Today, the large majority of patients with Hodgkin lymphoma are cured. However, treatment of patients with advanced-stage disease with optimal chemotherapy, such as doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), fails to cure as many as 15% to 25% of patients, necessitating secondary intensified treatment, which incurs major toxicity and is only successful in;50% of patients. Genuine improvement in these outcomes will require identification of novel effective agents that can be integrated with standard chemotherapy during primary treatment. One candidate agent is brentuximab vedotin (ADCETRIS, Seattle Genetics, Inc), an antibody drug conjugate that employs a protease cleavable covalent linker to combine a chimeric monoclonal antibody directed against the CD30 antigen found universally on the surface of Hodgkin Reed-Sternberg cells with monomethyl auristatin E, amicrotubule disrupting agent. Brentuximab vedotin has substantial effectiveness (complete response rate 34%; overall response rate 75%) against otherwise treatment-resistant classical Hodgkin lymphoma and confers only modest toxicity, primarily confined to reversible neuropathy, suggesting that it may be safely combined with standard primary chemotherapy. We previously conducted a phase 1 clinical trial with an expansion cohort testing the safety and effectiveness of the addition of brentuximab vedotin to ABVD or the same combination with omission of bleomycin. The addition of brentuximab vedotin was associated with excellent outcomes, including complete response in 45 of 47 assessable patients (95%). The addition of brentuximab vedotin was well tolerated, permitting full doses of 1.2 mg/kg every 2 weeks to be delivered without compromising the dosing of the other therapeutic chemotherapy agents; however, excessive pulmonary toxicity emerged when brentuximab vedotinwas added toABVD, indicating that brentuximab vedotin andbleomycin cannot be safely combined.At the conclusion of the original trial, we initiated a long-term follow-up study to determine the ultimate impact of the addition of brentuximab vedotin toABVDor doxorubicin, vinblastine, and dacarbazine (AVD). Inbrief, 51patientswith previouslyuntreated advanced-stage (stage IIA bulky, n5 3; IIB, n5 8; IIIA, n5 8; IVA, n5 9; IVB, n5 23) classical Hodgkin lymphoma were treated with ABVD (n 5 25) or AVD (n 5 26) plus brentuximab vedotin. Patients’ initial characteristics are summarized in Table 1. Brentuximab vedotin was given IV every 2weeks on the sameday as theABVDorAVD, and the dosewas escalated from 0.6 mg/kg to 1.2 mg/kg in planned cohorts (0.6 mg/kg, n 5 6; 0.9 mg/kg, n 5 13; 1.2 mg/kg, n 5 6). All 26 patients treated with AVD started their brentuximab vedotin at the full planned dose of 1.2 mg/kg every 2 weeks (n5 26). Additional details, including use of supportive medications such as neutrophil growth factors, are fully described in the original publication about this trial. Radiation, permitted at the treating physician’s discretion, was delivered to 4 patients (8%) at the conclusion of primary chemotherapy. Three of these 4 patients had bulkymediastinal tumors, and all 4 patients were treated with AVD plus brentuximab vedotin. None experienced pulmonary toxicity. After completion of the original trial, patients were enrolled in this long-term follow-up study. Periodically, each patient’s current vital and relapse status was determined and, if relapse had occurred, the date and planned treatment of relapsewere recorded, afterwhich onlyvital status and presence or absence of lymphoma were subsequently ascertained. Survival estimates were calculated using the method of Kaplan and Meier, and graphical plots were displayed using GraphPad Prism 7.0 software. Failure-free survival (FFS) was the interval from diagnosis to death from any cause, disease progression after initiation of primary treatment, or date of last follow-up. Overall survival (OS) was the interval from diagnosis to death from any cause or date of last followup. This study was approved by the respective institutional research ethics boards of each of the participating centers. Seattle Genetics, Inc provided funding to support the conduct of the study and was provided a copy of this manuscript in advance of publication but did not otherwise participate in its execution or interpretation. Two patients died because of pulmonary toxicity during treatment with ABVD plus brentuximab vedotin, and 1 patient initially treated with ABVD plus brentuximab withdrew consent after 1 cycle of treatment, leaving 48 patients available for the long-term follow-up

中文翻译：

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brentuximab vedotin 联合 ABVD 或 AVD 治疗晚期经典霍奇金淋巴瘤的五年随访

