Bone Marrow Transplantation in Young Adults With Severe Sickle Cell Disease
Condition: Sickle Cell Disease
MeSH terms: Anemia, Sickle Cell
Study type: Interventional
Phase: Phase 2

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.
    

Intervention name(s): Conditioning Regimen with Bone Marrow Transplant
Intervention type(s): Drug
Intervention description(s): 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
Other intervention name(s): Busulfan (BU); Myleran; Busulfex IV; Fludarabine (FLU); Fludara; Rabbit Anti-thymocyte globulin (ATG); Thymoglobulin
Intervention MeSH terms: Fludarabine; Busulfan; Thymoglobulin; Antilymphocyte Serum
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
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