Brentuximab vedotin combined with ABVD or AVD for patients with newly diagnosed Hodgkin's lymphoma: a phase 1, open-label, dose-escalation study
Brentuximab vedotin combined with ABVD or AVD for patients with newly diagnosed Hodgkin's lymphoma: a phase 1, open-label, dose-escalation study
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DOI：
10.1016/s1470-2045(13)70501-1
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发表时间：
2013-12-01
期刊：
影响因子：
51.1
通讯作者：
Ansell, Stephen M.
中科院分区：
文献类型：
--
作者：
Younes, Anas;Connors, Joseph M.;Ansell, Stephen M.
大约70-80%的晚期霍奇金淋巴瘤患者通过各种一线和二线治疗治愈，包括ABVD、BEACOPP和干细胞移植。维布妥昔单抗在复发性或难治性霍奇金淋巴瘤患者中显示出显著的临床活性，安全性特征可控。我们的目的是评估这种药物作为一线治疗的安全性和早期临床疗效与标准或修改标准治疗的患者与以前未经治疗的Hodgkin's lymphoma.Methods我们做了1期，开放标签，剂量递增的安全性研究比较维布妥昔单抗与标准（ABVD）或修改标准（AVD）治疗。患者按顺序入组。主要入选标准是新诊断的、未经治疗的、CD 30阳性的霍奇金淋巴瘤患者，其具有组织学证实的IIA期巨大病变或IIB-IV期病变，并且东部肿瘤协作组的体能状态为2或更低。或1.2 mg/kg维布妥昔单抗静脉输注，每2周一次，使用ABVD（25 mg/m2多柔比星、10单位/m2博莱霉素、6 mg/m2长春碱和375 mg/m2达卡巴嗪）或AVD（ABVD改良方案，不含博莱霉素）最多6个周期。我们的主要目的是评估维布妥昔单抗联合ABVD和AVD的安全性特征并确定最大耐受剂量（MTD）。评估了安全性人群的安全性特征和MTD。这项研究已经完成，并提出了最后分析。本研究注册于ClinicalTrials.gov，编号NCT 01060904。结果2010年1月29日至2012年9月17日期间，51例患者入组并接受了至少一剂维布妥昔单抗。维布妥昔单抗与ABVD或AVD联合给药时的最大耐受剂量不超过1.2 mg/kg。22例接受维布妥昔单抗和ABVD治疗的患者中有21例（95%）达到完全缓解，25例接受维布妥昔单抗和AVD治疗的患者中有24例（96%）达到完全缓解。不良事件通常为1级或2级;然而，维布妥昔单抗和ABVD组中发生肺毒性反应的患者数量不可接受（11/25 [44%]），超过了ABVD单独治疗的历史发生率。接受维布妥昔单抗+AVD治疗时，无患者发生肺毒性作用。最常见的3级或更严重的事件是中性粒细胞减少症（维布妥昔单抗和ABVD组20/25例患者[80%] vs维布妥昔单抗和AVD组20/26例患者[77%]），贫血（5例[20%] vs 3例[12%]），发热性中性粒细胞减少症（5例[20%] vs 2例[8%]），肺毒性作用（6 [24%] vs 0），晕厥（3例[12%] vs 2例[8%]），呼吸困难（3例[12%] vs 1例[4%]）、肺栓塞（3例[12%] vs 0例）、疲乏（各1例[4%]）和白细胞减少症（各1例[4%]）。41%的患者发生严重事件（维布妥昔单抗和ABVD组14例[56%]，维布妥昔单抗和AVD组7例[27%]）。总体上10%或以上患者发生的严重事件为发热性中性粒细胞减少症（维布妥昔单抗+ABVD组4例[16%] vs维布妥昔单抗+AVD组2例[8%]），并且仅在维布妥昔单抗+ABVD组中，肺毒性作用（6例[24%]）。解释维布妥昔单抗一般不应与博来霉素联合给药，也不应专门作为初治患者的一线治疗，晚期霍奇金淋巴瘤。1.2患者对mg/kg维布妥昔单抗联合AVD每2周一次给药的耐受性通常良好。目前，一项比较维布妥昔单抗联合AVD与ABVD单药治疗的III期试验正在进行中（ClinicalTrials.gov，编号NCT 01712490），将正式评估维布妥昔单抗联合AVD是否可能重新定义霍奇金淋巴瘤初治患者的治疗。
Background Roughly 70-80% of patients with advanced stage Hodgkin's lymphoma are cured with various first-line and second-line treatments, including ABVD, BEACOPP, and stem-cell transplantation. Brentuximab vedotin has shown significant clinical activity, with a manageable safety profile, in patients with relapsed or refractory Hodgkin's lymphoma. We aimed to assess the safety and early clinical efficacy of this drug as first-line treatment in combination with standard or modified-standard treatment in patients with previously untreated Hodgkin's lymphoma.Methods We did a phase 1, open-label, dose-escalation safety study comparing brentuximab vedotin in combination with standard (ABVD) or a modified-standard (AVD) treatment. Patients were enrolled into the groups sequentially. Main entry criteria were newly diagnosed, treatment-naive, CD30-positive patients with Hodgkin's lymphoma who had histologically confirmed stage IIA bulky disease or stage IIB-IV disease and an