血浆病毒DNA作为评估EB病毒阳性的霍奇金淋巴瘤的肿瘤疗效的标记物（III期试验E2496研究）

中国肿瘤化疗  发布日期：2012-7-1

2012ASCO年会 摘要号：8003武汉协和医院肿瘤中心刘红利

作者：Jennifer Ann Kanakry, Hailun Li, Lan L. Gellert等 作者单位：Johns Hopkins School of Medicine, Baltimore, MD; Dana-Farber Cancer Institute, Boston, MA，USA
 
背景：EB病毒（EBV）与霍奇金淋巴瘤（HL）相关；通过原位杂交（ISH）可检测出肿瘤细胞内的EB病毒核酸（EBER）。研究表明霍奇金淋巴瘤患者血浆EB病毒DNA与原位杂交检测到的肿瘤部位EBER之间存在相关性。我们既往研究了DNA酶对血浆EB病毒DNA的敏感性，结果发现：DNA酶的溶解作用并不能保护EBV阳性霍奇金淋巴瘤患者血浆中的EB病毒，这一作用与肿瘤源性DNA一致；然而DNA酶溶解作用可以保护没有合并EBV阳性肿瘤的艾滋病患者血浆中的EB病毒，这一作用与病毒颗粒的DNA一致。我们遂探究血浆EB病毒检查是否可替代EBER原位杂交检测以及血浆EB病毒的再现是否预测治疗失败。

方法：所有标本来自癌症合作组的E2496研究（比较治疗霍奇金淋巴瘤的Stanford V与ABVD方案的疗效）。采用EBER原位杂交技术和实时定量PCR技术分别检测患者接受治疗前的EB病毒状态和血浆EB病毒DNA拷贝数。对治疗前的血浆EB病毒数和肿瘤EBER检测结果 (n=121)进行ROC分析，确定血浆中60个病毒拷贝/100 μL为EBV阳性的统计界点（与EBER确定的EB病毒状态的一致性95％，敏感度92％，特异度96％）。按照这个分界点，治疗前的血浆标本(n=274)分为EBV阳性组（n = 54）或EBV阴性组（n = 220），并进行一系列随访。构建了以评估血浆EBV作为无失败生存（FFS）的预后因素的Cox比例风险模型。采用Kaplan-Meier法评估FFS。

结果：对国际预后评分，治疗分组和组织学进行调整后，患者治疗前血浆EBV阳性与治疗失败相关，风险比HR为2.1（95%CI 1.2-3.6，P =0.01）。EBV阳性且有随访标本的患者（n=45）中，治疗1个月后血浆EBV仍然阳性的患者（n=9）的FFS劣于EBV被清除的患者（n=36）（3年FFS分别为44％和69％，log rank P = 0.03）。

结论：基线血浆EBV阳性的霍奇金淋巴瘤患者的FFS较其他患者差。在基线血浆EBV阳性的霍奇金淋巴瘤患者中，治疗后血浆EBV持续阳性或再次阳性者的FFS较差。这类患者可能从临床研究或强化治疗中获益。

高岩 译

Plasma viral DNA as a marker of tumor response in EBV(+) Hodgkin lymphoma in a phase III study (E2496).

2012 ASCO Abstract No:8003 Citation:J Clin Oncol 30, 2012 (suppl; abstr 8003)
 
Author(s): Jennifer Ann Kanakry, Hailun Li, Lan L. Gellert etc; Johns Hopkins School of Medicine, Baltimore, MD; Dana-Farber Cancer Institute, Boston, MA，USA

Background: Epstein-Barr virus (EBV) is associated with Hodgkin lymphoma (HL) and can be detected by in situ hybridization (ISH) of viral nucleic acid (EBER) in tumor cells. Studies have suggested a correlation in HL between plasma EBV DNA and EBER ISH. We previously studied the DNase sensitivity of plasma EBV DNA and found plasma EBV of patients with EBV(+) HL was not protected from DNase digestion, consistent with tumor-derived DNA, while plasma EBV of patients with HIV without EBV(+) tumors was protected from DNase digestion, consistent with virion DNA. We sought to determine whether plasma EBV could serve as a surrogate for EBER ISH and whether reappearance of plasma EBV predicts treatment failure.

Methods: Specimens from a Cancer Cooperative Intergroup Trial (E2496/Stanford V versus ABVD for HL) were used to compare pretreatment plasma EBV DNA copy number, assessed by real-time quantitative PCR, with EBV status by EBER ISH. An ROC analysis was performed using patients with both pretreatment plasma EBV and EBER results (n=121), identifying a cutoff of 60 viral copies/100 μL plasma (95% concordance, 92% sensitivity, 96% specificity for EBV status by EBER). Using this cutoff, pretreatment plasma specimens (n=274) were designated EBV(+) (n=54) or EBV(-) (n=220), as were serial follow-up specimens. Cox proportional hazard models were constructed to evaluate plasma EBV as a prognostic factor for failure-free survival (FFS). FFS was estimated by the Kaplan-Meier method.

Results: Pretreatment EBV(+) plasma was associated with treatment failure with a hazard ratio of 2.1 (95% CI 1.2-3.6, p=0.01) after adjusting for International Prognostic Score, treatment arm, and histology. Of the EBV(+) patients with follow-up specimens (n=45), patients with EBV(+) plasma beyond 1 month of therapy (n=9) had inferior FFS compared to those who cleared their plasma of EBV (n=36), (3-year FFS 44% versus 69%, respectively; log rank p=0.03).

Conclusions: HL patients with EBV(+) plasma at baseline have inferior FFS compared to others. Among patients with EBV(+) plasma at baseline, those in whom plasma EBV persists or reappears after initiation of therapy have inferior FFS. Such patients may benefit from experimental or intensified therapies.