PDF(Pubmed)
Abstract：
BACKGROUND: The identification of oncogenic mutations in diffuse large B-cell lymphoma (DLBCL) has led to the development of drugs that target essential survival pathways, but whether targeting multiple survival pathways may be curative in DLBCL is unknown.
METHODS: We performed a single-center, phase 1b-2 study of a regimen of venetoclax, ibrutinib, prednisone, obinutuzumab, and lenalidomide (ViPOR) in relapsed or refractory DLBCL. In phase 1b, which included patients with DLBCL and indolent lymphomas, four dose levels of venetoclax were evaluated to identify the recommended phase 2 dose, with fixed doses of the other four drugs. A phase 2 expansion in patients with germinal-center B-cell (GCB) and non-GCB DLBCL was performed. ViPOR was administered every 21 days for six cycles.
RESULTS: In phase 1b of the study, involving 20 patients (10 with DLBCL), a single dose-limiting toxic effect of grade 3 intracranial hemorrhage occurred, a result that established venetoclax at a dose of 800 mg as the recommended phase 2 dose. Phase 2 included 40 patients with DLBCL. Toxic effects that were observed among all the patients included grade 3 or 4 neutropenia (in 24% of the cycles), thrombocytopenia (in 23%), anemia (in 7%), and febrile neutropenia (in 1%). Objective responses occurred in 54% of 48 evaluable patients with DLBCL, and complete responses occurred in 38%; complete responses were exclusively in patients with non-GCB DLBCL and high-grade B-cell lymphoma with rearrangements of MYC and BCL2 or BCL6 (or both). Circulating tumor DNA was undetectable in 33% of the patients at the end of ViPOR therapy. With a median follow-up of 40 months, 2-year progression-free survival and overall survival were 34% (95% confidence interval [CI], 21 to 47) and 36% (95% CI, 23 to 49), respectively.
CONCLUSIONS: Treatment with ViPOR was associated with durable remissions in patients with specific molecular DLBCL subtypes and was associated with mainly reversible adverse events. (Funded by the Intramural Research Program of the National Cancer Institute and the National Center for Advancing Translational Sciences of the National Institutes of Health and others; ClinicalTrials.gov number, NCT03223610.).
METHODS: We performed a single-center, phase 1b-2 study of a regimen of venetoclax, ibrutinib, prednisone, obinutuzumab, and lenalidomide (ViPOR) in relapsed or refractory DLBCL. In phase 1b, which included patients with DLBCL and indolent lymphomas, four dose levels of venetoclax were evaluated to identify the recommended phase 2 dose, with fixed doses of the other four drugs. A phase 2 expansion in patients with germinal-center B-cell (GCB) and non-GCB DLBCL was performed. ViPOR was administered every 21 days for six cycles.
RESULTS: In phase 1b of the study, involving 20 patients (10 with DLBCL), a single dose-limiting toxic effect of grade 3 intracranial hemorrhage occurred, a result that established venetoclax at a dose of 800 mg as the recommended phase 2 dose. Phase 2 included 40 patients with DLBCL. Toxic effects that were observed among all the patients included grade 3 or 4 neutropenia (in 24% of the cycles), thrombocytopenia (in 23%), anemia (in 7%), and febrile neutropenia (in 1%). Objective responses occurred in 54% of 48 evaluable patients with DLBCL, and complete responses occurred in 38%; complete responses were exclusively in patients with non-GCB DLBCL and high-grade B-cell lymphoma with rearrangements of MYC and BCL2 or BCL6 (or both). Circulating tumor DNA was undetectable in 33% of the patients at the end of ViPOR therapy. With a median follow-up of 40 months, 2-year progression-free survival and overall survival were 34% (95% confidence interval [CI], 21 to 47) and 36% (95% CI, 23 to 49), respectively.
