O'Brien Susan M, Cunningham Charles C, Golenkov Anatoliy K, Turkina Anna G, Novick Steven C, Rai Kanti R
M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 428, Houston, TX 77030-7305, USA.
J Clin Oncol. 2005 Oct 20;23(30):7697-702. doi: 10.1200/JCO.2005.02.4364. Epub 2005 Sep 26.
To determine the maximum-tolerated dose (MTD), efficacy, safety, and pharmacokinetics of oblimersen sodium in patients with advanced chronic lymphocytic leukemia (CLL).
Eligible patients had relapsed or refractory CLL after treatment with fludarabine. Oblimersen was administered at doses ranging from 3 to 7 mg/kg/d as a 5-day continuous intravenous infusion in cycle 1 and as a 7-day continuous intravenous infusion in subsequent cycles every 3 weeks in stable or responding patients.
Forty patients were enrolled and treated (14 patients in phase I and 26 patients in phase II). Dose-limiting reactions in phase I included hypotension and fever, and the MTD for phase II dosing was established at 3 mg/kg/d. Two (8%) of 26 assessable patients achieved a partial response. Other evidence of antitumor activity included > or = 50% reduction in splenomegaly (seven of 17 patients; 41%), complete disappearance of hepatomegaly (two of seven patients; 29%), > or = 50% reduction of lymphadenopathy (seven of 22 patients; 32%), and > or = 50% reduction in circulating lymphocyte counts (11 of 22 patients; 50%). Adverse events included transient hypotension, fever, fatigue, night sweats, diarrhea, nausea, vomiting, hypokalemia, and cough. Plasma concentrations of oblimersen (parent drug) and its major metabolites were variable. Renal clearance represented only a small portion of total parent drug clearance.
Dosing with oblimersen sodium in patients with CLL is limited by development of a cytokine release syndrome that is characterized by fever, hypotension, and back pain. Oblimersen sodium has modest single-agent activity in heavily pretreated patients with advanced CLL, and further evaluation of its activity in combination with cytotoxic drugs is warranted.
确定oblimersen钠在晚期慢性淋巴细胞白血病（CLL）患者中的最大耐受剂量（MTD）、疗效、安全性和药代动力学。
符合条件的患者在接受氟达拉滨治疗后出现复发或难治性CLL。在第1周期，oblimersen以3至7mg/kg/d的剂量进行为期5天的持续静脉输注，对于病情稳定或有反应的患者，在随后的周期中每3周进行为期7天的持续静脉输注。
40例患者入组并接受治疗（I期14例，II期26例）。I期的剂量限制性反应包括低血压和发热，II期给药的MTD确定为3mg/kg/d。26例可评估患者中有2例（8%）获得部分缓解。其他抗肿瘤活性证据包括脾肿大缩小≥50%（17例患者中的7例；41%）、肝肿大完全消失（7例患者中的2例；29%）、淋巴结病缩小≥50%（22例患者中的7例；32%）以及循环淋巴细胞计数减少≥50%（22例患者中的11例；50%）。不良事件包括短暂性低血压、发热、疲劳、盗汗、腹泻、恶心、呕吐、低钾血症和咳嗽。oblimersen（母体药物）及其主要代谢物的血浆浓度各不相同。肾脏清除仅占母体药物总清除的一小部分。
CLL患者使用oblimersen钠给药受到以发热、低血压和背痛为特征的细胞因子释放综合征的限制。oblimersen钠在晚期CLL的重度预处理患者中具有适度的单药活性，有必要进一步评估其与细胞毒性药物联合使用的活性。
