上皮性卵巢癌化疗和PARPi治疗相关血液学毒副作用:临床表现,诊断和管理

2021-01-31 张丽丽 张师前 张师前公众号

上皮性卵巢癌(EOC)是女性中第五大最常见的癌症,是妇科恶性肿瘤中致死率最高的肿瘤,确诊时通常已是晚期。手术后进行铂类化疗仍然是金标准治疗。但是,大多数患者会复发,在最近几年中,多聚-ADP-核糖聚合

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上皮性卵巢癌(EOC)是女性中第五大最常见的癌症,是妇科恶性肿瘤中致死率最高的肿瘤,确诊时通常已是晚期。手术后进行铂类化疗仍然是金标准治疗。但是,大多数患者会复发,在最近几年中,多聚-ADP-核糖聚合酶的抑制剂(PARPi)已被开发为新型且有效的抗癌疗法,尤其是对于乳腺癌基因(BRCA1 / BRCA2)突变携带者。几项临床试验表明PARPi在EOC中的疗效,在复发情况下的无进展生存期有显著改善。在BRCA突变的患者(SOLO2试验)和BRCA野生型患者(OV16/ NOVA,ARIEL3试验)中均显示了生存获益。最近,SOLO1试验证明,在新诊断为BRCA突变的EOC的患者中,奥拉帕利维持治疗可将疾病进展或死亡的风险降低70%。这些研究通过批准PARPi的维持治疗,开创了EOC管理的新纪元,目前有多个临床试验评估多种PARPi的疗效。

PARPi通过所谓的“合成致死性”机制发挥其抗癌活性,精通同源重组修复(HRR)的正常细胞能够在PARP抑制下存活。但是,正常细胞,特别是快速分裂的细胞,例如造血细胞,也可能会受到DNA修复过程中影响。已经有报道PARPi治疗后的血液毒性是频繁的不良事件。最近的一项荟萃分析显示,接受PARPi的患者中3级或4级中性粒细胞减少,血小板减少和贫血的发生率分别为32.9%,15.9%和9.1%。这些副作用通常在治疗的最初几个月内发生,通过暂时的治疗中断,或剂量减少来控制。但是对晚期血液学毒性了解较少。如果在药物中断后仍无法消除血液学毒性,建议定期进行血液检查监测,并进行其他检查。

为了评估PARPi的长期血液学并发症,本文对米兰欧洲肿瘤研究所(IEO)接受PARPi治疗的130例患者进行了回顾性分析。并描述与治疗有关的血液系统疾病(tr-HDs)的早期诊断及其管理。

研究方法

本文分析了2010年至2018年之间在米兰欧洲肿瘤研究所(IEO)连续接受PARPi治疗的130例EOC患者。开始PARPi之前,在每个新周期和每月间隔,收集外周血进行细胞血计数(CBC)。对表现出持续和/或明显血液学异常的患者进行骨髓(BM)评估,包括形态,免疫表型,细胞遗传学和FISH分析,使用Ion Reporter软件进行分析。采用描述性统计用于报告与患者人口统计学、临床病理特征和治疗相关的数据。

研究结果

研究显示,所有发展为tr-HDs的患者均在PARPi之前接受了铂和紫杉烷类的一线化疗以及铂类为基础的化疗。在中位数22.8个月的PARPi治疗后,有9名患者(6.9%)出现了tr-HD。其中,奥拉帕利组7例患者发生tr-HDs,卢卡帕利组2例患者发生tr-HDs,尼拉帕利组未发生tr-HDs。9名患者分别为:1名患者被诊断为患有不确定性克隆性细胞减少症(CCUS),5名患有MDS(4名患有MDS的母细胞过多(EB):3名EB2和1名EB1;1例MDS无法分类),另外2例患者被诊断为急性粒细胞白血病(AML)(1例AML-FAB M6和1例伴有骨髓增生异常相关变化(MRC)的AML),1例患者被诊断为急性淋巴细胞性白血病(ALL),FAB L3。在tr-HD诊断后,除CCUS患者外,所有患者均停止PARPi。2名MDS-EB2患者过早死亡,无法治疗。2名患者(CCUS和MDS-U)没有积极治疗的指征,目前正在进行严密的血液学监测。另5例患者接受了化疗,其中3例接受了同种异体造血移植:3例在13、19、25个月时血液病和妇科恶性肿瘤完全缓解,其余2例患者因血液病进展而死亡。

 Table1 130例EOC化疗后应用PARPi及PARPi治疗期间出现tr-HD患者的临床特点

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Table2  与治疗有关的血液病患者的特征和治疗

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Table 3 异基因造血干细胞移植患者的特征

 

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研究结论

研究表明了接受化疗及后续长期PARPi治疗的EOC患者存在晚期血液毒性的潜在风险,与其他研究报告相比,本研究中的tr-HDs发病率更高。建议进行仔细的血液学监测,以便在大样本和长期随访中最终确定PARPi患者中tr-HD的实际风险。做好PARPi下患者tr-HD的管理,及时诊断和适当的处理可以使严重的血液学并发症得以缓解。

参考文献:

Todisco, E; Gigli, F; Mantiero, M; Tarella, C; et al,Clinical presentation, diagnosis andmanagement of Therapy-Related Hematological Disorders in Women with EpithelialOvarian Cancer treated with Chemotherapy and Poly-ADP-Ribose PolymeraseInhibitors (PARP-i): a single Center experience. Int J Cancer. 2021 Jan 01;148(1):170-177.

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  4. 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time=2021-02-02, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1621380, encodeId=ba9f16213800a, content=<a href='/topic/show?id=49b313e56ad' target=_blank style='color:#2F92EE;'>#PARP#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=39, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=13756, encryptionId=49b313e56ad, topicName=PARP)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=fd4d20248280, createdName=lishiwen, createdTime=Tue Feb 02 09:26:40 CST 2021, time=2021-02-02, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=921732, encodeId=7434921e322d, content=<a href='/topic/show?id=08f236865a8' target=_blank style='color:#2F92EE;'>#卵巢癌#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=165, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=36865, encryptionId=08f236865a8, topicName=卵巢癌)], attachment=null, 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    2021-04-23 lishizhe
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    2021-02-02 lishiwen
  9. 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