University of Texas, MD Anderson Cancer Center, Box 428, 1515 Holcombe Blvd, Houston, TX 77025, USA.
J Clin Oncol. 2011 Jun 20;29(18):2521-7. doi: 10.1200/JCO.2010.34.4226. Epub 2011 May 16.
To 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 received 1 cycle of subcutaneous (SC) azacitidine (75 mg/m2) 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.
Overall, 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 (i.e., complete remission, hematologic improvement, or RBC or platelet transfusion independence) was 35% in previously treated patients and 73% in previously untreated patients.
Oral azacitidine was bioavailable and demonstrated biologic and clinical activity in patients with MDSs and CMML.
确定口服阿扎胞苷在骨髓增生异常综合征（MDSs）、慢性粒单核细胞白血病（CMML）或急性髓系白血病（AML）患者中的最大耐受剂量（MTD）、安全性、药代动力学和药效学特征以及临床疗效。
患者在第 1 周期的前 7 天接受 1 个周期的皮下（SC）阿扎胞苷（75mg/m2），然后在每个 28 天周期的前 7 天每天接受口服阿扎胞苷（120 至 600mg）。在第 1 和第 2 周期期间评估药代动力学和药效学特征。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但未应答的患者，允许交叉使用 SC 阿扎胞苷。
总体而言，41 例患者接受了 SC 和口服阿扎胞苷治疗（MDSs，n=29；CMML，n=4；AML，n=8）。在 600mg 剂量时出现剂量限制毒性（3/4 级腹泻），MTD 为 480mg。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症（19.5%）和疲劳（9.8%）。随着口服剂量的增加，阿扎胞苷的暴露量增加。平均相对口服生物利用度为 6.3%至 20%。口服和 SC 阿扎胞苷降低了血液中的 DNA 甲基化，在每个周期的第 15 天达到最大效果。MDSs 和 CMML 患者出现血液学反应。在先前治疗的患者中，总缓解率（即完全缓解、血液学改善或 RBC 或血小板输血独立）为 35%，在未接受过治疗的患者中为 73%。
口服阿扎胞苷在 MDSs 和 CMML 患者中具有生物利用度，并表现出生物学和临床疗效。
