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Venetoclax with dose-adjusted EPOCH-R as initial therapy for patients with aggressive B-cell lymphoma: a single-arm, multicentre, phase 1 study.
The Lancet Haematology ( IF 15.4 ) Pub Date : 2021-10-08 , DOI: 10.1016/s2352-3026(21)00273-8
Sarah C Rutherford 1 , Jeremy S Abramson 2 , Nancy L Bartlett 3 , Stefan K Barta 4 , Nadia Khan 5 , Robin Joyce 6 , Kami Maddocks 7 , Trisha Ali-Shaw 1 , Silvia Senese 1 , Ying Yuan 8 , Jason Westin 9 , John P Leonard 1
Affiliation  

BACKGROUND Dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) is a front-line treatment for patients with aggressive B-cell lymphomas. Bcl-2 is associated with chemoresistance due to BCL2 gene rearrangement or protein overexpression and is antagonised by venetoclax. We aimed to assess the safety of venetoclax with dose-adjusted EPOCH-R as initial therapy in aggressive B-cell lymphoma. METHODS We conducted a single-arm, phase 1 study across seven treatment centres in the USA. Eligible patients were aged 18-80 years with histologically confirmed, previously untreated diffuse large B-cell lymphoma, transformed indolent non-Hodgkin lymphoma, high-grade B-cell lymphoma with double-hit or not otherwise specified, or primary mediastinal B-cell lymphoma, with Ann Arbor stage II-IV and Eastern Cooperative Oncology Group performance status of 0-2. Participants received six cycles of oral venetoclax 400 mg, 600 mg, or 800 mg once daily for 10 days per cycle with dose-adjusted EPOCH-R (one cycle every 3 weeks; baseline doses were intravenous rituximab 375 mg/m2 on day 1, intravenous etoposide 50 mg/m2 on days 1-4, oral prednisone 60 mg/m2 twice daily on days 1-5, intravenous vincristine 0·4 mg/m2 on days 1-4, intravenous cyclophosphamide 750 mg/m2 on day 5, and intravenous doxorubicin 10 mg/m2 on days 1-4). A subsequent cohort received venetoclax 600 mg once daily for 5 days per cycle. The primary endpoints were the maximum tolerated dose, dose-limiting toxicities, and the recommended phase 2 dose of venetoclax. Analyses were done per protocol. This trial is registered with ClinicalTrials.gov, NCT03036904, and enrolment is now closed. FINDINGS Between Feb 3, 2017, and June 4, 2019, 34 patients were assessed for eligibility, and 30 were enrolled and received venetoclax with dose-adjusted EPOCH-R. The median patient age was 64·0 years (IQR 51·6-69·4). The maximum tolerated dose was 800 mg for 10 days and the established recommended phase 2 dose was 600 mg for 5 days due to tolerability for treatment duration. One (3%) of 30 patients had a dose-limiting toxicity in cycle one (grade 4 thrombocytopenia with 800 mg dose). The most common grade 3-4 adverse events were cytopenias (28 [93%] of 30 patients); febrile neutropenia occurred in 19 (63%) patients. Grade 3-4 non-haematological adverse events included hypophosphataemia (n=10), hypokalaemia (n=7), and hyperglycaemia (n=5). Serious adverse events included infection (n=7) and gastrointestinal toxicities including abdominal pain (n=3), colonic perforation (n=1), and small intestinal obstruction (n=1). There was one treatment-related death (sepsis). Overall response rate was 96·7% (95% CI 82·8-99·9); 28 (93·3% [77·9-99·2]) of 30 patients had complete response and one (3·3% [0·1-17·2]) had a partial response. INTERPRETATION Venetoclax with dose-adjusted EPOCH-R showed an acceptable safety profile at the recommended phase 2 dose and had encouraging preliminary activity in this population at high risk of adverse outcomes, and is worthy of further study. The combination is being investigated in Alliance 051701 (NCT03984448). FUNDING Genentech.

中文翻译:

