聚乙二醇化脂质体多柔比星致晚期乳腺癌患者速发型超敏反应与抗聚乙二醇抗体的相关性研究

Study on the correlation between immediate hypersensitivity induced by pegylated liposomal doxorubicin and the anti-polyethylene glycol antibody in patients with advanced breast cancer

目的探讨聚乙二醇化脂质体多柔比星(PLD)致晚期乳腺癌患者速发型超敏反应与血浆抗聚乙二醇(PEG)抗体的相关性。方法研究设计为前瞻性非干预性临床研究,研究对象选自中山大学孙逸仙纪念医院收治的晚期乳腺癌女性患者,治疗方案为PLD单药治疗(盐酸多柔比星脂质体注射液50 mg/m^(2)入5%葡萄糖注射液250 ml静脉滴注90 min,给药前不进行地塞米松或其他药物预处理)。给药前所有患者行血浆抗PEG抗体水平检查,以抗体水平>2 ng/L为阳性;对给药开始后30 min内发生超敏反应者寻找时机尽快采血行血清IgE和C3、C4水平检查。根据是否发生速发型超敏反应将患者分为超敏反应组和无超敏反应组,比较2组患者临床特征和血浆抗PEG抗体携带情况;根据抗PEG抗体携带情况将患者分为抗PEG抗体阳性组和阴性组,比较2组患者的临床特征和超敏反应发生率。结果纳入研究的患者共12例,年龄37~68岁,中位年龄50岁;10例既往使用过非PEG化蒽环类药物,经等效剂量换算后,累积剂量相当于多柔比星329(185,418)mg/m^(2)。用药开始后2~18 min共7例患者发生超敏反应,超敏反应组与无超敏反应组患者年龄、身高、体重、体表面积、既往蒽环类药物应用情况、累积剂量等临床特征差异均无统计学意义(均P>0.05),抗PEG抗体阳性率差异也无统计学意义(4/7比2/5,P=1.000)。12例患者中抗PEG抗体阳性和阴性者各6例,2组患者上述临床特征和超敏反应发生率(3/6比4/6)差异均无统计学意义(均P>0.05)。超敏反应组有4例患者行血清IgE和C3、C4水平检查,2例抗PEG抗体阳性者血清IgE水平升高(分别为404、545μg/L),其中1例血清C4水平也升高(486 mg/L),而2例抗PEG抗体阴性者血清IgE和C3、C4水平均正常。结论未发现PLD诱导速发型超敏反应与抗PEG抗体相关,可能与研究样本量小有关,不排除抗PEG抗体可能参与诱发IgE介导的速发型超敏反应,在部分患者中还可能由补体介导。

Objective To explore the correlation between immediate hypersensitivity induced by pegylated liposomal doxorubicin(PLD)and the plasma anti-polyethylene glycol(anti-PEG)antibody in advanced breast cancer patients.Methods The study was designed as a prospective and noninterventional study.The subjects were selected from advanced breast cancer patients in Sun Yat-Sen Memorial Hospital,Sun Yat-Sen University,who received monotherapy with PLD(an IV infusion of PLD 50 mg/m^(2) in 5%glucose solution 250 ml for 90 minutes without pretreatment with dexamethasone or other drugs).Anti-PEG antibody before administration were detected for all the patients and antibody level>2 ng/L was defined as positive.Blood in patients who had hypersensitivity within 30 minutes after the start of infusion was collected(finding the opportunity as soon as possible)and IgE,C3,and C4 levels in serum were detected.According to whether there was an immediate hypersensitivity reaction,the patients were divided into hypersensitivity group and non-hypersensitivity group and the clinical characteristics and plasma anti-PEG antibody carrying status in patients between the 2 groups were compared;according to anti-PEG antibody carrying status,the patients were divided into anti-PEG antibody positive group and negative group and the clinical characteristics and the incidence of hypersensitivity in patients between the 2 groups were compared.Results A total of 12 patients were included in the study,aged from 37 to 68 years with a median age of 50(37-68)years.Ten patients had previously used non-pegylated anthracyclines and the median cumulative dose was 329(185,418)mg/m^(2) after a doxorubicin equivalent dose conversion.Seven patients developed hypersensitivity within 2-18 minutes after the start of infusion.Between the hypersensitivity group and the non-hypersensitivity group,differences in clinical characteristics such as age,height,weight,body surface area,previous application of anthracyclines,and the cumulative doses in patients were not significant(all P>0.05);the difference in positive rate of anti-PEG antibodies in patients was also not statistically significant(4/7 vs.2/5,P=1.000).Among the 12 patients,6 were positive for anti-PEG antibody and 6 were negative and the differences in the above-mentioned clinical characteristics or the incidence of hypersensitivity(3/6 vs.4/6)in patients between the 2 groups(all P>0.05)were not significant.In the hypersensitivity group,IgE,C3,and C4 levels in serum were detected in 4 patients.Two patients with positive anti-PEG antibody had increased IgE levels(404 and 545µg/L,respectively),1 of which had also increased C4 level(486 mg/L);the other 2 patients with negative anti-PEG antibody had normal IgE,C3,and C4 levels.Conclusions It has not been found that PLD-induced immediate hypersensitivity is related to the anti-PEG antibody,which may be due to the small sample size of the study.It cannot be ruled out that anti-PEG antibody may be involved in the induction of the IgE-mediated immediate hypersensitivity,which may also be mediated by complement in some patients.