Eastern Cooperative Oncology Group performance status of two or less. Patients received doses of 0.6, 0.9, or 1.2 mg/kg brentuximab vedotin by intravenous infusion every 2 weeks with either ABVD (25 mg/m(2) doxorubicin, 10 units/m(2) bleomycin, 6 mg/m(2) vinblastine, and 375 mg/m(2) dacarbazine) or AVD (ABVD modified regimen without the inclusion of bleomycin) for up to six cycles. Our primary objectives were to assess the safety profile and establish the maximum tolerated dose (MTD) of brentuximab vedotin in combination with ABVD and AVD. The safety profile and MTD was assessed for the safety population. The study has completed and the final analysis is presented. This study was registered with ClinicalTrials.gov, number NCT01060904.Findings Between Jan 29, 2010, and Sept 17, 2012, 51 patients were enrolled and received at least one dose of brentuximab vedotin. The maximum tolerated dose of brentuximab vedotin when combined with ABVD or AVD was not exceeded at 1.2 mg/kg. 21 (95%) of 22 patients given brentuximab vedotin and ABVD achieved complete remission, as did 24 (96%) of 25 patients given brentuximab vedotin and AVD. Adverse events were generally grade 1 or 2; however, an unacceptable number of patients in the brentuximab vedotin and ABVD groups had pulmonary toxic effects (11 [44%] of 25), which exceeded the historical incidence for ABVD alone. No patients experienced pulmonary toxic effects when treated with brentuximab vedotin plus AVD. The most common grade 3 or worse events were neutropenia (20 [80%] of 25 patients in the brentuximab vedotin and ABVD group vs 20 [77%] of 26 patients in the brentuximab vedotin and AVD group), anaemia (five [20%] vs three [12%]), febrile neutropenia (five [20%] vs two [8%]), pulmonary toxic effects (six [24%] vs 0), syncope (three [12%] vs two [8%]), dyspnoea (three [12%] vs one [4%]), pulmonary embolism (three [12%] vs 0), fatigue (one [4%] each), and leucopenia (one [4%] each). Serious events occured in 41% of all patients (14 [56%] in the brentuximab vedotin and ABVD group and seven [27%] in the brentuximab vedotin and AVD group). Serious events occurring in 10% of patients or more overall were febrile neutropenia (four [16%] in the brentuximab vedotin and ABVD group vs two [8%] in the brentuximab vedotin and AVD group), and, in the brentuximab vedotin and ABVD group only, pulmonary toxic effects (six [24%]).Interpretation Brentuximab vedotin should not be given with bleomycin in general or specifically as first-line therapy for patients with treatment naive, advanced stage Hodgkin's lymphoma. 1.2 mg/kg brentuximab vedotin combined with AVD given every 2 weeks was generally well tolerated by patients. At present, a phase 3 trial comparing brentuximab vedotin plus AVD to ABVD alone is ongoing (ClinicalTrials.gov, number NCT01712490) and will formally assess whether brentuximab vedotin plus AVD might redefine therapy in treatment-naive patients with Hodgkin's lymphoma.