Tolerability, pharmacodynamics, and pharmacokinetics studies of depsipeptide (Romidepsin) in patients with acute myelogenous leukemia or advanced myelodysplastic syndromes
Tolerability, pharmacodynamics, and pharmacokinetics studies of depsipeptide (Romidepsin) in patients with acute myelogenous leukemia or advanced myelodysplastic syndromes
复制标题
DOI：
10.1158/1078-0432.ccr-07-0318
复制
发表时间：
2008-02-01
影响因子：
11.5
通讯作者：
Nimer, Stephen D.
中科院分区：
文献类型：
--
作者：
Klimek, Virginia M.;Fircanis, Sophia;Nimer, Stephen D.
目的：基因表达的表观遗传调节在癌症（包括白血病）中发挥重要作用。此外，组蛋白脱乙酰酶抑制剂可能诱导对正常造血至关重要的基因的重新表达或抑制。本研究的目的是评估组蛋白脱乙酰酶抑制剂 depsipeptide 在骨髓增生异常综合征 (MDS) 或急性髓性白血病 (AML) 患者中的毒性、药代动力学特征和选定的药效学特性。 实验设计：以 18 mg/m(2) 静脉注射（实体瘤）I 期剂量向 MDS 或 AML 患者施用 Depsipeptide。每 3 周的第 1 天和第 5 天。监测毒性和临床活性，并进行药代动力学和药效学研究。结果：12 名患者（9 名患有 AML，3 名患有 MDS）接受了 1 至 5 个周期的缩酚肽治疗。最常见的 3/4 级毒性是发热性中性粒细胞减少症/感染（5 名患者）、中性粒细胞减少症/血小板减少症（9 名患者）、恶心（9 名患者）和无症状低磷血症（3 名患者）。没有观察到临床上显着的心脏毒性。 11 名接受评估的患者的最佳反应是 1 名 AML 患者完全缓解，6 名患者疾病稳定，4 名患者疾病进展。探索性实验室研究表明细胞凋亡适度但快速增加，并且骨髓成熟标志物表达发生变化。对 5 名患者的组蛋白 H3 和 H4 乙酰化水平进行了评估；没有观察到一致的变化。结论：可以进行缩酚肽治疗，且短期毒性可接受。然而，胃肠道症状和疲劳似乎在多个周期后限制了治疗。缩肽单一疗法在未经选择的 AML/MDS 患者中的临床活性有限。
Purpose: Epigenetic modulation of gene expression plays an important role in cancer, including leukemia. Furthermore, histone deacetylase inhibitors may induce the reexpression or repression of genes critical for normal hematopoiesis. The purpose of this study was to evaluate the toxicity, pharmacokinetic profile, and selected pharmacodynamic properties of the histone deacetylase inhibitor depsipeptide in patients with myelodysplastic syndromes (MDS) or acute myelogenous leukemia (AML).Experimental Design: Depsipeptide was administered to MDS or AML patients at a (solid tumor) phase I dose of 18 mg/m(2) i.v. on days 1 and 5 every 3 weeks. Toxicities and clinical activity were monitored and pharmacokinetic and pharmacodynamic studies were done.Results: Twelve patients (nine with AML, three with MDS) received one to five cycles of depsipeptide. The most common grade 3/4 toxicities were febrile neutropenia/infection (five patients), neutropenia/thrombocytopenia (nine patients), nausea (nine patients), and asymptomatic hypo-phosphatemia (three patients). No clinically significant cardiac toxicity was observed. The best response of 11 assessed patients was one complete remission in a patient with AML, stable disease in six patients, and progression of disease in four patients. Exploratory laboratory studies showed modest but rapid increases in apoptosis and changes in myeloid maturation marker expression. Histone H3 and H4 acetylation levels were evaluated in five patients; no consistent changes were observed.Conclusion: Depsipeptide therapy can be administered with acceptable short-term toxicity. However, gastrointestinal symptoms and fatigue seem to be treatment-limiting after multiple cycles. Depsipeptide monotherapy has limited clinical activity in unselected AML/MDS patients.