Giles Francis J, Tallman Martin S, Garcia-Manero Guillermo, Cortes Jorge E, Thomas Deborah A, Wierda William G, Verstovsek Srdan, Hamilton Marta, Barrett Emma, Albitar Maher, Kantarjian Hagop M
Department of Leukemia, The University of Texas M D Anderson Cancer Center, Houston, Texas 77030-4095, USA.
Cancer. 2004 Apr 1;100(7):1449-58. doi: 10.1002/cncr.20132.
OSI-211 is a low-clearance, unilamellar liposomal formulation of a water-soluble camptothecin analogue, lurtotecan. OSI-211 has significant activity in severe combined immunodeficient mouse models of human leukemia.
This study was conducted to define the dose-limiting toxicities (DLT) and pharmacokinetics of OSI-211 in patients with refractory myeloid leukemias. Patients with refractory acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), or chronic myelogenous leukemia in blastic phase (CML-BP) were eligible. OSI-211 was given as an intravenous infusion over 30 minutes daily for 3 days. The starting dose was 1.5 mg/m2 per day (4.5 mg/m2 per course). The dose was escalated by 50% until Grade 2 toxicity was observed and then by 30-35% until the DLT was defined. Serial plasma and urine samples were collected, and drug levels were determined by high-performance liquid chromatography with fluorescence detection.
Twenty patients (18 patients [90%] with AML, and 1 patient each [5%] with MDS and CML-BP) were treated. Mucositis and diarrhea were considered to be the DLTs. The maximum tolerated dose was 3.7 mg/m2 per day. Fourteen of 18 evaluable patients (78%) with AML or MDS achieved transient bone marrow aplasia. The mean systemic clearance of lurtotecan in plasma was 0.946 +/- 1.53 L/hour/m2. Urinary recovery of lurtotecan was 6.66% +/- 5.26% (range, 1.05-18.4%).
Liposomal encapsulation of lurtotecan altered its metabolism significantly. There was no evident correlation between exposure, as measured by plasma pharmacokinetics of lurtotecan, and clinical response or toxicities. OSI-211 merits further study in hematologic malignancies.
OSI-211是水溶性喜树碱类似物鲁替康的低清除率单层脂质体制剂。OSI-211在人白血病严重联合免疫缺陷小鼠模型中具有显著活性。
本研究旨在确定OSI-211在难治性髓系白血病患者中的剂量限制性毒性（DLT）和药代动力学。难治性急性髓系白血病（AML）、骨髓增生异常综合征（MDS）或急变期慢性髓性白血病（CML-BP）患者符合条件。OSI-211通过静脉输注给药，每天30分钟，共3天。起始剂量为每天1.5mg/m²（每疗程4.5mg/m²）。剂量以50%递增，直至观察到2级毒性，然后以30%-35%递增，直至确定DLT。采集系列血浆和尿液样本，通过荧光检测高效液相色谱法测定药物水平。
治疗了20例患者（18例[90%]AML患者，1例[5%]MDS患者和1例[5%]CML-BP患者）。黏膜炎和腹泻被认为是DLT。最大耐受剂量为每天3.7mg/m²。18例可评估的AML或MDS患者中有14例（78%）出现短暂性骨髓抑制。血浆中鲁替康的平均全身清除率为0.946±1.53L/小时/m²。鲁替康的尿回收率为6.66%±5.26%（范围为1.05%-18.4%）。
鲁替康的脂质体包裹显著改变了其代谢。通过鲁替康血浆药代动力学测量的暴露与临床反应或毒性之间没有明显相关性。OSI-211在血液系统恶性肿瘤中值得进一步研究。