今天，绝大多数霍奇金淋巴瘤患者已经治愈。然而，采用阿霉素、博来霉素、长春碱和达卡巴嗪 (ABVD) 等最佳化疗方案治疗晚期疾病患者，无法治愈多达 15% 至 25% 的患者，需要二次强化治疗，这会导致严重的并发症。毒性并且仅在; 50％的患者中成功。这些结果的真正改善将需要确定新的有效药物，这些药物可以在初级治疗期间与标准化疗相结合。一种候选药物是 brentuximab vedotin (ADCETRIS, Seattle Genetics, Inc)，一种抗体药物偶联物，它采用蛋白酶可切割的共价接头将针对 CD30 抗原的嵌合单克隆抗体与普遍存在于 Hodgkin Reed-Sternberg 细胞表面的单甲基 auristatin E（一种微管破坏剂）相结合。Brentuximab vedotin 对其他治疗耐药的经典霍奇金淋巴瘤具有显着的有效性（完全缓解率为 34%；总体缓解率为 75%），并且仅具有适度的毒性，主要限于可逆性神经病变，表明它可以安全地与标准的初级化疗联合使用。我们之前进行了一项扩展队列的 1 期临床试验，以测试将 brentuximab vedotin 添加到 ABVD 或与省略博来霉素的相同组合的安全性和有效性。添加 brentuximab vedotin 与出色的结果相关，包括 47 名可评估患者中的 45 名（95%）完全缓解。添加 brentuximab vedotin 具有良好的耐受性，允许每 2 周提供 1.2 mg/kg 的全剂量，而不会影响其他治疗性化疗药物的剂量；然而，将 brentuximab vedotin 添加到 ABVD 时出现了过度的肺毒性，表明 brentuximab vedotin 和博来霉素不能安全地联合使用。 在原始试验结束时，我们启动了一项长期随访研究以确定添加 brentuximab 的最终影响vedotin 到 ABV 或阿霉素、长春碱和达卡巴嗪 (AVD)。简而言之，51 名先前未经治疗的晚期患者（IIA 期大块，n5 3；IIB，n5 8；IIIA，n5 8；IVA，n5 9；IVB，n5 23) 经典霍奇金淋巴瘤用 ABVD (n 5 25) 或 AVD (n 5 26) 加 brentuximab vedotin 治疗。患者的初始特征总结在表 1 中。在 ABVD 或 AVD 的同一天，每 2 周静脉给予一次 Brentuximab vedotin，并且在计划的队列中剂量从 0.6 mg/kg 增加到 1.2 mg/kg（0.6 mg/kg，n 5 6； 0.9 mg/kg，n 5 13；1.2 mg/kg，n 5 6)。所有 26 名接受 AVD 治疗的患者以每 2 周 1.2 mg/kg 的完整计划剂量开始他们的 brentuximab vedotin (n5 26)。其他详细信息，包括使用中性粒细胞生长因子等支持性药物，在有关该试验的原始出版物中有完整描述。在主治医师的判断下，放射治疗在初级化疗结束时对 4 名患者 (8%) 进行了治疗。这 4 名患者中有 3 名患有巨大的纵隔肿瘤，所有 4 名患者均接受 AVD 加 brentuximab vedotin 治疗。没有人经历过肺毒性。完成原始试验后，患者被纳入这项长期随访研究。定期确定每位患者当前的生命和复发状态，如果发生复发，则记录复发的日期和计划治疗，之后仅确定生命状态和淋巴瘤的存在与否。使用 Kaplan 和 Meier 的方法计算生存估计，并使用 GraphPad Prism 7.0 软件显示图形。无失败生存期 (FFS) 是从诊断到任何原因死亡、开始主要治疗后疾病进展或最后一次随访日期的时间间隔。总生存期 (OS) 是从诊断到因任何原因或最后一次随访日期死亡的时间间隔。这项研究得到了每个参与中心各自的机构研究伦理委员会的批准。Seattle Genetics, Inc 提供资金支持研究的开展，并在出版前获得了这份手稿的副本，但并未参与其执行或解释。2 名患者在 ABVD 联合 brentuximab vedotin 治疗期间因肺毒性死亡，1 名最初接受 ABVD 联合 brentuximab 治疗的患者在 1 个治疗周期后撤回同意，剩下 48 名患者可用于长期随访 Inc 提供资金支持研究的进行，并在出版前获得了这份手稿的副本，但没有参与其执行或解释。2 名患者在 ABVD 联合 brentuximab vedotin 治疗期间因肺毒性死亡，1 名最初接受 ABVD 联合 brentuximab 治疗的患者在 1 个治疗周期后撤回同意，剩下 48 名患者可用于长期随访 Inc 提供资金支持研究的进行，并在出版前获得了这份手稿的副本，但没有参与其执行或解释。2 名患者在 ABVD 联合 brentuximab vedotin 治疗期间因肺毒性死亡，1 名最初接受 ABVD 联合 brentuximab 治疗的患者在 1 个治疗周期后撤回同意，剩下 48 名患者可用于长期随访