Substantial Susceptibility of Chronic Lymphocytic Leukemia to BCL2 Inhibition: Results of a Phase I Study of Navitoclax in Patients With Relapsed or Refractory Disease
Substantial Susceptibility of Chronic Lymphocytic Leukemia to BCL2 Inhibition: Results of a Phase I Study of Navitoclax in Patients With Relapsed or Refractory Disease
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DOI：
10.1200/jco.2011.34.7898
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发表时间：
2012-02-10
影响因子：
45.3
通讯作者：
Humerickhouse, Rod
中科院分区：
文献类型：
--
作者：
Roberts, Andrew W.;Seymour, John F.;Humerickhouse, Rod
目的BCL2过度表达是慢性淋巴细胞白血病(CLL)的一个标志。新型BH3类似物Navitoclax(ABT263)能特异性地抑制bcl2及其相关蛋白bclx(L)和bclw，在体外能有效地诱导CLL细胞的凋亡。患者和方法29例复发或难治性CLL患者接受每日14天(10、110、200或250 mg/d；n=15)或21天(125、200、250 mg/d；n=14)的治疗，每21天为一个周期。结果在21例基线淋巴细胞增多的患者中，有19例的淋巴细胞计数降低了50%以上。在26例接受NAVITOCLAX=110 mg/d治疗的患者中，9例(35%)部分缓解，7例病情稳定超过6个月。中位治疗时间为7个月(1~29个月)。中位无进展生存期为25个月。在氟达拉滨难治性疾病、巨大腺病和del(17P)CLL患者中观察到活性。抑制bclx(L)所致的血小板减少是主要的剂量限制性毒性，且呈剂量依赖关系。白血病细胞中MCL1的低表达和BIM：MCL1或BIM：BCL2的高比率与疗效相关。结论BCL2是治疗慢性淋巴细胞性白血病的有效靶点，其对BCL2的抑制作用值得进一步研究。J Clin Oncol30：488-496。(C)2011年美国临床肿瘤学会
PurposeBCL2 overexpression is a hallmark of chronic lymphocytic leukemia (CLL). The novel BH3 mimetic navitoclax (ABT-263) specifically inhibits BCL2 and related proteins BCL-x(L) and BCL-w, potently inducing apoptosis of CLL cells in vitro. A phase I trial in patients with CLL was conducted to evaluate the safety, pharmacokinetics, and biologic activity of oral navitoclax.Patients and MethodsTwenty-nine patients with relapsed or refractory CLL received daily navitoclax for 14 days (10, 110, 200, or 250 mg/d; n = 15) or 21 days (125, 200, 250, or 300 mg/d; n = 14) of each 21-day cycle. Dose escalation decisions were informed by continual reassessment methodology.ResultsLymphocytosis was reduced by more than 50% in 19 of 21 patients with baseline lymphocytosis. Among 26 patients treated with navitoclax >= 110 mg/d, nine (35%) achieved a partial response and seven maintained stable disease for more than 6 months. Median treatment duration was 7 months (range, 1 to >= 29 months). Median progression-free survival was 25 months. Activity was observed in patients with fludarabine-refractory disease, bulky adenopathy, and del(17p) CLL. Thrombocytopenia due to BCL-x(L) inhibition was the major dose-limiting toxicity and was dose-related. Low MCL1 expression and high BIM:MCL1 or BIM: BCL2 ratios in leukemic cells correlated with response. We determined that the navitoclax dose of 250 mg/d in a continuous dosing schedule was optimal for phase II studies.ConclusionBCL2 is a valid therapeutic target in CLL, and its inhibition by navitoclax warrants further evaluation as monotherapy and in combination in this disease. J Clin Oncol 30: 488-496. (C) 2011 by American Society of Clinical Oncology