A phase 2 randomized multicenter study of 2 extended dosing schedules of oral ezatiostat in low to intermediate-1 risk myelodysplastic syndrome
A phase 2 randomized multicenter study of 2 extended dosing schedules of oral ezatiostat in low to intermediate-1 risk myelodysplastic syndrome
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DOI：
10.1002/cncr.26469
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发表时间：
2012-04-15
期刊：
影响因子：
6.2
通讯作者：
Sekeres, Mikkael
中科院分区：
文献类型：
--
作者：
Raza, Azra;Galili, Naomi;Sekeres, Mikkael
背景：Ezatiostat 是一种谷胱甘肽类似物前药谷胱甘肽 S-转移酶 P1-1 (GSTP1-1) 抑制剂。本研究对 89 名接受过多次治疗的低至中 1 风险骨髓增生异常综合征 (MDS) 患者进行了 2 种口服 ezatiostat 延长剂量方案的评估。方法：根据 1 个分层因素（基线血细胞减少（仅贫血与贫血伴额外血细胞减少））将患者随机分配至 2 种延长给药方案中的 1 种。根据国际工作组 2006 年标准评估多系血液学改善 (HI) 反应。结果：总体而言，38 名红细胞 (RBC) 输注依赖患者中有 11 名 (29%) 出现 HI-红细胞 (HI-E) 反应。 HI-E 反应的中位持续时间为 34 周。观察到多谱系反应。 del (5q) MDS 患者中有 1 例细胞遗传学完全缓解。一个重要的趋势是既往治疗对反应的影响。在既往使用来那度胺且未使用低甲基化药物 (HMA) 的患者中观察到 40% 的 HI-E 率（15 名患者中的 6 名），其中 11 名患者中的 5 名（45%）实现了红细胞输血显着减少，11 名患者中的 3 名（27%）实现了输血独立。在既往未接受过来那度胺和 HMA 的患者中观察到 28% 的 HI-E 率（18 名患者中的 5 名），其中 8 名患者中的 4 名（50%）实现了临床显着的红细胞输注减少。最常见的 ezatiostat 相关不良事件是 1 级和 2 级胃肠道事件，包括：恶心（45%、17%）、腹泻（26%、7%）和呕吐（30%、12%）。结论：Ezatiostat 是第一个 GSTP1-1 抑制剂，可导致 MDS 患者红细胞输注、输血独立性和多谱系反应的临床显着持续减少。 ezatiostat 的耐受性和活性特征可能为 MDS 患者提供新的治疗选择。癌症2012； 118：2138-47。 (C) 2011 年美国癌症协会。
BACKGROUND: Ezatiostat is a glutathione analog prodrug glutathione S-transferase P1-1 (GSTP1-1) inhibitor. This study evaluated 2 extended dose schedules of oral ezatiostat in 89 heavily pretreated patients with low to intermediate-1 risk myelodysplastic syndrome (MDS). METHODS: Patients were randomized by 1 stratification factor-baseline cytopenia (anemia only vs anemia with additional cytopenias)-to 1 of 2 extended dosing schedules. Multilineage hematologic improvement (HI) responses were assessed by International Working Group 2006 criteria. RESULTS: Overall, 11 of 38 (29%) red blood cell (RBC) transfusion-dependent patients had HI-Erythroid (HI-E) response. The median duration of HI-E response was 34 weeks. Multilineage responses were observed. There was 1 cytogenetic complete response in a del (5q) MDS patient. An important trend was the effect of prior therapy on response. A 40% HI-E rate (6 of 15 patients) was observed in patients who had prior lenalidomide and no prior hypomethylating agents (HMAs), with 5 of 11 (45%) patients achieving significant RBC transfusion reduction and 3 of 11 (27%) achieving transfusion independence. A 28% HI-E rate (5 of 18 patients) was observed in patients who were both lenalidomide and HMA naive, with 4 of 8 (50%) patients achieving clinically significant RBC transfusion reductions. Most common ezatiostatrelated adverse events were grade 1 and 2 gastrointestinal including: nausea (45%, 17%), diarrhea (26%, 7%), and vomiting (30%, 12%). CONCLUSIONS: Ezatiostat is the first GSTP1-1 inhibitor shown to cause clinically significant and sustained reduction in RBC transfusions, transfusion independence, and multilineage responses in MDS patients. The tolerability and activity profile of ezatiostat may offer a new treatment option for patients with MDS. Cancer 2012; 118: 2138-47. (C) 2011 American Cancer Society.