Efficacy and safety of extended dosing schedules of CC-486 (oral azacitidine) in patients with lower-risk myelodysplastic syndromes.
Efficacy and safety of extended dosing schedules of CC-486 (oral azacitidine) in patients with lower-risk myelodysplastic syndromes.
复制标题
DOI：
10.1038/leu.2015.265
复制
发表时间：
2016-04
期刊：
影响因子：
11.4
通讯作者：
Skikne B
中科院分区：
文献类型：
--
作者：
Garcia-Manero G;Gore SD;Kambhampati S;Scott B;Tefferi A;Cogle CR;Edenfield WJ;Hetzer J;Kumar K;Laille E;Shi T;MacBeth KJ;Skikne B
CC-486是阿扎胞苷（AZA）的口服制剂，是一种表观遗传修饰剂和DNA甲基转移酶抑制剂，临床开发用于治疗恶性血液病。在一项I期剂量探索研究中评价了CC-486给药7天/28天治疗周期。AZA的血浆半衰期较短，DNA掺入受S期限制;延长CC-486暴露时间可能会增加AZA影响的病变靶细胞数量，并使治疗效果最大化。低风险骨髓增生异常综合征（MDS）患者接受300 mg CC-486每日一次，持续14天（n=28）或21天（n=27），重复28天周期。中位患者年龄为72岁（范围31-87岁），75%的患者患有国际预后评分系统中1风险MDS。对于14天给药方案，CC-486治疗周期的中位数为7（范围2-24），对于21天给药方案，为6（1-24）。36%接受14天给药的患者和41%接受21天给药的患者达到总体缓解（完全或部分缓解、红细胞（RBC）或血小板输注不依赖性（TI）或血液学改善）（国际工作组2006）。两种给药方案的RBC TI率相似（分别为31%和38%）。CC-486通常耐受良好。口服CC-486的延长给药方案可能为低风险MDS患者提供有效的长期治疗。
CC-486, the oral formulation of azacitidine (AZA), is an epigenetic modifier and DNA methyltransferase inhibitor in clinical development for treatment of hematologic malignancies. CC-486 administered for 7 days per 28-day treatment cycle was evaluated in a phase 1 dose-finding study. AZA has a short plasma half-life and DNA incorporation is S-phase-restricted; extending CC-486 exposure may increase the number of AZA-affected diseased target cells and maximize therapeutic effects. Patients with lower-risk myelodysplastic syndromes (MDS) received 300 mg CC-486 once daily for 14 days (n=28) or 21 days (n=27) of repeated 28-day cycles. Median patient age was 72 years (range 31–87) and 75% of patients had International Prognostic Scoring System Intermediate-1 risk MDS. Median number of CC-486 treatment cycles was 7 (range 2–24) for the 14-day dosing schedule and 6 (1–24) for the 21-day schedule. Overall response (complete or partial remission, red blood cell (RBC) or platelet transfusion independence (TI), or hematologic improvement) (International Working Group 2006) was attained by 36% of patients receiving 14-day dosing and 41% receiving 21-day dosing. RBC TI rates were similar with both dosing schedules (31% and 38%, respectively). CC-486 was generally well-tolerated. Extended dosing schedules of oral CC-486 may provide effective long-term treatment for patients with lower-risk MDS.