Phase 1 dose-ranging study of ezatiostat hydrochloride in combination with lenalidomide in patients with non-deletion (5q) low to intermediate-1 risk myelodysplastic syndrome (MDS).
Phase 1 dose-ranging study of ezatiostat hydrochloride in combination with lenalidomide in patients with non-deletion (5q) low to intermediate-1 risk myelodysplastic syndrome (MDS).
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DOI：
10.1186/1756-8722-5-18
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发表时间：
2012-04-30
影响因子：
28.5
通讯作者：
Mesa RA
中科院分区：
文献类型：
--
作者：
Raza A;Galili N;Mulford D;Smith SE;Brown GL;Steensma DP;Lyons RM;Boccia R;Sekeres MA;Garcia-Manero G;Mesa RA
Ezatiostat是一种谷胱甘肽S-转移酶P1-1抑制剂，可促进造血祖细胞成熟并诱导癌细胞凋亡。19例非缺失型（5 q）骨髓增生异常综合征（MDS）患者在28天周期的第1-21天接受两种剂量（2000 mg或2500 mg/天）之一的Ezatiostat联合10 mg来那度胺给药。未发生非预期毒性，不良事件（AE）的发生率和严重程度与每种药物单独使用的预期结果一致。与ezatiostat联合来那度胺相关的最常见非血液学AE主要为1级和2级疲乏、厌食、恶心、腹泻和呕吐;与来那度胺相关的血液学AE为血小板减少症、中性粒细胞减少症和贫血。根据2006年MDS国际工作组（IWG）标准，2500/10 mg剂量组的4例可评价患者中有1例（25%）出现红系血液学改善（HI-E）缓解。2000 mg/10 mg剂量组10例可评价患者中有4例（40%）出现HI-E应答。7例红细胞（RBC）输注依赖性患者中有3例（43%）变为不依赖RBC输注，包括1例既往来那度胺单药治疗无效的患者。5例血小板减少症患者中有3例（60%）出现HI-血小板（HI-P）应答。5例患者中有3例（60%）发生了双系HI-E和HI-P反应，3例HI-E和HI-N患者中有1例（33%）发生了双系HI-E和HI-P反应，3例HI-N和HI-P患者中有1例（33%）发生了双系HI-N反应。3例全血细胞减少症患者中有1例（33%）出现完全三系缓解。在推荐用于未来研究的2000/10 mg剂量中观察到所有多谱系应答。ezatiostat与来那度胺联合给药的耐受性和活性特征支持ezatiostat与来那度胺联合治疗MDS的进一步开发，也鼓励在来那度胺具有活性的其他血液恶性肿瘤中进行这种联合治疗的研究。Clinicaltrials.gov：NCT01062152
Ezatiostat, a glutathione S-transferase P1-1 inhibitor, promotes the maturation of hematopoietic progenitors and induces apoptosis in cancer cells. Ezatiostat was administered to 19 patients with non-deletion(5q) myelodysplastic syndrome (MDS) at one of two doses (2000 mg or 2500 mg/day) in combination with 10 mg of lenalidomide on days 1–21 of a 28-day cycle. No unexpected toxicities occurred and the incidence and severity of adverse events (AEs) were consistent with that expected for each drug alone. The most common non-hematologic AEs related to ezatiostat in combination with lenalidomide were mostly grade 1 and 2 fatigue, anorexia, nausea, diarrhea, and vomiting; hematologic AEs due to lenalidomide were thrombocytopenia, neutropenia, and anemia. One of 4 evaluable patients (25%) in the 2500/10 mg dose group experienced an erythroid hematologic improvement (HI-E) response by 2006 MDS International Working Group (IWG) criteria. Four of 10 evaluable patients (40%) in the 2000 mg/10 mg dose group experienced an HI-E response. Three of 7 (43%) red blood cell (RBC) transfusion-dependent patients became RBC transfusion independent, including one patient for whom prior lenalidomide monotherapy was ineffective. Three of 5 (60%) thrombocytopenic patients had an HI-platelet (HI-P) response. Bilineage HI-E and HI-P responses occurred in 3 of 5 (60%), 1 of 3 with HI-E and HI-N (33%), and 1 of 3 with HI-N and HI-P (33%). One of 3 patients (33%) with pancytopenia experienced a complete trilineage response. All multilineage responses were observed in the 2000/10 mg doses recommended for future studies. The tolerability and activity profile of ezatiostat co-administered with lenalidomide supports the further development of ezatiostat in combination with lenalidomide in MDS and also encourages studies of this combination in other hematologic malignancies where lenalidomide is active. Clinicaltrials.gov: NCT01062152
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影响因子：
20.3
作者：
Raza, Azra;Reeves, James A.;List, Alan F.
通讯作者：
List, Alan F.
影响因子：
20.3
作者：
Greenberg, P;Cox, C;Bennett, J
通讯作者：
Bennett, J
影响因子：
20.3
作者：
Fenaux, Pierre;Giagounidis, Aristoteles;Hellstrom-Lindberg, Eva
通讯作者：
Hellstrom-Lindberg, Eva
影响因子：
6.2
作者：
Raza, Azra;Galili, Naomi;Sekeres, Mikkael
通讯作者：
Sekeres, Mikkael
影响因子：
20.3
作者：
Raza, Azra;Galili, Naomi;List, Alan
通讯作者：
List, Alan