Division de Investigación Clínica, Instituto Nacional de Cancerología (INCan), Mexico City, Mexico.
Ann Hematol. 2011 Apr;90(4):379-87. doi: 10.1007/s00277-010-1090-2. Epub 2010 Oct 5.
Decitabine and azacitidine, two DNA methyltransferase (DNMT) inhibitors, are the current standard of treatment for myelodysplastic syndrome (MDS). Histone deacetylase (HDAC) inhibitors are also being tested against MDS. Both drug classes synergize in their gene reactivating and anticancer activities. The combination of hydralazine and valproate (Transkrip®), a DNMT and HDAC inhibitor, respectively), has been developed as epigenetic therapy under the drug repositioning concept. To evaluate the clinical efficacy and safety of hydralazine and valproate against MDS, an open phase-II study for previously treated patients with MDS was conducted. The hydralazine dose was given according with the acetylator phenotype, and valproate was dosed at 30 mg/kg/day. Response was graded with International Working Group criteria. Toxicity was evaluated by the Common Toxemia Criteria-National Cancer Institute version 3 scale. From November 2007 to January 2010, 12 patients were included. Median age±SD was 53±19.78 years (range, 23-79 years); median time from diagnosis to inclusion in the study was 7.9 months (range 2.6-36.1 months). Median of previous treatment was 2 (range, 1-6). Refractory cytopenia with multilineage dysplasia was diagnosed in ten cases, and refractory anemia with excess of blasts in two. Overall response was documented in six (50%) of 12 cases, including one CR, one PR, and four hematological improvements of the erythroid series. Two patients (16.6%) progressed to acute myeloid leukemia. Hemoglobin increased from 7.4 to 10.3 g/dL (in 13 weeks), neutrophils, from 1.1 to 2.0 (in 3 weeks), and platelets, from 66×10(9) to 72×10(9)/L (in 2 weeks). Transfusional requirements decreased from 2.3 to 0 U bi-monthly for red blood cells and from 0.5 to 0 U bi-monthly for platelets in responding patients. Main toxicities were mild, including somnolence and nausea. Preliminary results of this phase-II study suggest that the combination of hydralazine and valproate is a promising non-toxic and effective therapy for MDS.
地西他滨和阿扎胞苷是两种 DNA 甲基转移酶(DNMT)抑制剂,是骨髓增生异常综合征(MDS)的现行标准治疗方法。组蛋白去乙酰化酶(HDAC)抑制剂也正在针对 MDS 进行测试。这两类药物在基因激活和抗癌活性方面具有协同作用。分别作为 DNMT 和 HDAC 抑制剂的肼屈嗪和丙戊酸钠(Transkrip®)组合,已根据药物重新定位概念开发为表观遗传治疗药物。为了评估肼屈嗪和丙戊酸钠对 MDS 的临床疗效和安全性,对先前接受治疗的 MDS 患者进行了一项开放的 II 期研究。根据乙酰化表型给予肼屈嗪剂量,丙戊酸钠剂量为 30mg/kg/天。用国际工作组标准进行反应分级。毒性采用常见毒性标准-国家癌症研究所 3 版量表进行评估。从 2007 年 11 月至 2010 年 1 月,共纳入 12 例患者。中位年龄±SD 为 53±19.78 岁(范围,23-79 岁);从诊断到纳入研究的中位时间为 7.9 个月(范围,2.6-36.1 个月)。中位先前治疗次数为 2(范围,1-6)。10 例诊断为难治性多系发育不良性细胞减少症,2 例诊断为难治性贫血伴原始细胞过多。12 例中有 6 例(50%)记录到总体反应,包括 1 例完全缓解(CR)、1 例部分缓解(PR)和 4 例红细胞系的血液学改善。2 例(16.6%)进展为急性髓系白血病。血红蛋白从 7.4 增加到 10.3g/dL(在 13 周内),中性粒细胞从 1.1 增加到 2.0(在 3 周内),血小板从 66×10(9)增加到 72×10(9)/L(在 2 周内)。对红细胞的输血需求从每月 2 次 2.3U 减少到每月 0 次,对血小板的输血需求从每月 0.5 次减少到每月 0 次。在有反应的患者中。主要毒性反应轻微,包括嗜睡和恶心。这项 II 期研究的初步结果表明,肼屈嗪和丙戊酸钠的联合治疗是一种有前途的非毒性、有效治疗骨髓增生异常综合征的方法。