Evaluating the Safety and Effectiveness of Bone Marrow Transplants in Children With Sickle Cell Disease (BMT CTN 0601)
Condition: Sickle Cell Disease
MeSH terms: Anemia, Sickle Cell
Intervention: Hematopoietic Stem Cell Transplantation
Intervention description: The stem cell transplant preparative regimen is listed 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.
Alemtuzumab: Children weighing 10 kg or more will receive 10 mg, 15 mg, and 20 mg intravenously (IV) on Days -21, -20, and -19, respectively
Fludarabine: 30 mg/m^2/day IV on Days -8 through -4
Melphalan: 140 mg/m^2 IV on Day -3
Rest on Days -2 and -1
Transplant occurs on Day 0
GVHD prophylaxis: Tacrolimus or cyclosporine beginning Day -3, methotrexate (7.5 mg/m2/day) Day 1, 3 and 6 and methylprednisolone/prednisone on Day +7 to +28 followed by a taper if there is no GVHD
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 30.0
Sex: All
Minimum age: 3 Years
Maximum age: 19 Years
Healthy volunteers: No
Keywords: Sickle Cell Disease; Sickle Cell Anemia

Summary:

      Sickle cell disease (SCD), also known as sickle cell anemia, is an inherited blood disease
      that can cause organ damage, stroke, and intense pain episodes. A blood stem cell transplant
      is a treatment option for someone with a severe form of the disease. Prior to undergoing a
      transplant, people typically receive a conditioning regimen of high doses of chemotherapy and
      other medications to prepare the body to accept the transplant. A conditioning regimen that
      uses lower doses of chemotherapy and medications may be safer for transplant recipients. This
      study will evaluate the safety and effectiveness of blood stem cell transplants, using bone
      marrow from unrelated donors, in children with severe SCD who receive a reduced intensity
      conditioning regimen prior to the transplant.
    

Eligibility criteria:

        Inclusion Criteria:

          -  SCD (genotype hemoglobin SS disease [Hb SS], genotype hemoglobin SC disease
             [HbSC],sickle ß°[Sß°] thalassemia, or sickle ß^+[Sß^+]thalassemia) with one or more of
             the following:

               1. Patients must have symptomatic SCD (genotype Hb SS, Hb SC, Sß° thalassemia or Sß+
                  thalassemia), AND have 1 or more of the following clinical complications:(i)
                  Clinically significant neurologic event (stroke) or any neurologic deficit
                  lasting more than 24 hours that is accompanied by an infarct on cerebral MRI; OR
                  (ii) patients who have a Transcranial Doppler (TCD) velocity that exceeds 200
                  cm/sec by the non-imaging technique (or TCD measurement greater than 185 cm/sec
                  by the imaging technique) measured at a minimum of 2 separate occasions one month
                  or more apart; OR,

               2. Minimum of two episodes of acute chest syndrome in the 2 years before study
                  entry, defined as new pulmonary alveolar consolidation involving at least one
                  complete lung segment (associated with acute symptoms including fever, chest
                  pain, tachypnea, wheezing, rales, or cough that is not attributed to asthma or
                  bronchiolitis) despite adequate supportive care measures

               3. History of 3 or more severe pain events per year in the 2 years before study
                  entry

          -  Lansky/Karnofsky performance score greater than or equal to 40

          -  Patients must have an unrelated adult bone marrow donor who is Human Leukocyte Antigen
             (HLA)-matched at 8 of 8 HLA-A, -B, -C and -DRB1 at high resolution using DNA-based
             typing.

          -  Patients with adequate physical function: a)Cardiac: Left ventricular ejection
             fraction (LVEF) greater than 40%, or LV shortening fraction greater than 26%; b)
             Pulmonary: Pulse oxymetry with a baseline O2 saturation of greater than or equal to
             85% is required for all patients, Carbon Monoxide Diffusing Capacity (DLCO) greater
             than 40% (corrected for hemoglobin) for patients in whom pulmonary function testing
             can be performed; c) Renal: Serum creatinine less than or equal to 1.5 x upper limit
             of normal for age and glomerular filtration rate (GFR) greater than 100 mL/min/1.73 m.
             For patients older than or equal to 16 years of age, GFR should be greater than 70
             mL/min/1.73 m^2; d) Hepatic: Serum conjugated (direct) bilirubin less than 2x upper
             limit of normal for age as per local laboratory; alanine transaminase (ALT) and
             aspartate transaminase (AST) less than 5 times upper limit of normal as per local
             laboratory.

          -  If the patient has been receiving chronic transfusion therapy for more than or equal
             to 1 year AND has clinical evidence of iron overload (serum ferritin level of greater
             than 1000 ng/ml), a liver biopsy shall be obtained within 90 days of starting
             conditioning therapy (alemtuzumab). Histologic exam of the liver must document absence
             of bridging fibrosis or cirrhosis of the liver. In other cases, a liver biopsy is
             optional.

          -  Hemoglobin S (Hb S) level less than or equal to 45%, seven days prior to initiation of
             alemtuzumab

        Exclusion Criteria:

          -  Evidence of uncontrolled bacterial, viral or fungal infections (currently taking
             medication and progression of clinical symptoms) within 1 month prior to starting the
             conditioning regimen. Patients with fever or suspected minor infection should await
             resolution of symptoms before starting the conditioning regimen

          -  Pregnant or breastfeeding

          -  Patients with 8/8 HLA-matched family donors able to donate

          -  Seropositivity for HIV

          -  Prior allogeneic marrow or stem cell transplant

          -  Iron chelation must be discontinued more than or equal to 48 hours before initiating
             the conditioning regimen

          -  Hydroxyurea (if receiving this therapy) must be discontinued more than or equal to 48
             hours before initiating the conditioning regimen