Phase I Study of Oral Azacitidine in Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, and Acute Myeloid Leukemia
Phase I Study of Oral Azacitidine in Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, and Acute Myeloid Leukemia
复制标题
DOI：
10.1200/jco.2010.34.4226
复制
发表时间：
2011-06-20
影响因子：
45.3
通讯作者：
Skikne, Barry
中科院分区：
文献类型：
--
作者：
Garcia-Manero, Guillermo;Gore, Steven D.;Skikne, Barry
目的确定阿扎胞苷口服制剂在骨髓增生异常综合征（mds）、慢性髓细胞白血病（CMML）或急性髓细胞白血病（AML）患者中的最大耐受剂量（MTD）、安全性、药代动力学和药理学特征以及临床活性。患者和方法患者在第一个周期的前7天接受1个周期的皮下（75 mg/m(2)）阿扎胞苷，然后在每个额外的28天周期的前7天每天口服阿扎胞苷（120至600 mg）。在第1和第2周期评估药代动力学和药效学概况。记录不良事件和血液学反应。对于接受>= 6个周期口服阿扎胞苷的无应答者，允许交叉到SC阿扎胞苷。结果共41例患者接受SC联合口服阿扎胞苷治疗（mds 29例，CMML 4例，AML 8例）。剂量限制毒性（3/4级腹泻）发生在600 mg剂量，MTD为480 mg。最常见的3/4级不良事件是腹泻（12.2%）、恶心（7.3%）、呕吐（7.3%）、发热性中性粒细胞减少（19.5%）和疲劳（9.8%）。阿扎胞苷暴露随着口服剂量的增加而增加。平均相对口服生物利用度为6.3%至20%。口服和SC阿扎胞苷降低血液中的DNA甲基化，在每个周期的第15天效果最大。mds和CMML患者出现血液学反应。总体缓解率（即完全缓解、血液学改善或红细胞或血小板输注不依赖）在先前接受治疗的患者中为35%，在先前未接受治疗的患者中为73%。结论口服阿扎胞苷对MDSs和CMML患者具有生物利用度和生物学及临床活性。[J]中华医学杂志，29(5):521- 527。(C) 2011年美国临床肿瘤学会
PurposeTo determine the maximum-tolerated dose (MTD), safety, pharmacokinetic and pharmacodynamic profiles, and clinical activity of an oral formulation of azacitidine in patients with myelodysplastic syndromes (MDSs), chronic myelomonocytic leukemia (CMML), or acute myeloid leukemia (AML).Patients and MethodsPatients received 1 cycle of subcutaneous (SC) azacitidine (75 mg/m(2)) on the first 7 days of cycle 1, followed by oral azacitidine daily (120 to 600 mg) on the first 7 days of each additional 28-day cycle. Pharmacokinetic and pharmacodynamic profiles were evaluated during cycles 1 and 2. Adverse events and hematologic responses were recorded. Cross-over to SC azacitidine was permitted for nonresponders who received >= 6 cycles of oral azacitidine.ResultsOverall, 41 patients received SC and oral azacitidine (MDSs, n = 29; CMML, n = 4; AML, n = 8). Dose-limiting toxicity (grade 3/4 diarrhea) occurred at the 600-mg dose and MTD was 480 mg. Most common grade 3/4 adverse events were diarrhea (12.2%), nausea (7.3%), vomiting (7.3%), febrile neutropenia (19.5%), and fatigue (9.8%). Azacitidine exposure increased with escalating oral doses. Mean relative oral bioavailability ranged from 6.3% to 20%. Oral and SC azacitidine decreased DNA methylation in blood, with maximum effect at day 15 of each cycle. Hematologic responses occurred in patients with MDSs and CMML. Overall response rate (ie, complete remission, hematologic improvement, or RBC or platelet transfusion independence) was 35% in previously treated patients and 73% in previously untreated patients.ConclusionOral azacitidine was bioavailable and demonstrated biologic and clinical activity in patients with MDSs and CMML. J Clin Oncol 29:2521-2527. (C) 2011 by American Society of Clinical Oncology