PD-1/PD-L1引起的心电图改变对心脏不良反应的临床预测价值

Clinical predictive value of PD-1/PD-L1-induced electrocardiogram changes for cardiotoxicity

目的观察程序性死亡受体1(PD-1)/程序性死亡受体配体1(PD-L1)免疫检查点抑制剂在临床抗肿瘤过程中患者免疫治疗前后的心电图改变,探讨免疫检查点抑制剂心脏不良反应的发生及影响因素。方法筛选2019年10月1日至2020年9月30日于中国医学科学院肿瘤医院病理诊断确诊为局部晚期或转移性实体瘤患者93例,行PD-1/PD-L1抑制剂单药治疗,根据治疗剂量不同分组,A组(PD-1单抗,药物代号:609A)剂量1 mg/kg,21 d为1个周期(16例);B组(PD-1单抗,药物代号:HX008)剂量200 mg,21 d为1个周期(23例);C组(PD-1单抗,杰诺单抗)剂量3 mg/kg,14 d为1个周期(28例);D组(PD-L1单抗,药物代号:LP002)剂量900 mg,14 d为1个周期(26例),各自按疗程进行,监测随访10个周期,分别记录各组患者心电图检查结果,分析心电图异常情况与心脏不良反应发生的相关性。结果共有75例患者相继出现符合诊断标准的心电图异常情况,A组患者免疫治疗前后的心电图异常率差异无统计学意义(P>0.05),而B组免疫治疗前后心电图异常率增加且差异有统计学意义(均P<0.05),C组和D组免疫治疗后心电图异常率显著升高,自身免疫治疗前后差异有统计学意义(P<0.001)。A组出现心电图异常的患者例数(8例,50.0%,8/16)低于和B组(20例,87.0%,20/23),差异有统计学意义(P<0.05),C组出现心电图异常的患者例数(24例,85.7%,24/28)与D组(23例,88.4%,23/26)比较,差异无统计学意义(P>0.05),但心电图异常率均高于A组。合并基础病的患者在免疫治疗过程中心电不良事件的发生率为无基础病患者的1.938倍。B组、C组和D组患者免疫治疗过程中心电不良事件的发生率分别是A组患者的6.667倍、6.000倍、7.667倍。结论免疫检查点抑制剂引起的心电图早期改变敏感性较高,能够及早预测相关心脏不良反应,是否合并基础病和药物剂量是发生心电不良事件的相关因素,心电图早期的改变为临床治疗及预防提供依据。

ObjectiveTo observe the electrocardiogram(ECG)changes of programmed death receptor 1(PD-1)/programmed death receptor-ligand 1(PD-L1)immune checkpoint inhibitors before and after immunotherapy of patients during clinical antitumor process,and to explore the occurrence and influencing factors of cardiotoxicity of immune checkpoint inhibitors.MethodsA total of 93 patients with locally advanced or metastatic solid tumors confirmed by pathological diagnosis in Cancer Hospital of Chinese Academy of Medical Sciences from October 1,2019 to September 30,2020 were selected and treated with PD-1/PD-L1 inhibitor monotherapy.Groups were divided according to immunotherapy regimen:Group A(drug code:609A),16 patients were given 1 mg/kg of the drug for 21 days;Group B(drug code:HX008),23 patients were treated with 200mg for 21 days;Group C(drug code:GB226),28 patients were treated with 3mg/kg for 14 days;Group D(drug code:LP002),26 patients were treated with 900mg for 14 days.The patients were monitored and followed up for 10 cycles.The ECG results of each group were recorded,and the correlation between ECG abnormality and cardiotoxicity was analyzed.ResultsA total of 75 patients showed abnormal ECG that met the diagnostic criteria.There was no significant difference in abnormal ECG rate after immunotherapy in group A(P>0.05),while the incidence of adverse cardiac events increased after immunotherapy in group B(P<0.05),and the abnormal ECG rate increased significantly after chemotherapy in group C and group D.There was statistical difference before and after immunotherapy(P<0.001).The number of abnormal cases in group A(8 cases,50.0%,8/16)was significantly lower than that of group B(20 cases,87.0%,20/23).The number of abnormal cases in group C and group D was 24(85.7%)and 23(88.4%),respectively,without statistical difference(P>0.05),but their abnormal rates of ECG were higher than that in group A.The incidence of electrical adverse events in immunotherapy center of patients with underlying diseases was 1.93 times higher than that of patients without underlying diseases.The incidence of central electrical adverse events during immunotherapy in group B,C and D was 6.667,6.000 and 7.667 times higher than that in group A,respectively.ConclusionsThe high sensitivity of early ECG changes induced by immune checkpoint inhibitors enables early prediction of related cardiotoxicity.The presence or absence of comorbid underlying disease and drug dosage are correlated with the occurrence of adverse cardiac events,and these early changes provide a evidence for clinical treatment and prevention.