Safety and clinical activity of the combination of 5-azacytidine, valproic acid, and all-trans retinoic acid in acute myeloid leukemia and myelodysplastic syndrome
Safety and clinical activity of the combination of 5-azacytidine, valproic acid, and all-trans retinoic acid in acute myeloid leukemia and myelodysplastic syndrome
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DOI：
10.1182/blood-2007-03-078576
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发表时间：
2007-10-01
期刊：
影响因子：
20.3
通讯作者：
Garcia-Manero, Guillermo
中科院分区：
文献类型：
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作者：
Soriano, Andres O.;Yang, Hui;Garcia-Manero, Guillermo
DNA低甲基化药物与组蛋白去乙酰化酶抑制剂联合使用具有协同抗白血病活性，并可能恢复对全反式维甲酸（ATRA）的敏感性。我们对急性髓系白血病或高危骨髓增生异常综合征患者进行了5 - 氮杂胞苷（5 - AZA）、丙戊酸（VPA）和ATRA联合用药的1/2期研究。5 - AZA以75 mg/m²的固定剂量皮下注射，每日1次，连续7天。VPA进行剂量递增，并在与5 - AZA同时口服，每日1次，连续7天。ATRA从第3天开始，以45 mg/m²的剂量口服，每日1次，连续5天。共有53名患者接受了治疗。他们的中位年龄为69岁（范围为5 - 84岁）。在此联合用药中，VPA的最大耐受剂量为每日50 mg/kg，连续7天。剂量限制性毒性为可逆性神经毒性。总体缓解率为42%。在先前未接受治疗的老年患者中，缓解率为52%。达到缓解的中位疗程数为1（范围为1 - 3个疗程）。中位缓解持续时间为26周，中位生存期尚未达到。实现了整体DNA甲基化的显著降低和组蛋白乙酰化的诱导。应答者的VPA血药浓度较高（P <...此处原文似乎不完整）
The combination of a DNA hypomethylating agent with a histone deacetylase inhibitor has synergistic antileukemia activity and may restore sensitivity to all-trans retinoic acid (ATRA). We conducted a phase 1/2 study of the combination of 5-azacitidine (5-AZA), valproic acid (VPA), and ATRA in patients with acute myeloid leukemia or high-risk myelodysplastic syndrome. 5-AZA was administered subcutaneously at a fixed dose of 75 mg/m(2) daily for 7 days. VPA was dose-escalated and given orally daily for 7 days concomitantly with 5-AZA. ATRA was given at 45 Mg/M2 orally daily for 5 days, starting on day 3. A total of 53 patients were treated. Their median age was 69 years (range, 5-84 years). The maximum tolerated dose of VPA in this combination was 50 mg/kg daily for 7 days. Dose-limiting toxicity was reversible neurotoxicity. The overall response rate was 42%. In previously untreated older patients, the response rate was 52%. Median number of courses to response was 1 (range, 1-3 courses). Median remission duration was 26 weeks, and median survival has not been reached. A significant decrease in global DNA methylation and induction of histone acetylation were achieved. VPA blood levels were higher in responders (P