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

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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.