Determining the Safety and Efficacy of Prophylactic Defibrotide Administration in Children, Adolescents, and Young Adults with Sickle Cell Disease Following Myeloimmunoablative Conditioning (MAC) and Haploidentical Stem Cell Transplantation Utilizing CD34+ Selection and T-Cell (CD3) Addback (IND127812)

Background Sickle cell disease (SCD) is a hemoglobinopathy and vasculopathy resulting in vaso-occlusive crises, chronic end-organ damage, and shortened life span. The only curative therapy is allogeneic stem cell transplant (AlloSCT) (Talano/Cairo, EJH, 2015). Unfortunately, only approximately 16% of the sickle cell population has an HLA matched unaffected sibling (Bhatia/Cairo, BMT, 2014). We have demonstrated the safety and efficacy of familial haploidentical transplants (FHI) in this population with 100% engraftment (Cairo et al, JAMA Peds, 2019). However, the incidence of sinusoidal obstructive syndrome (SOS) in SCD AlloSCT recipients is approximately 32% (McPherson, BMT, 2011). Defibrotide primarily targets endothelium and can reduce endothelial cell injury (Falanga et al, Leukemia, 2003 and Scallia et al, Clin Pharm, 1996). Corbaciolgu et al (Lancet 2012) demonstrated the safety and efficacy of prophylactic defibrotide in high-risk pediatric AlloSCT recipients to significantly reduce the incidence of SOS. Objective To determine the safety and efficacy of defibrotide prophylaxis for SOS in children, adolescents and young adults (CAYA) with high-risk SCD following MAC and FHI AlloSCT, utilizing CD34+ selection with CD3 addback. Design/Methods Patients with SCD aged 2 to 35 years with high-risk SCD (stroke, ≥2 acute chest syndrome in past 2 years, ≥3 pain crises in last 2 years, abnormal TCD study, ≥1 silent infarct lesion on MRI) were enrolled after being consented (NCT02675959). Patients were in two cohorts (2 to 17.99 years and 18 to 34.99 years of age) for age-based analysis and treatment (Table 1 and 2). All patients received a MAC regimen prior to receipt of an FHI with CD34+ selection and CD3 addback peripheral blood stem cell transplantation (PBSCT), as we have already demonstrated (Cairo et al, ASH, 2018). Defibrotide was given day -10 during conditioning through day +21 following transplant. Baseline studies of organ function and biomarkers were obtained prior to transplantation. Results We have enrolled eight patients, five in cohort 1 (median age 9.9 years) and three in cohort 2 (median age of 24 years) with a gender ratio (M/F) of 4/4. Patients had hemoglobin SS (n=7) or hemoglobin SC (n=1). Patients had either a maternal (n=7) or sibling (n=1) donor. Patients had early neutrophil engraftment (median day +11 (day +7 to day +14)). All tolerated 109 ± 11doses of defibrotide. There were no severe adverse or bleeding events probably or directly related to defibrotide. No patient developed SOS. Conclusion The preliminary data suggests defibrotide is safe and well tolerated in CAYA patients with high-risk SCD following MAC and FHI AlloSCT, utilizing CD34+ selection with CD3 addback. A larger cohort and/or follow-up will be required to confirm these preliminary findings. Supported by FDA R01FD004090 and Jazz Pharmaceuticals.