口服 Ezatiostat HCl (Telintra)，一种谷胱甘肽类似物前药 GSTP1-1 抑制剂，用于治疗骨髓生长因子抵抗的特发性慢性中性粒细胞减少症 (ICN) 患者,Blood

当前位置： X-MOL 学术 › Blood › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

口服 Ezatiostat HCl (Telintra)，一种谷胱甘肽类似物前药 GSTP1-1 抑制剂，用于治疗骨髓生长因子抵抗的特发性慢性中性粒细胞减少症 (ICN) 患者
Blood ( IF 21.0 ) Pub Date : 2012-11-16 , DOI: 10.1182/blood.v120.21.4394.4394
Roger M. Lyons ₁ , Sharon T. Wilks ₁ , David J. Friedman ₁ , Shelby A Young ₂ , Gail Brown ₂

Affiliation

摘要 4394 简介：特发性慢性中性粒细胞减少症（ICN）是一组以低循环中性粒细胞、反复发热、粘膜炎症和全身感染为特征的疾病。并发症的风险与绝对中性粒细胞计数 (ANC) 成反比，最严重的是 ANC 为 9 /L。大多数患者对每天皮下注射粒细胞集落刺激因子 (G-CSF) 有反应；然而，有些患者没有反应。接受 G-CSF 治疗的患者还经常出现骨骼和肌肉疼痛、血小板减少症和脾肿大，这些都使治疗变得复杂。Ezatiostat 是一种谷胱甘肽 S-转移酶 (GST) 抑制剂，可激活 Jun 激酶，促进造血祖细胞的生长和成熟，是一种用于治疗 ICN 的研究药物。该报告描述了 4 名对 ezatiostat 有反应的长期 ICN 患者，他们在治疗前都因败血症频繁住院、抗生素疗程延长以及对骨髓生长因子的反应不佳。方法：该 2 期试验招募了患有严重 ICN 和 ANC 对 G-CSF 反应不足的患者（pts）。在 2000 mg 的初始起始剂量每天两次 (bid) 剂量平衡超过 4 周后，患者每天接受 ezatiostat 治疗 3 周，然后停药 1 周。给予治疗直到缺乏 ANC 反应或不可接受的毒性。临床获益由 ANC 反应、无感染期、抗生素使用和感染住院决定。结果：招募了四名年龄范围为 23-63 岁、ANC 中位数为 200 (50-400) 的女性患者。患者 1 62 岁有长期感染史和 G-CSF 治疗。在进入研究之前，她尽管接受了生长因子治疗，但仍反复出现耳部、唇部、左大腿、肺部和鼻窦感染，对此她有严重反应。基线白细胞 (WBC)/ANC 比率为 2.2/0.7。使用ezatiostat 4 个月后，WBC/ANC 改善至3.62/1.71，感染得到解决。患者 2，63 岁，患有 ICN 26 年，G-CSF 治疗的中位基线 WBC/ANC 为 3.1/.180，曾因败血症、不愈合的会阴部和褥疮溃疡多次入院，以及复发性高停止注射抗生素后 4 天内发烧，需要重新开始。ezatiostat 治疗后中位 ANC 为 3.1（范围 1.6-3.75），持续无感染期超过 22 个月，无需住院或抗生素治疗。患者 3，23 岁，从 10 岁开始患 ICN，最初对 G-CSF 有反应，但尽管注射了投标但停止反应，ANC 从未升至 1000 以上。她最后一次住院是因为耐甲氧西林金黄色葡萄球菌皮肤感染、上呼吸道感染和宫颈炎腺病和口腔溃疡。她每 3 个月感染一次，基线 WBC/ANC 为 1.4/0.13。在 4 个月的观察中，她的反应最小，最高值为 2.65/0.92，中位 ANC 为 0.40，但没有进一步的细菌感染或使用 G-CSF。患者 4，39 岁，ICN 病程 10 年9，G-CSF 出现严重骨痛，反应时间短（1-2 天）。此前，她每年住院和急诊室就诊 4-5 次，每周患病 2-3 次，患有复发性尿路感染、肺炎（每年 4-5 次）、口腔溃疡、鼻窦和胃肠道感染、疖和牙科工作后的感染。基线 WBC/ANC 为 1.23/0.20。目前，她的 WBC/ANC 为 1.50/0.26。虽然 ANC 没有增加，但感染率下降了，而且她超过 5 个月没有去急诊室就诊或入院。她对单次 300 mcg 剂量的 G-CSF 有反应，ANC 为 1.0，持续一周，表明对 G-CSF 重新敏感。最常见的 ezatiostat 相关不良事件是 1 级恶心、异常尿液/粪便气味和味觉障碍。结论：Ezatiostat 是一种新型 GSTP1-1 抑制剂和 jun 激酶调节剂，用于治疗 ICN 和 4 级中性粒细胞减少症患者对骨髓生长因子无反应，导致持久的 ANC 反应和临床上严重感染的显着减少。结果表明，ezatiostat 作为 G-CSF 的口服替代疗法或辅助疗法，在治疗 G-CSF 无反应的 ICN 患者中具有潜在作用。对这种靶向治疗的反应也可能有助于深入了解 ICN 的病理生理学，有必要进一步研究。披露：里昂：Telik, Inc.：研究资金。Wilks：Telik, Inc.：研究资金。弗里德曼：Telik, Inc.：研究资金。Young：Telik, Inc.：就业、股权。布朗：Telik, Inc.：就业、股权。Telik, Inc.：就业、股权。布朗：Telik, Inc.：就业、股权。Telik, Inc.：就业、股权。布朗：Telik, Inc.：就业、股权。

