Defibrotide for Patients with Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome: Interim Results from a Treatment IND Study
Defibrotide for Patients with Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome: Interim Results from a Treatment IND Study
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DOI：
10.1016/j.bbmt.2017.03.008
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发表时间：
2017-06-01
影响因子：
4.3
通讯作者：
Soiffer, Robert J.
中科院分区：
文献类型：
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作者：
Richardson, Paul G.;Smith, Angela R.;Soiffer, Robert J.
肝静脉闭塞性疾病或肝窦阻塞综合征 (VOD/SOS) 是造血干细胞移植 (HSCT) 预处理或单独化疗方案的严重且可能致命的并发症。去纤苷是一种单链聚脱氧核糖核苷酸的复杂混合物，在美国被批准用于治疗 HSCT 后伴有肾或肺功能障碍的肝脏 VOD/SOS，并在欧盟、以色列和韩国被批准用于治疗 HSCT 后严重的肝脏 VOD/SOS。去纤维蛋白多核苷酸此前曾在美国作为一种研究药物通过治疗方案（治疗 IND）研究获得。本文介绍了针对 VOD/SOS 伴或不伴多器官功能障碍（MOD；也称为多器官衰竭）患者的大型治疗 IND 研究的中期结果。静脉注射去纤维蛋白多核苷酸。每 6 小时 6.25 毫克/公斤（25 毫克/公斤/天），建议治疗持续时间至少 21 天。纳入的患者 (n = 681) 根据巴尔的摩或修改后的西雅图标准或肝活检分析被诊断为 VOD/SOS。在 573 名 HSCT 接受者中，288 名（50.3%；95% 置信区间 [CI]，46.2% 至 54.4%）在 HSCT 后+100 天仍存活。儿童（16 岁）亚组的+100 天生存率分别为 54.5%（95% CI，49.1% 至 60.0%；n = 319 人中的 174 人）和 44.9%（95% CI，38.8% 至 51.0%；n = 254 人中的 114 人）。在 MOD 亚组中，351 名患者中有 159 名患者（45.3%；95% CI，40.1% 至 50.5%）在 HSCT 后+100 天时存活。一般采用去纤苷治疗。耐受性良好，且药物相关毒性与之前的研究一致。 69.6% 的可安全评估患者（573 例中的 399 例）报告了不良事件。除了 VOD/SOS 和相关的 MOD 症状外，最常报告的治疗紧急不良事件是低血压 (13.8%)。本试验中观察到的第 100 天生存结果与之前在成人和儿童患者中使用去纤维蛋白多核苷酸进行 VOD/SOS 试验的结果一致。这些数据支持去纤维蛋白多核苷酸在治疗 VOD/SOS 患者群体（包括患有和不患有 MOD 的患者）方面的潜在益处。 (C) 2017 年美国血液和骨髓移植学会。
Hepatic veno-occlusive disease, or sinusoidal obstruction syndrome (VOD/SOS), is a serious and potentially fatal complication of conditioning for hematopoietic stem cell transplantation (HSCT) or of chemotherapy regimens alone. Defibrotide is a complex mixture of single-stranded polydeoxyribonucleotides that is approved in the United States for treating hepatic VOD/SOS with renal or pulmonary dysfunction post-HSCT and in the European Union, Israel, and South Korea for treating severe hepatic VOD/SOS post-HSCT. Defibrotide was previously available in the United States as an investigational drug through a treatment protocol (treatment IND) study. Interim results of that large, treatment IND study of patients with VOD/SOS and with or without multiorgan dysfunction (MOD; also known as multiorgan failure) are presented here. Defibrotide was administered i.v. at 6.25 mg/kg every 6 hours (25 mg/kg/day), with a recommended treatment duration of at least 21 days. Enrolled patients (n = 681) were diagnosed with VOD/SOS based on Baltimore or modified Seattle criteria or liver biopsy analysis. Among the 573 HSCT recipients, 288 (50.3%; 95% confidence interval [CI], 46.2% to 54.4%) were alive at day +100 post-HSCT. Day +100 survival for the pediatric (16 years) subgroups was 54.5% (95% CI, 49.1% to 60.0%; n = 174 of 319) and 44.9% (95% CI, 38.8% to 51.0%; n = 114 of 254), respectively. In the MOD subgroup, 159 of 351 patients (45.3%; 95% CI, 40.1% to 50.5%) of patients were alive at day +100 post-HSCT. Treatment with defibrotide was generally. ell tolerated, and drug-related toxicities were consistent with previous studies. Adverse events were reported in 69.6% of safety-evaluable patients (399 of 573). Other than VOD/SOS and associated MOD symptoms, the most commonly reported treatment emergent adverse.event was hypotension (13.8%). Day +100 survival results observed in this trial were consistent with results seen in previous trials of defibrotide for VOD/SOS in adult and pediatric patients. These data support the potential benefit of defibrotide in treating a VOD/SOS patient population that includes those with and without MOD. (C) 2017 American Society for Blood and Marrow Transplantation.