Phase 2 Defibrotide PPX in High Risk SCD Pts w/MAC&Haplo AlloSCT IND127812 9-3-15

项目摘要 镰状细胞病（SCD）是一种罕见的孤儿疾病在美国（US），影响约100，000 美国的人。SCD的特征是严重的血管闭塞性疾病，导致内皮细胞 功能障碍、慢性器官损伤、健康相关生活质量（HRQL）差和早期死亡。唯一的 已知的用于高风险SCD患者的治愈性疗法是异基因干细胞移植（AlloSCT）， 未受影响的HLA匹配的同胞供体（MSD）。然而，只有15%的SCD高危患者有这种情况。 捐助者。在上一个资助周期中，我们成功地证明了家族性单倍体相合的安全性和可行性。 (FHI)骨髓免疫清除性预处理后利用CD 34富集和CD 3（T细胞）回加的AlloSCT （MIAC）儿童和青少年（IND #14359）（5 R 01 FD 004090）（NCT 61461837）。在那个资助周期里 利用CliniMACS®技术的CD 34富集方法获得FDA批准，部分原因是 调查的结果这种方法的局限性包括：1）缺乏年轻人的安全性数据 患有高危SCD; 2）继发于内皮功能障碍的移植相关死亡风险高， 窦阻塞综合征（SOS）; 3）潜在的长期毒性，特别是不孕症。Defibrotide 是多分散寡核苷酸的混合物，其靶向小血管内皮，具有抗血栓作用， 纤溶活性去纤维蛋白肽在欧洲获得批准，但在美国尚未获得批准， MIAC AlloSCT后发生严重SOS的患者死亡率显著增加。我们的FHI AlloSCT SCD 财团（www.sicklecelltransplantconsortium.org）已获得新IND（127812），以研究 在MIAC和FHI AlloSCT之前和期间预防去纤维蛋白多核苷酸的安全性、可行性和疗效 CD 34富集和T细胞回加在儿童，青少年和年轻成人与高风险SCD。的 具体目的包括（简要）：1）评估去纤维蛋白多核苷酸预防性治疗的安全性、毒性和有效性， SOS; 2）研究MIAC中环磷酰胺剂量降低50%的安全性和有效性; 3） 鉴定与SOS相关的新的内皮生物标志物和非侵入性肝成像方法; 4） 确定当前队列和两个新队列的迟发效应发生率，重点是生育力保持; 5)确定急性和慢性GVHD的可能性，以及全血和RBC富集供体的水平 嵌合体和细胞免疫重建; 6）估计肺、心血管和 肺血管功能;和7）表征神经成像、神经认知功能和 HRQL。长期目标是获得足够的数据，以促进FDA批准去纤肽 预防措施，以防止严重的SOS在高风险的SCD患者，促进这种成功的治疗 对于SCD高危年轻成人，将MIAC方案中环磷酰胺的剂量减少50% 并维持强大的造血和细胞免疫重建、供体嵌合、低风险的急性和 慢性GVHD和稳健的EFS/OS在没有HLA MSD的高危SCD患者中。

PROJECT SUMMARY Sickle cell disease (SCD) is a rare orphan disease in the United States (US), affecting approximately 100,000 people in the US. SCD is characterized by severe vaso-occlusive disease, resulting in endothelial cell dysfunction, chronic organ damage, poor health-related quality of life (HRQL) and early mortality. The only known curative therapy for patients with high-risk SCD is allogeneic stem cell transplantation (AlloSCT) from an unaffected HLA-matched sibling donor (MSD). However, only 15% of high-risk patients with SCD have such donors. In the last grant cycle we successfully demonstrated the safety and feasibility of familial haploidentical (FHI) AlloSCT utilizing CD34 enrichment and CD3 (T cell) addback after myeloimmunoablative conditioning (MIAC) in children and adolescents (IND#14359) (5R01FD004090) (NCT61461837). During that grant cycle the CD34 enrichment methodology utilizing the CliniMACS® technology was approved by the FDA, in part due to the results of this investigation. Limitations of this approach include: 1) lack of safety data in young adults with high-risk SCD; 2) high risk of transplant-related mortality secondary to endothelial dysfunction and sinusoidal obstructive syndrome (SOS); and 3) potential for long-term toxicity, especially infertility. Defibrotide is a mixture of polydisperse oligonucleotides that targets small vessel endothelium with antithrombotic and fibrinolytic activity. Defibrotide is approved in Europe, but not the US, and has been demonstrated to reduce mortality significantly in patients who have develop severe SOS post-MIAC AlloSCT. Our FHI AlloSCT SCD consortium (www.sicklecelltransplantconsortium.org) has obtained a new IND (127812) to investigate the safety, feasibility and efficacy of defibrotide prophylaxis prior to and during MIAC and FHI AlloSCT utilizing CD34 enrichment and T cell addback in children, adolescents and young adults with high-risk SCD. The specific aims include (brief): 1) assess safety, toxicity and efficacy of defibrotide prophylaxis to prevent severe SOS; 2) investigate safety and efficacy of decreasing the dose of cyclophosphamide in the MIAC by 50%; 3) identify new endothelial biomarkers and methods of non-invasive hepatic imaging associated with SOS; 4) determine the incidence of late effects in the current and two new cohorts, with a focus on fertility preservation; 5) determine the probability of acute and chronic GVHD, and levels of whole blood and RBC-enriched donor chimerism, and cellular immune reconstitution; 6) estimate changes in pulmonary, cardiovascular and pulmonary vascular function; and 7) characterize changes in neuroimaging, neurocognitive function and HRQL. The long-term objectives are to obtain sufficient data to contribute to FDA approval of defibrotide prophylaxis to prevent severe SOS in high-risk patients with SCD, facilitate this successful therapeutic approach to at-risk young adults with SCD, reduce the dose of cyclophosphamide by 50% in the MIAC regimen and maintain robust hematopoietic and cellular immune reconstitution, donor chimerism, low risk of acute and chronic GVHD and a robust EFS/OS in patients with high-risk SCD without an HLA MSD.