Division of Pediatric Cardiology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
Division of Pediatric Oncology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
Biol Blood Marrow Transplant. 2018 Aug;24(8):1590-1595. doi: 10.1016/j.bbmt.2018.05.014. Epub 2018 May 14.
Immunotherapy with chimeric antigen receptor (CAR)-modified T cells targeting CD19 for pediatric acute lymphoblastic leukemia (ALL) has demonstrated significant efficacy. The principle toxicity is cytokine release syndrome with resultant hypotension. However, the spectrum of cardiovascular effects associated with CAR T cell therapy has not been systematically evaluated. We reviewed all patients who received CD19-directed CAR T cells at the Children's Hospital of Philadelphia between April 2012 and September 2016. The primary endpoint was hypotension-requiring inotropic support. Secondary endpoints included echocardiographic dysfunction at discharge and 6-month follow-up. Descriptive and univariate analyses were performed, and 98 encounters were included (55% male patients; mean age, 11.8 years [range, 1.7 to 27.1]); 98% had B-ALL. Before infusion 10 had cardiomyopathy and 1 had single-ventricle physiology. Primary endpoint occurred in 24 patients with mean onset 4.6 days (range, 1 to 9) after CAR T cell infusion, including 6 patients receiving milrinone. Worsened systolic function occurred in 10 patients; there were no cardiac-related deaths. Pretreatment factors associated with primary endpoint included higher pretreatment blast percentage on bone marrow biopsy (blast > 25%: odds ratio, 15.5; 95% confidence interval, 5.1 to 47.1; P < .001) and baseline lower ejection fraction (P = .019) or diastolic dysfunction (P = .021); neither pre-existing cardiomyopathy (P = .062), total body irradiation (P = .629), nor anthracycline dose (P = .444) were associated. At discharge, 7 patients had worsened echocardiographic function, but persistent dysfunction by the 6-month follow-up was rare. Pretreatment factors were not associated with persistent dysfunction at discharge. This is the first study to describe the cardiovascular effects of pediatric CAR T cell therapy. Although 10% had new systolic dysfunction after treatment, persistence was rare. Pretreatment blast count > 25% or pre-existing cardiac dysfunction increased the risk for hypotension-requiring inotropic support; these patients may warrant close observation.
嵌合抗原受体 (CAR)-修饰 T 细胞针对 CD19 的免疫疗法治疗小儿急性淋巴细胞白血病 (ALL) 已显示出显著疗效。其主要毒性是细胞因子释放综合征，导致低血压。然而，与 CAR T 细胞治疗相关的心血管效应谱尚未得到系统评估。我们回顾了 2012 年 4 月至 2016 年 9 月期间在费城儿童医院接受 CD19 定向 CAR T 细胞治疗的所有患者。主要终点是需要正性肌力支持的低血压。次要终点包括出院时和 6 个月时的超声心动图功能障碍。进行了描述性和单变量分析，共纳入 98 次就诊（55%为男性患者；平均年龄为 11.8 岁[范围为 1.7 至 27.1]）；98%为 B-ALL。输注前 10 例有心肌病，1 例有单心室生理。主要终点发生在 24 例患者中，CAR T 细胞输注后平均发病时间为 4.6 天（范围为 1 至 9），其中 6 例接受米力农治疗。10 例患者出现收缩功能恶化；无与心脏相关的死亡。与主要终点相关的预处理因素包括骨髓活检中较高的预处理 blast 百分比（blast > 25%：比值比，15.5；95%置信区间，5.1 至 47.1；P <.001）和较低的射血分数（P =.019）或舒张功能障碍（P =.021）；均无预先存在的心肌病（P =.062）、全身照射（P =.629）或蒽环类药物剂量（P =.444）。出院时，7 例患者超声心动图功能恶化，但 6 个月随访时持续性功能障碍罕见。出院时，预处理因素与持续性功能障碍无关。这是第一项描述儿科 CAR T 细胞治疗心血管效应的研究。尽管 10%的患者在治疗后出现新的收缩功能障碍，但持续性功能障碍很少见。预处理 blast 计数 > 25%或预先存在的心脏功能障碍增加了需要正性肌力支持的低血压风险；这些患者可能需要密切观察。
