晚期及复发性卵巢上皮性癌患者PARP抑制剂相关贫血的临床特点分析

Analysis of PARP inhibitors induced anemia in advanced and relapsed epithelial ovarian cancer

目的探讨晚期及复发性卵巢上皮性癌(卵巢癌)患者聚二磷酸腺苷核糖聚合酶(PARP)抑制剂相关贫血的临床特点。方法收集2015年1月至2020年10月在中国医学科学院北京协和医学院肿瘤医院接受单药PARP抑制剂治疗>1个月的晚期及复发性卵巢癌患者的临床资料,包括服用的PARP抑制剂种类、用药时间及实验室检查指标,分析PARP抑制剂相关贫血的临床特点。结果(1)本研究纳入了98例接受单药PARP抑制剂治疗的卵巢癌患者,其中位年龄为56.5岁(30~82岁);其中,Ⅲ期52例、Ⅳ期15例,复发患者31例;晚期卵巢癌一线化疗后维持治疗67例、复发性卵巢癌化疗后维持治疗15例、卵巢癌复发后治疗16例;服用奥拉帕利65例、尼拉帕利17例、氟唑帕利16例,中位用药时间为37.5周(4~119周)。(2)98例卵巢癌患者中,发生PARP抑制剂相关贫血39例,发生率为40%(39/98),其中Ⅰ、Ⅱ、Ⅲ、Ⅳ度贫血的发生率分别为5%(5/98)、14%(14/98)、11%(11/98)、9%(9/98)。14例PARP抑制剂治疗前Ⅰ度贫血患者与80例无贫血患者发生PARP抑制剂相关贫血的比例分别为7/14和35%(28/80),两者比较,差异有统计学意义(χ²=4.281,P=0.039)。(3)PARP抑制剂相关贫血的中位发生时间为用药后7.0周(1~52周),其中治疗开始后第1~4周的发生率为41%(16/39)、第5~8周为26%(10/39)、第9~12周为13%(5/39)、第13~16周为3%(1/39)、第17~20周为10%(4/39)、≥21周为8%(3/39)。39例PARP抑制剂相关贫血患者的血红蛋白达最低水平时,中位红细胞平均体积(MCV)为106 fl,MCV高于正常值上限(>100 fl)的比例为74%(29/39);中位红细胞平均血红蛋白含量(MCH)为36 pg,MCH高于正常值上限(>34 pg)的比例为54%(21/39);中位红细胞平均血红蛋白浓度(MCHC)为320 g/L,MCHC正常(正常值为320~360 g/L)的比例为69%(27/39);血清铁正常的比例为92%(36/39),血清转铁蛋白正常的比例为79%(31/39)。74%(29/39)的贫血患者为大细胞正色素性贫血。(4)39例PARP抑制剂相关贫血患者中,20例(51%,20/39)患者因Ⅲ~Ⅳ度贫血导致停药,其中10例患者(50%,10/20)在中位停药5.5周(2~10周)后恢复PARP抑制剂治疗,另外10例则因贫血未恢复而永久停药。结论贫血是晚期及复发性卵巢癌患者应用PARP抑制剂治疗后常见的不良反应,多发生在用药的前3个月。PARP抑制相关贫血主要表现为大细胞正色素性贫血,半数的Ⅲ~Ⅳ度贫血患者因无法纠正而终止PARP抑制剂治疗。

Objective To explore the clinical features of poly ADP-ribose polymerase(PARP)inhibitor-related anemia in advanced and relapsed epithelial ovarian cancer(EOC).Methods Patients diagnosed with advanced or relapsed EOC and treated with PARP inhibitor at National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital,Chinese Academy of Medical Sciences and Peking Union Medical College between January 2015 to October 2020 were accrued.The data included PARP inhibitors,treatment details,and lab tests before treatment and during treatment were collected and the clinical characteristics of PARP inhibitor-related anemia were analyzed.Results(1)A total of 98 patients with a median age of 56.5 years old(30-82 years old)were enrolled in this study.All patients were treated with PARP inhibitor(65 cases of olaparib,17 cases of niraparib,and 16 cases of fluzoparib).The median treatment duration was 37.5 weeks(4-119 weeks).(2)The anemia rate was 40%(39/98),including 5%(5/98)of gradeⅠ,14%(14/98)of gradeⅡ,11%(11/98)of gradeⅢ,and 9%(9/98)of gradeⅣ.Fourteen patients with pre-treatment gradeⅠanemia had a higher rate of anemia events than the 80 patients without pre-treatment anemia,7/14 vs 35%(28/80;χ2=4.281,P=0.039).(3)The median anemia occurrence time was 7.0 weeks(1-52 weeks),including 41%(16/39)of anemia cases occurred in 1-4 weeks,26%(10/39)occurred in 5-8 weeks,13%(5/39)occurred in 9-12 weeks,3%(1/39)occurred in 13-16 weeks,10%(4/39)occurred in 17-20 weeks,8%(3/39)occurred≥21 weeks.At the time of the lowest hemoglobulin tested,the median value of mean corpuscular volume(MCV)was 106 fl,which was higher than the up limit of normal range(100 fl),74%(29/39)of anemia patients had an elevated MCV level;the median value of mean corpuscular hemoglobin(MCH)was 36 pg,54%(21/39)of anemia patients had an elevated MCH level;the median value of mean corpuscular hemoglobin concentration(MCHC)was 320 g/L,69%(27/39)of anemia patients had a higher MCHC level;92%(36/39)of anemia patients had a normal level of serum iron;79%(31/39)of anemia patients had a normal level of transferrin.74%(29/39)of the anemia patients were macrocytic orthochromatic anemia.(4)Among the 39 patients with anemia,20 patients(51%,20/39)withhold the treatment of PARP inhibitor due to gradeⅢorⅣanemia,including 10 patients(50%,10/20)who resumed the PARP inhibitor treatment by suppling iron,folate,and vitamin B12.The median stopping time of PARP inhibitor was 5.5 weeks(2-10 weeks),while the other 10 patients terminated the PARP inhibitor treatment for not recovering from severe anemia.Conclusions One of the common adverse effects of PARP inhibitors is anemia,which mostly happened in the first 3 months of treatment.In the treatment of EOC,PARP inhibitor-related anemia mainly manifest as macrocytic orthochromatic anemia,and most patients with normal serum iron and transferrin.