Hypothesis/Aims
Hypothesis
1.0 Defibrotide prophylaxis during myeloimmunoablative conditioning (MIAC) and up to 30 days post familial haploidentical (FHI) allogeneic stem cell transplantation (AlloSCT) utilizing CD34 enrichment and T cell addback in children, adolescent and young adult (CAYA) patients with high-risk sickle cell disease (SCD) will be safe and well tolerated and result in a low incidence of sinusoidal obstruction syndrome (SOS).
1.1 Primary Objectives/Aims
1.1.1. To determine the safety, toxicity and efficacy (day 100 transplant-related mortality [TRM], 1yr EFS and 1yr OS) of prophylactic defibrotide in children and adolescents (1.0-17.99 yrs) (Cohort #1) and young adults (18-34.99yrs) (Cohort #2) with high-risk SCD following MIAC and FHI AlloSCT, utilizing CD34 enrichment and T cell addback.
1.1.2 To maintain robust and rapid hematopoietic engraftment and donor chimerism following a 50% reduction of cyclophosphamide (200 to 100 mg/kg) during MIAC and FHI AlloSCT, utilizing CD34 enrichment and T cell addback.
1.1.3 To measure the changes in endothelial biomarkers and hepatic size, blood flow properties, and parenchymal stiffness by gray-scale, Doppler and elastography ultrasound imaging before, during and after prophylactic defibrotide in both cohorts of patients with high-risk SCD following MIAC and FHI AlloSCT, utilizing CD34 enrichment and T cell addback.
1.1.4 To analyze long-term outcomes in the current FHI AlloSCT SCD patient cohort with a special focus on the incidence of fertility preservation.
1.2 Secondary Objectives/Aims
1.2.1 To calculate the probability of Grade II-IV acute GVHD (aGVHD) and chronic GVHD (cGVHD), whole blood and RBC donor chimerism, and cellular immune reconstitution in each cohort of patients (1 and 2) with high-risk SCD following prophylactic defibrotide, MIAC and FHI AlloSCT, utilizing CD34 enrichment and T cell addback.
1.2.2 To measure the differences in respiratory and pulmonary vascular function in the current and of the new cohorts (1 and 2) of high-risk SCD patients following prophylactic defibrotide, MIAC and FHI AlloSCT, utilizing CD34 enrichment and T cell addback.
1.2.3 To determine the changes in neuroimaging, neurocognitive sequelae and disparity in health-related quality of life (HRQL) in the pilot cohort and both new cohorts (1 and 2) of high-risk SCD patients following prophylactic defibrotide, MIAC and FHI AlloSCT, utilizing CD34 enrichment and T cell addback.
1.0 Defibrotide prophylaxis during myeloimmunoablative conditioning (MIAC) and up to 30 days post familial haploidentical (FHI) allogeneic stem cell transplantation (AlloSCT) utilizing CD34 enrichment and T cell addback in children, adolescent and young adult (CAYA) patients with high-risk sickle cell disease (SCD) will be safe and well tolerated and result in a low incidence of sinusoidal obstruction syndrome (SOS).
1.1 Primary Objectives/Aims
1.1.1. To determine the safety, toxicity and efficacy (day 100 transplant-related mortality [TRM], 1yr EFS and 1yr OS) of prophylactic defibrotide in children and adolescents (1.0-17.99 yrs) (Cohort #1) and young adults (18-34.99yrs) (Cohort #2) with high-risk SCD following MIAC and FHI AlloSCT, utilizing CD34 enrichment and T cell addback.
1.1.2 To maintain robust and rapid hematopoietic engraftment and donor chimerism following a 50% reduction of cyclophosphamide (200 to 100 mg/kg) during MIAC and FHI AlloSCT, utilizing CD34 enrichment and T cell addback.
1.1.3 To measure the changes in endothelial biomarkers and hepatic size, blood flow properties, and parenchymal stiffness by gray-scale, Doppler and elastography ultrasound imaging before, during and after prophylactic defibrotide in both cohorts of patients with high-risk SCD following MIAC and FHI AlloSCT, utilizing CD34 enrichment and T cell addback.
1.1.4 To analyze long-term outcomes in the current FHI AlloSCT SCD patient cohort with a special focus on the incidence of fertility preservation.
1.2 Secondary Objectives/Aims
1.2.1 To calculate the probability of Grade II-IV acute GVHD (aGVHD) and chronic GVHD (cGVHD), whole blood and RBC donor chimerism, and cellular immune reconstitution in each cohort of patients (1 and 2) with high-risk SCD following prophylactic defibrotide, MIAC and FHI AlloSCT, utilizing CD34 enrichment and T cell addback.
1.2.2 To measure the differences in respiratory and pulmonary vascular function in the current and of the new cohorts (1 and 2) of high-risk SCD patients following prophylactic defibrotide, MIAC and FHI AlloSCT, utilizing CD34 enrichment and T cell addback.
1.2.3 To determine the changes in neuroimaging, neurocognitive sequelae and disparity in health-related quality of life (HRQL) in the pilot cohort and both new cohorts (1 and 2) of high-risk SCD patients following prophylactic defibrotide, MIAC and FHI AlloSCT, utilizing CD34 enrichment and T cell addback.