Conditions: Sickle Cell Disease
Keywords: Severe Sickle Cell Disease Hematopoietic cell transplantation (HCT) Hematopoietic Stem Cell Therapy Bone Marrow Transplant Hematologic Diseases Genetic Diseases Anemia Hemolytic Congenital Human Leukocyte Antigen HLA
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 22
Healthy volunteers: no

Brief summary:
This is a Phase II, single arm, multi-center trial. It is designed to estimate the efficacy and toxicity of hematopoietic stem cell transplantation (HSCT) in patients with sickle cell disease (SCD) who have high risk features.

The primary goal of this multi-center Phase II study is to determine the safety and feasibility of a conditioning regimen consisting of busulfan (Bu)/ fludarabine (Flu)/ anti-thymocyte globulin (ATG) in adult patients with severe SCD. A two-component design will be used for this study. The first component will be restricted to patients who have an HLA-identical sibling donor. Five patients will be transplanted during the first component of the study. If no more than 2 of the first 5 patients experience unacceptable toxicity, including death, within the first six months after transplantation, then the safety of the regimen will be considered promising in adult SCD patients.

The second component will include patients who have a related or an unrelated human leukocyte antigen (HLA) matched donor. Up to 15 additional patients will be transplanted in this component of the study which will evaluate the safety and feasibility of unrelated donor hematopoietic cell transplantation (HCT) in adults with SCD. Data related to study endpoints for 1 year after transplantation will be collected; however, participating centers will be encouraged to conduct long-term follow-up evaluations of patients according to standard institutional guidelines. The purpose of this pilot safety trial is to see if this approach is feasible and meets accrual goals lending support to the development of a subsequent full scale investigation of HCT and comparing outcomes in a transplantation cohort to a control cohort of adults eligible for, but unwilling or unable to receive HCT treated by supportive therapy with a primary endpoint of five years survival for this full scale comparative trial.

Detailed description:
This is a Phase II, single arm, multi-center trial. It is designed to estimate the efficacy and toxicity of hematopoietic stem cell transplantation (HSCT) in patients with sickle cell disease (SCD) who have high risk features.

The primary goal of this multi-center Phase II study is to determine the safety and feasibility of a conditioning regimen consisting of busulfan (Bu)/ fludarabine (Flu)/ anti-thymocyte globulin (ATG) in adult patients with severe SCD. A two-component design will be used for this study. The first component will be restricted to patients who have an HLA-identical sibling donor. Five patients will be transplanted during the first component of the study. If no more than 2 of the first 5 patients experience unacceptable toxicity, including death, within the first six months after transplantation, then the safety of the regimen will be considered promising in adult SCD patients.

The second component will include patients who have a related or an unrelated human leukocyte antigen (HLA) matched donor. Up to 15 additional patients will be transplanted in this component of the study which will evaluate the safety and feasibility of unrelated donor hematopoietic cell transplantation (HCT) in adults with SCD. Data related to study endpoints for 1 year after transplantation will be collected; however, participating centers will be encouraged to conduct long-term follow-up evaluations of patients according to standard institutional guidelines. The purpose of this pilot safety trial is to see if this approach is feasible and meets accrual goals lending support to the development of a subsequent full scale investigation of HCT and comparing outcomes in a transplantation cohort to a control cohort of adults eligible for, but unwilling or unable to receive HCT treated by supportive therapy with a primary endpoint of five years survival for this full scale comparative trial.

The primary objective is to determine event-free survival (EFS) at 1 year after hematopoietic cell transplantation (HCT) using bone marrow in patients with sickle cell disease. Death, disease recurrence or graft rejection by 1 year will be considered events for this endpoint.

Secondary objectives include determining the effect of HCT on clinical and laboratory manifestations of severe sickle cell disease and determining the incidence of other transplant-related outcomes.

Arms:
arm 1: Adults with sickle cell disease undergoing a bone marrow transplant from an HLA-identical sibling donor or an unrelated HLA-matched donor.

Interventions: intervention 1: Conditioning Regimen with Bone Marrow Transplant
Intervention descriptions: intervention 1: The bone marrow transplant regimen is below. Day 0 is the day of the transplant. The - sign is the number of days before and the + sign is the number of days after the transplant.

Day -8 BU 3.2 mg/ kg/dose IV

Day -7 BU 3.2 mg/kg/dose IV, FLU 35mg/m2 IV

Day -6 BU 3.2 mg/kg/dose IV, FLU 35mg/m2 IV, ATG 0.5mg/kg IV

Day -5 BU 3.2 mg/kg/dose IV, FLU 35mg/m2 IV, ATG 1.0mg/kg IV

Day -4 FLU 35mg/m2 IV, ATG 1.5mg/kg IV

Day -3 FLU 35mg/m2 IV, ATG 1.5mg/kg IV

Day -2 ATG 1.5mg/kg IV

Day -1 Rest

Day 0 Stem cell infusion

Graft Versus Host Disease (GVHD) Regimen

Day -3 Calcineurin Inhibitor (Cyclosporine or Tacrolimus) therapeutic doses through day 180, then taper

Day 0 Stem cell infusion

Day +1 Methotrexate 7.5 mg/m2 IV

Day +3 Methotrexate 7.5 mg/m2 IV

Day +6 Methotrexate 7.5 mg/m2 IV

Day+11 Methotrexate 7.5 mg/m2 IV

Protocol document: