Bone Marrow Transplantation in Young Adults With Severe Sickle Cell Disease
Condition: Sickle Cell Disease
MeSH terms: Anemia, Sickle Cell
Intervention: Conditioning Regimen with Bone Marrow Transplant
Intervention description: 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
Intervention MeSH terms: Fludarabine; Busulfan; Thymoglobulin; Antilymphocyte Serum
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 22.0
Sex: All
Minimum age: 16 Years
Maximum age: 40 Years
Healthy volunteers: No
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

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.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Diagnosis of severe sickle cell disease and have one or more of the following:

               1. Clinically significant neurologic event (stroke) or any neurological deficit
                  lasting > 24 hours

               2. History of two or more episodes of acute chest syndrome (ACS) in the 2-year
                  period preceding enrollment despite the institution of supportive care measures
                  (i.e. asthma therapy and/or hydroxyurea). Acute Chest Syndrome (ACS) is defined
                  as new pulmonary alveolar consolidation (or infiltrate) involving at least one
                  complete lung segment associated with acute symptoms including one or more of the
                  following: fever ≥ 38.5 Celsius, chest pain, tachypnea per age adjusted normal,
                  intercostal retractions/nasal flaring/use of accessory muscles of respiration,
                  wheezing, rales or cough that is not attributed to asthma or bronchiolitis.

               3. History of three or more severe pain crises per year in the 2-year period
                  preceding enrollment despite the institution of supportive care measures (i.e. a
                  pain management plan and/or treatment with hydroxyurea). Pain Crisis is defined
                  as new onset of pain that last for at least 2 hours for which there is no other
                  explanation (i.e. vaso-occlusive, priapism).

               4. Administration of regular red blood cell (RBC) transfusion therapy, defined as
                  receiving 8 or more transfusions per year for greater than or equal to 1 year to
                  prevent vaso-occlusive clinical complications (i.e. pain, stroke, and acute chest
                  syndrome)

               5. Trans-thoracic echocardiograph evidence of tricuspid valve regurgitant jet (TRJ)
                  velocity greater than or equal to 2.7 m/sec.

          -  Adequate physical function as measured by:

               1. Karnofsky performance score greater than or equal to 60

               2. Cardiac function: Left ventricular ejection fraction (LVEF) > 40%; or LV
                  shortening fraction > 26% by cardiac echocardiogram or by multigated acquisition
                  (MUGA) scan.

               3. Pulmonary function: Pulse oximetry with a baseline O2 saturation of greater than
                  or equal to 85% and diffusing capacity of the lungs for carbon monoxide (DLCO) >
                  40% (corrected for hemoglobin)

               4. Renal function: Serum creatinine ≤ 1.5 x upper limit of normal for age and
                  24-hour urine creatinine clearance > 70 mL/min/1.73 m2 by radionuclide glomerular
                  filtration rate (GFR); or GFR > 70 mL/min/1.73 m2 by radionuclide GFR.

               5. Hepatic function: Serum conjugated (direct) bilirubin < 2x upper limit of normal
                  for age as per local laboratory; and alanine aminotransferase (ALT) and aspartate
                  aminotransferase (AST) < 5 times upper limit of normal as per local laboratory.
                  Patients whose hyperbilirubinemia is the result of hyperhemolysis, or a severe
                  drop in hemoglobin post blood transfusion, are not excluded

               6. If the patient has been receiving chronic transfusion therapy for greater than or
                  equal to 1 year and has clinical evidence of iron overload by serum ferritin
                  (mean of 3 ferritin levels >1000 and chronic transfusions >20 in a lifetime or
                  MRI), evaluation by liver biopsy is required. Histological examination of the
                  liver must document the absence of cirrhosis, bridging fibrosis and active
                  hepatitis. The absence of bridging fibrosis will be determined using the
                  histological grading and staging scale as described by Ishak and colleagues
                  (1995).

          -  Patients must have a related or unrelated bone marrow donor with HLA-matched at 8 of 8
             HLA-A, B, C, and DRB1 loci by allelic testing. Umbilical cord blood or peripheral
             blood stem cell donors will not be accepted.

        Exclusion Criteria:

          -  Patients with cirrhosis of the liver, uncontrolled bacterial, viral or fungal
             infection in the 6 weeks before enrollment, or seropositivity for HIV

          -  Patients who have received prior HCT

          -  Patients who within 3 months of enrollment have participated in another clinical trial
             in which the patient received an investigational drug or device or off-label use of a
             drug or device

          -  Patients who demonstrate lack of compliance with prior medical care

          -  Patients who are unwilling to use approved contraception for at least 6 months after
             transplant

          -  Patients who have a history of substance abuse in the last 5 years that interferes
             with their care

          -  Patients who are pregnant or breast feeding

          -  Patients unable to provide consent