should be aware of expanding use of this breakthrough therapy and implications for critical care units in cancer centers.