"点击查看英文标题和摘要"

Oral Ezatiostat HCl (Telintra), a Glutathione Analog Prodrug GSTP1-1 Inhibitor, for Treatment of Patients with Myeloid Growth Factor-Resistant Idiopathic Chronic Neutropenia (ICN)

Abstract 4394 Introduction: Idiopathic chronic neutropenia (ICN) is a group of diseases characterized by low circulating neutrophils, recurrent fevers, mucosal inflammation, and systemic infections. The risk of complications is inversely proportional to the absolute neutrophil count (ANC), with the most severe occurring with ANC of 9 /L. Most patients respond to daily s.c. administration of granulocyte colony stimulating factors (G-CSF); however, some patients do not respond. Patients undergoing G-CSF therapy also often have bone and muscle pain, thrombocytopenia and splenomegaly, complicating therapy. Ezatiostat, a glutathione S-transferase (GST) inhibitor that activates Jun kinase, promoting growth and maturation of hematopoietic progenitors, is an investigational agent in development for treatment of ICN. This report describes 4 patients with longstanding ICN who responded to ezatiostat, all of whom prior to treatment had frequent hospitalizations for sepsis, prolonged courses of antibiotics and poor response to myeloid growth factors. Methods: Patients (pts) with severe ICN and inadequate ANC response to G-CSF were enrolled in this phase 2 trial. After initial starting dose of 2000 mg in divided doses twice daily (b.i.d.) dose-equilibration over 4 weeks, pts were treated with ezatiostat daily for 3 weeks followed by 1 week off. Treatment was given until lack of ANC response or unacceptable toxicity. Clinical benefit was determined by ANC response, infection-free periods, antibiotic use and hospitalizations for infections. Results: Four female pts, age range 23–63, with median ANC of 200 (50–400) were enrolled. Patient 1 is 62 y.o. with longstanding history of infections and treatment with G-CSF. Before entering study, she had recurrent ear, labial, left thigh, pulmonary and sinus infections despite growth factor treatment, to which she had severe reactions. Baseline white blood cell (WBC)/ANC ratio was 2.2/0.7. WBC/ANC improved with ezatiostat for 4 mo to 3.62/1.71 and infections resolved. Patient 2, a 63 y.o. with ICN for 26 years, had a median baseline WBC/ANC on G-CSF treatment of 3.1/.180 and a history of multiple hospital admissions for sepsis, non-healing perineal and decubitus ulcers, and recurrent high fevers within 4 days of cessation of parenteral antibiotics, necessitating resumption. Post-ezatiostat treatment median ANC was 3.1 (range 1.6–3.75) with a persistent infection-free period of over 22 mo with no hospitalizations or antibiotic therapy required. Patient 3, a 23 y.o. with ICN since age 10, initially responded to G-CSF but stopped responding despite injections b.i.d., and ANC never rose above 1000. Her last hospitalization was for methicillin-resistant staphylococcus aureus skin infection, upper respiratory infection with cervical adenopathy, and oral ulcers. She had infections every 3 months and baseline WBC/ANC of 1.4/0.13. She had minimal response over 4 mo of observation, with highest values 2.65/0.92 and median ANC of 0.40, but had no further bacterial infection or use of G-CSF. Patient 4, a 39 y.o. with ICN of 10 years9 duration, had severe bone pain with G-CSF and responses were brief (1–2days). Previously, she had hospital admissions and emergency room visits 4–5 times a year and was ill 2–3 times a week with recurrent urinary tract infections, pneumonias (4–5 times per year), oral ulcers, sinus and gastrointestinal infections, furuncles, and infection after dental work. Baseline WBC/ANC was 1.23/0.20. Currently, her WBC/ANC is 1.50/0.26. While ANC did not increase, infection rate decreased and she had no ER visits or admissions for over 5 mo. She responded to a single 300 mcg dose of of G-CSF with an ANC of 1.0 for a week, suggesting re-sensitization to G-CSF. Most common ezatiostat-related adverse events were grade 1 nausea, abnormal urine/stool odor, and dysgeusia. Conclusions: Ezatiostat, a novel GSTP1-1 inhibitor and jun kinase modulator as treatment of patients with ICN and grade 4 neutropenia not responsive to myeloid growth factors, results in a durable ANC response and clinically significant reductions in serious infections. Results suggest a potential role for ezatiostat as an oral therapy alternative or adjunct to G-CSF in the treatment of ICN in patients who are not responsive to G-CSF. Response to this targeted therapy may also give insight into the pathophysiology of ICN and further study is warranted. Disclosures: Lyons: Telik, Inc.: Research Funding. Wilks: Telik, Inc.: Research Funding. Friedman: Telik, Inc.: Research Funding. Young: Telik, Inc.: Employment, Equity Ownership. Brown: Telik, Inc.: Employment, Equity Ownership.

更新日期：2012-11-16

点击分享查看原文

点击收藏

阅读更多本刊新发论文本刊介绍/投稿指南