Richardson Paul G, Smith Angela R, Triplett Brandon M, Kernan Nancy A, Grupp Stephan A, Antin Joseph H, Lehmann Leslie, Shore Tsiporah, Iacobelli Massimo, Miloslavsky Maja, Hume Robin, Hannah Alison L, Nejadnik Bijan, Soiffer Robert J
Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
University of Minnesota, Minneapolis, Minnesota.
Biol Blood Marrow Transplant. 2017 Jun;23(6):997-1004. doi: 10.1016/j.bbmt.2017.03.008. Epub 2017 Mar 8.
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) and adult (>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 well 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.
肝静脉闭塞病，即窦性阻塞综合征（VOD/SOS），是造血干细胞移植（HSCT）预处理或单纯化疗方案的一种严重且可能致命的并发症。去纤苷是一种单链多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VOD/SOS，在欧盟、以色列和韩国被批准用于治疗HSCT后的严重肝VOD/SOS。去纤苷此前在美国作为一种研究性药物通过一项治疗方案（治疗性IND）研究提供。本文介绍了该项针对VOD/SOS患者、伴有或不伴有多器官功能障碍（MOD；也称为多器官衰竭）的大型治疗性IND研究的中期结果。去纤苷通过静脉注射给药，剂量为6.25mg/kg，每6小时一次（25mg/kg/天），推荐治疗持续时间至少为21天。入组患者（n = 681）根据巴尔的摩或改良西雅图标准或肝活检分析被诊断为VOD/SOS。在573例HSCT受者中，288例（50.3%；95%置信区间[CI]，46.2%至54.4%）在HSCT后第100天存活。儿科（≤16岁）和成人（>16岁）亚组的第100天生存率分别为54.5%（95%CI，49.1%至60.0%；319例中的174例）和44.9%（95%CI，38.8%至51.0%；254例中的114例）。在MOD亚组中，351例患者中有159例（45.3%；95%CI，40.1%至50.5%）在HSCT后第100天存活。去纤苷治疗总体耐受性良好，与先前研究一致的药物相关毒性。69.6%的可进行安全性评估的患者（573例中的399例）报告了不良事件。除了VOD/SOS及相关的MOD症状外，最常报告的治疗中出现的不良事件是低血压（13.8%）。该试验中观察到的第100天生存结果与先前去纤苷治疗成人和儿科VOD/SOS患者的试验结果一致。这些数据支持去纤苷在治疗包括伴有和不伴有MOD的VOD/SOS患者群体中的潜在益处。
