在复发的慢性淋巴细胞白血病中使用维奈托克靶向BCL2
Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia.
作者信息
Roberts Andrew W, Davids Matthew S, Pagel John M, Kahl Brad S, Puvvada Soham D, Gerecitano John F, Kipps Thomas J, Anderson Mary Ann, Brown Jennifer R, Gressick Lori, Wong Shekman, Dunbar Martin, Zhu Ming, Desai Monali B, Cerri Elisa, Heitner Enschede Sari, Humerickhouse Rod A, Wierda William G, Seymour John F
机构信息
From the Department of Clinical Haematology and the Bone Marrow Transplantation Unit, Royal Melbourne Hospital (A.W.R., M.A.A.), the Division of Cancer and Haematology, Walter and Eliza Hall Institute of Medical Research (A.W.R., M.A.A.), and the Victorian Comprehensive Cancer Centre (A.W.R., J.F.S.), Parkville, VIC, and the University of Melbourne (A.W.R., J.F.S.) and Peter MacCallum Cancer Centre (J.F.S.), Melbourne, VIC - all in Australia; Dana-Farber Cancer Institute, Boston (M.S.D., J.R.B.); the Swedish Medical Center, Seattle (J.M.P.); Washington University, St. Louis (B.S.K.); University of Arizona, Tucson (S.D.P.); Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York (J.F.G.); University of California, San Diego, San Diego (T.J.K.); AbbVie, North Chicago, IL (L.G., S.W., M.D., M.Z., M.B.D., E.C., S.H.E., R.A.H.); and University of Texas M.D. Anderson Cancer Center, Houston (W.G.W.).
出版信息
N Engl J Med. 2016 Jan 28;374(4):311-22. doi: 10.1056/NEJMoa1513257. Epub 2015 Dec 6.
BACKGROUND
New treatments have improved outcomes for patients with relapsed chronic lymphocytic leukemia (CLL), but complete remissions remain uncommon. Venetoclax has a distinct mechanism of action; it targets BCL2, a protein central to the survival of CLL cells.
METHODS
We conducted a phase 1 dose-escalation study of daily oral venetoclax in patients with relapsed or refractory CLL or small lymphocytic lymphoma (SLL) to assess safety, pharmacokinetic profile, and efficacy. In the dose-escalation phase, 56 patients received active treatment in one of eight dose groups that ranged from 150 to 1200 mg per day. In an expansion cohort, 60 additional patients were treated with a weekly stepwise ramp-up in doses as high as 400 mg per day.
RESULTS
The majority of the study patients had received multiple previous treatments, and 89% had poor prognostic clinical or genetic features. Venetoclax was active at all dose levels. Clinical tumor lysis syndrome occurred in 3 of 56 patients in the dose-escalation cohort, with one death. After adjustments to the dose-escalation schedule, clinical tumor lysis syndrome did not occur in any of the 60 patients in the expansion cohort. Other toxic effects included mild diarrhea (in 52% of the patients), upper respiratory tract infection (in 48%), nausea (in 47%), and grade 3 or 4 neutropenia (in 41%). A maximum tolerated dose was not identified. Among the 116 patients who received venetoclax, 92 (79%) had a response. Response rates ranged from 71 to 79% among patients in subgroups with an adverse prognosis, including those with resistance to fludarabine, those with chromosome 17p deletions (deletion 17p CLL), and those with unmutated IGHV. Complete remissions occurred in 20% of the patients, including 5% who had no minimal residual disease on flow cytometry. The 15-month progression-free survival estimate for the 400-mg dose groups was 69%.
CONCLUSIONS
Selective targeting of BCL2 with venetoclax had a manageable safety profile and induced substantial responses in patients with relapsed CLL or SLL, including those with poor prognostic features. (Funded by AbbVie and Genentech; ClinicalTrials.gov number, NCT01328626.).
背景
新的治疗方法改善了复发慢性淋巴细胞白血病（CLL）患者的治疗结果，但完全缓解仍然不常见。维奈克拉具有独特的作用机制；它靶向BCL2，一种对CLL细胞存活至关重要的蛋白质。
方法
我们对复发或难治性CLL或小淋巴细胞淋巴瘤（SLL）患者进行了每日口服维奈克拉的1期剂量递增研究，以评估安全性、药代动力学特征和疗效。在剂量递增阶段，56名患者在八个剂量组之一接受积极治疗，剂量范围为每天150至1200毫克。在一个扩展队列中，另外60名患者接受了每周逐步增加剂量至每天高达400毫克的治疗。
结果
大多数研究患者此前接受过多种治疗，89%具有不良预后的临床或遗传特征。维奈克拉在所有剂量水平均有活性。剂量递增队列中的56名患者中有3名发生临床肿瘤溶解综合征，1例死亡。在调整剂量递增方案后，扩展队列中的60名患者均未发生临床肿瘤溶解综合征。其他毒性作用包括轻度腹泻（52%的患者）、上呼吸道感染（48%）、恶心（47%）和3或4级中性粒细胞减少（41%）。未确定最大耐受剂量。在接受维奈克拉治疗的116名患者中，92名（79%）有反应。在预后不良的亚组患者中，包括对氟达拉滨耐药的患者、有17号染色体p缺失（17p缺失CLL）的患者和IGHV未突变的患者，缓解率在71%至79%之间。20%的患者实现完全缓解，其中5%的患者流式细胞术检测无微小残留病。400毫克剂量组的15个月无进展生存估计为69%。
结论
维奈克拉选择性靶向BCL2具有可控的安全性，可使复发CLL或SLL患者，包括那些具有不良预后特征的患者产生显著反应。（由艾伯维和基因泰克资助；ClinicalTrials.gov编号，NCT01328626。）
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