Venetoclax 与剂量调整的 EPOCH-R 作为侵袭性 B 细胞淋巴瘤患者的初始治疗:单臂、多中心、1 期研究。

背景 剂量调整的 EPOCH-R(依托泊苷、泼尼松、长春新碱、环磷酰胺、多柔比星和利妥昔单抗)是侵袭性 B 细胞淋巴瘤患者的一线治疗药物。由于 BCL2 基因重排或蛋白质过度表达,Bcl-2 与化疗耐药相关,并被 venetoclax 拮抗。我们旨在评估 venetoclax 与剂量调整后的 EPOCH-R 作为侵袭性 B 细胞淋巴瘤初始治疗的安全性。方法 我们在美国的七个治疗中心进行了一项单组 1 期研究。符合条件的患者年龄在 18-80 岁,且经组织学证实、既往未治疗的弥漫性大 B 细胞淋巴瘤、转化惰性非霍奇金淋巴瘤、双重打击或未指定的高级别 B 细胞淋巴瘤,或原发性纵隔 B 细胞淋巴瘤淋巴瘤,安娜堡 II-IV 期和东部肿瘤合作小组的表现状态为 0-2。参与者接受了 6 个周期的口服 venetoclax 400 mg、600 mg 或 800 mg 每天一次,每个周期 10 天,并使用剂量调整的 EPOCH-R(每 3 周一个周期;基线剂量为第 1 天静脉注射利妥昔单抗 375 mg/m2,第 1-4 天静脉注射依托泊苷 50 mg/m2,第 1-5 天口服泼尼松 60 mg/m2,每天两次,第 1-4 天静脉注射长春新碱 0·4 mg/m2,第 5 天静脉注射环磷酰胺 750 mg/m2,第 1-4 天静脉注射多柔比星 10 mg/m2)。随后的队列每天一次接受 venetoclax 600 mg,每个周期 5 天。主要终点是最大耐受剂量、剂量限制性毒性和 venetoclax 的推荐 2 期剂量。根据方案进行分析。该试验已在 ClinicalTrials.gov 注册,NCT03036904,注册现已关闭。结果 2017 年 2 月 3 日至 2019 年 6 月 4 日期间,34 名患者接受了资格评估,30 名患者入组并接受了剂量调整 EPOCH-R 的 venetoclax。患者的中位年龄为 64·0 岁 (IQR 51·6-69·4)。由于治疗持续时间的耐受性,最大耐受剂量为 800 毫克,持续 10 天,确定的 2 期推荐剂量为 600 毫克,持续 5 天。30 名患者中有 1 名 (3%) 在第一周期出现剂量限制性毒性(800 mg 剂量的 4 级血小板减少症)。最常见的 3-4 级不良事件是血细胞减少症(30 名患者中的 28 名 [93%]);19 名 (63%) 患者出现发热性中性粒细胞减少症。3-4 级非血液学不良事件包括低磷血症 (n=10)、低钾血症 (n=7) 和高血糖症 (n=5)。严重的不良事件包括感染 (n=7) 和胃肠道毒性,包括腹痛 (n=3)、结肠穿孔 (n=1) 和小肠梗阻 (n=1)。有 1 例治疗相关死亡(败血症)。总体反应率为 96·7% (95% CI 82·8-99·9);30 名患者中有 28 名 (93·3% [77·9-99·2]) 完全缓解,1 名 (3·3% [0·1-17·2]) 部分缓解。解释 经剂量调整的 EPOCH-R 的 Venetoclax 在推荐的 2 期剂量下显示出可接受的安全性特征,并且在这一具有不良结局高风险的人群中具有令人鼓舞的初步活性,值得进一步研究。Alliance 051701 (NCT03984448) 正在研究这种组合。资助基因泰克。有 1 例治疗相关死亡(败血症)。总体反应率为 96·7% (95% CI 82·8-99·9);30 名患者中有 28 名 (93·3% [77·9-99·2]) 完全缓解,1 名 (3·3% [0·1-17·2]) 部分缓解。解释 经剂量调整的 EPOCH-R 的 Venetoclax 在推荐的 2 期剂量下显示出可接受的安全性特征,并且在这一具有不良结局高风险的人群中具有令人鼓舞的初步活性,值得进一步研究。Alliance 051701 (NCT03984448) 正在研究这种组合。资助基因泰克。有 1 例治疗相关死亡(败血症)。总体反应率为 96·7% (95% CI 82·8-99·9);30 名患者中有 28 名 (93·3% [77·9-99·2]) 完全缓解,1 名 (3·3% [0·1-17·2]) 部分缓解。解释 经剂量调整的 EPOCH-R 的 Venetoclax 在推荐的 2 期剂量下显示出可接受的安全性特征,并且在这一具有不良结局高风险的人群中具有令人鼓舞的初步活性,值得进一步研究。Alliance 051701 (NCT03984448) 正在研究这种组合。资助基因泰克。解释 经剂量调整的 EPOCH-R 的 Venetoclax 在推荐的 2 期剂量下显示出可接受的安全性特征,并且在这一具有不良结局高风险的人群中具有令人鼓舞的初步活性,值得进一步研究。Alliance 051701 (NCT03984448) 正在研究这种组合。资助基因泰克。解释 经剂量调整的 EPOCH-R 的 Venetoclax 在推荐的 2 期剂量下显示出可接受的安全性特征,并且在这一具有不良结局高风险的人群中具有令人鼓舞的初步活性,值得进一步研究。Alliance 051701 (NCT03984448) 正在研究这种组合。资助基因泰克。
更新日期:2021-10-08
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