CONCLUSIONS: Treatment with ViPOR was associated with durable remissions in patients with specific molecular DLBCL subtypes and was associated with mainly reversible adverse events. (Funded by the Intramural Research Program of the National Cancer Institute and the National Center for Advancing Translational Sciences of the National Institutes of Health and others; ClinicalTrials.gov number, NCT03223610.).
摘要：
背景：弥漫性大B细胞淋巴瘤（DLBCL）中致癌基因突变的鉴定导致了靶向基本生存途径的药物的开发，但靶向多种生存途径是否可治愈DLBCL尚不清楚.
方法：我们执行了单中心，维奈托克方案的1b-2期研究，伊布替尼,泼尼松,奥比努珠单抗，来那度胺（ViPOR）治疗复发或难治性DLBCL。在阶段1b，其中包括DLBCL和惰性淋巴瘤患者，评估了四种剂量水平的维奈托克，以确定推荐的2期剂量，固定剂量的其他四种药物。在生发中心B细胞（GCB）和非GCBDLBCL患者中进行了2期扩增。ViPOR每21天给药6个周期。
结果：在研究的第1b阶段，涉及20例患者（10例DLBCL），发生3级颅内出血的单剂量限制性毒性作用，结果确定维奈托克的剂量为800mg作为推荐的2期剂量。第二阶段包括40例DLBCL患者。在所有患者中观察到的毒性作用包括3或4级中性粒细胞减少症（占周期的24％），血小板减少症（23%），贫血（7%），和发热性中性粒细胞减少症（1%）。48名可评估的DLBCL患者中有54％出现客观反应，38%的患者出现完全缓解;完全缓解仅发生在非GCBDLBCL和高度B细胞淋巴瘤患者中,MYC和BCL2或BCL6(或两者)重排.在ViPOR治疗结束时，有33％的患者无法检测到循环肿瘤DNA。中位随访时间为40个月，2年无进展生存率和总生存率为34%(95%置信区间[CI]，21至47)和36%(95%CI，23至49)，分别。
结论：ViPOR治疗与特定分子DLBCL亚型患者的持续缓解相关，并且主要与可逆的不良事件相关。（由美国国家癌症研究所的校内研究计划和美国国立卫生研究院的国家促进转化科学中心等资助；ClinicalTrials.gov编号，NCT03223610。).
方法：我们执行了单中心，维奈托克方案的1b-2期研究，伊布替尼,泼尼松,奥比努珠单抗，来那度胺（ViPOR）治疗复发或难治性DLBCL。在阶段1b，其中包括DLBCL和惰性淋巴瘤患者，评估了四种剂量水平的维奈托克，以确定推荐的2期剂量，固定剂量的其他四种药物。在生发中心B细胞（GCB）和非GCBDLBCL患者中进行了2期扩增。ViPOR每21天给药6个周期。
结果：在研究的第1b阶段，涉及20例患者（10例DLBCL），发生3级颅内出血的单剂量限制性毒性作用，结果确定维奈托克的剂量为800mg作为推荐的2期剂量。第二阶段包括40例DLBCL患者。在所有患者中观察到的毒性作用包括3或4级中性粒细胞减少症（占周期的24％），血小板减少症（23%），贫血（7%），和发热性中性粒细胞减少症（1%）。48名可评估的DLBCL患者中有54％出现客观反应，38%的患者出现完全缓解;完全缓解仅发生在非GCBDLBCL和高度B细胞淋巴瘤患者中,MYC和BCL2或BCL6(或两者)重排.在ViPOR治疗结束时，有33％的患者无法检测到循环肿瘤DNA。中位随访时间为40个月，2年无进展生存率和总生存率为34%(95%置信区间[CI]，21至47)和36%(95%CI，23至49)，分别。
结论：ViPOR治疗与特定分子DLBCL亚型患者的持续缓解相关，并且主要与可逆的不良事件相关。（由美国国家癌症研究所的校内研究计划和美国国立卫生研究院的国家促进转化科学中心等资助；ClinicalTrials.gov编号，NCT03223610。).
