Davids Matthew S, Roberts Andrew W, Seymour John F, Pagel John M, Kahl Brad S, Wierda William G, Puvvada Soham, Kipps Thomas J, Anderson Mary Ann, Salem Ahmed Hamed, Dunbar Martin, Zhu Ming, Peale Franklin, Ross Jeremy A, Gressick Lori, Desai Monali, Kim Su Young, Verdugo Maria, Humerickhouse Rod A, Gordon Gary B, Gerecitano John F
Matthew S. Davids, Dana-Farber Cancer Institute, Boston, MA; Andrew W. Roberts, John F. Seymour, and Mary Ann Anderson, University of Melbourne; Andrew W. Roberts and Mary Ann Anderson, Royal Melbourne Hospital and Eliza Hall Institute of Medical Research; and John F. Seymour, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; John M. Pagel, Swedish Cancer Institute, Seattle, WA; Brad S. Kahl, Washington University Medical School, St Louis, MO; William G. Wierda, University of Texas MD Anderson Cancer Center, Houston, TX; Soham Puvvada, University of Arizona, Tucson, AZ; Thomas J. Kipps, University of California San Diego, San Diego, CA; Ahmed Hamed Salem, Martin Dunbar, Ming Zhu, Jeremy A. Ross, Lori Gressick, Monali Desai, Su Young Kim, Maria Verdugo, Rod A. Humerickhouse, and Gary B. Gordon, AbbVie, Chicago, IL; Ahmed Hamed Salem, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt; Franklin Peale, Genentech, South San Francisco, CA; John F. Gerecitano, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical Center, New York, NY.
J Clin Oncol. 2017 Mar 10;35(8):826-833. doi: 10.1200/JCO.2016.70.4320. Epub 2017 Jan 17.
Purpose B-cell leukemia/lymphoma-2 (BCL-2) overexpression is common in many non-Hodgkin lymphoma (NHL) subtypes. A phase I trial in patients with NHL was conducted to determine safety, pharmacokinetics, and efficacy of venetoclax, a selective, potent, orally bioavailable BCL-2 inhibitor. Patients and Methods A total of 106 patients with relapsed or refractory NHL received venetoclax once daily until progressive disease or unacceptable toxicity at target doses from 200 to 1,200 mg in dose-escalation and safety expansion cohorts. Treatment commenced with a 3-week dose ramp-up period for most patients in dose-escalation cohorts and for all patients in safety expansion. Results NHL subtypes included mantle cell lymphoma (MCL; n = 28), follicular lymphoma (FL; n = 29), diffuse large B-cell lymphoma (DLBCL; n = 34), DLBCL arising from chronic lymphocytic leukemia (Richter transformation; n = 7), Waldenström macroglobulinemia (n = 4), and marginal zone lymphoma (n = 3). Venetoclax was generally well tolerated. Clinical tumor lysis syndrome was not observed, whereas laboratory tumor lysis syndrome was documented in three patients. Treatment-emergent adverse events were reported in 103 patients (97%), a majority of which were grade 1 to 2 in severity. Grade 3 to 4 events were reported in 59 patients (56%), and the most common were hematologic, including anemia (15%), neutropenia (11%), and thrombocytopenia (9%). Overall response rate was 44% (MCL, 75%; FL, 38%; DLBCL, 18%). Estimated median progression-free survival was 6 months (MCL, 14 months; FL, 11 months; DLBCL, 1 month). Conclusion Selective targeting of BCL-2 with venetoclax was well tolerated, and single-agent activity varied among NHL subtypes. We determined 1,200 mg to be the recommended single-agent dose for future studies in FL and DLBCL, with 800 mg being sufficient to consistently achieve durable response in MCL. Additional investigations including combination therapy to augment response rates and durability are ongoing.
B细胞淋巴瘤-2（BCL-2）过表达在许多非霍奇金淋巴瘤（NHL）亚型中很常见。开展了一项针对NHL患者的I期试验，以确定维奈托克（一种选择性、强效、口服生物利用度高的BCL-2抑制剂）的安全性、药代动力学和疗效。患者与方法：106例复发或难治性NHL患者每天接受一次维奈托克治疗，直至疾病进展或出现不可接受的毒性，剂量递增队列和安全性扩展队列的目标剂量为200至1200mg。剂量递增队列中的大多数患者以及安全性扩展队列中的所有患者在治疗开始时都有一个为期3周的剂量爬坡期。结果：NHL亚型包括套细胞淋巴瘤（MCL；n = 28）、滤泡性淋巴瘤（FL；n = 29）、弥漫性大B细胞淋巴瘤（DLBCL；n = 34）、由慢性淋巴细胞白血病引起的DLBCL（里氏转化；n = 7）、华氏巨球蛋白血症（n = 4）和边缘区淋巴瘤（n = 3）。维奈托克总体耐受性良好。未观察到临床肿瘤溶解综合征，而有3例患者记录到实验室肿瘤溶解综合征。103例患者（97%）报告了治疗中出现的不良事件，其中大多数严重程度为1至2级。59例患者（56%）报告了3至4级事件，最常见的是血液学事件，包括贫血（15%）、中性粒细胞减少（11%）和血小板减少（9%）。总体缓解率为44%（MCL为75%；FL为38%；DLBCL为18%）。估计中位无进展生存期为6个月（MCL为14个月；FL为11个月；DLBCL为1个月）。结论：维奈托克对BCL-2的选择性靶向耐受性良好，单药活性在NHL亚型中有所不同。我们确定1200mg为未来FL和DLBCL研究的推荐单药剂量，800mg足以在MCL中持续实现持久缓解。包括联合治疗以提高缓解率和缓解持久性的进一步研究正在进行中。
