Transplantation for Patients With Sickle Cell Disease From Mismatched Family Donors of Bone Marrow
Condition: Sickle Cell Disease
MeSH terms: Anemia, Sickle Cell
Intervention: Bone Marrow Transplant (BMT); Hydroxyurea; Thiotepa; Fludarabine monophosphate; Cyclophosphamide; Rabbit Anti-thymocyte Globulin; Total Body Irradiation
Intervention description: Participants will receive a bone marrow infusion from a human leukocyte antigen (HLA) mismatched donor through a central venous catheter.; Hydroxyurea is part of the bone marrow transplant preparative regimen. Hydroxyurea will be administered at a dose of 30 mg/kg orally as a single daily dose for 90 days (from day -100 to day-10). Hydroxyurea dosing will be based on adjusted body weight in participants weighing >125% ideal body weight.; Thiotepa is part of the bone marrow transplant preparative regimen. Thiotepa will be administered at a dose of 10mg/kg intravenously (IV) over 2 hours or per institutional guidelines on day -7. Thiotepa dosing will be based on adjusted body weight in patients weighing >125% ideal body weight.; Fludarabine is part of the bone marrow transplant preparative regimen. Fludarabine 30 mg/m2/day will be administered from day -7 to day -3 (for a total of 150 mg/m2 over 5 consecutive days) and administered intravenously (IV) over a minimum of 30 minutes. In participants weighing > 125% ideal body weight, fludarabine will be dose based upon adjusted body weight.; Cyclophosphamide is part of the bone marrow transplant preparative regimen. Cyclophosphamide will be administered on days -6 and -5 prior to bone marrow infusion at a dose of 14.5 mg/kg intravenously (IV) infused over 1-2 hours.
Post bone marrow infusion cyclophosphamide will be infused on days +3 (between 60 and 72 hours post marrow infusion) and +4 (approximately 24 hours after day +3 dose) at a dose of 50 mg/kg IV infused over 1-2 hours.
For participants weighing more than 125% of their ideal body weight, dosing will be based on adjusted ideal body weight.; Rabbit anti-thymocyte globulin (ATG) is part of the bone marrow transplant preparative regimen. It is an infusion of rabbit-derived antibodies against human T cells used for prevention of acute rejection in organ transplantation. Rabbit ATG will be administered on day -9 at 0.5 mg/kg and on days -8 and -7 at 2 mg/kg (for a total dose 4.5 mg/kg).; Participants will receive 200 cGy of TBI in a single fraction.
Intervention MeSH terms: Cyclophosphamide; Thiotepa; Fludarabine; Fludarabine phosphate; Hydroxyurea; Antilymphocyte Serum; Thymoglobulin
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 10.0
Sex: All
Minimum age: 15 Years
Maximum age: 40 Years
Healthy volunteers: No
Keywords: bone marrow transplant

Summary:

      The purpose of this study is to learn if it is possible and safe to treat persons with severe
      sickle cell disease (SCD) by bone marrow transplant (BMT) from human leukocyte antigen (HLA)
      half-matched related donors. Preparation before transplant includes the chemotherapy drugs
      hydroxyurea, fludarabine, thiotepa, anti-thymocyte globulin, and cyclophosphamide. It also
      includes radiation.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Disease severity: Participants with SCD who have 1 or more of the following (i-v).

               -  Clinically significant neurologic event (stroke) or any neurological deficit
                  lasting > 24 hours;

               -  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);

               -  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);

               -  Administration of regular red blood cell (RBC) transfusion therapy, defined as
                  receiving 8 or more transfusions per year for ≥ 1 year to prevent vaso-occlusive
                  clinical complications (i.e. pain, stroke, and ACS). Patients on chronic
                  transfusion who have to discontinue transfusion because of allo-sensitization
                  will be eligible.

               -  An echocardiographic finding of tricuspid valve regurgitant jet (TRJ) velocity ≥
                  2.7 m/sec. Patients under the age of 18 years must have cardiac catheterization
                  proven pulmonary arterial hypertension to qualify on this eligibility criterion.

          2. Age: Patients must be 15 - 40 years of age inclusive OR if younger than 15 years must
             be pubertal

          3. Adequate physical function as measured by:

               -  Karnofsky/Lansky performance score ≥ 60

               -  Cardiac function: Left ventricular ejection fraction (LVEF) > 40% or LV
                  shortening fraction > 26% by cardiac echocardiogram or by MUGA scan.

               -  Pulmonary function: Pulse oximetry with a baseline O2 saturation of ≥ 85% and
                  DLCO > 40% (corrected for hemoglobin).

               -  Renal function: Serum creatinine ≤ 1.5 x the upper limit of normal for age as per
                  local laboratory and 24 hour urine creatinine clearance > 70 mL/min/1.73 m2 or
                  GFR > 70 mL/min/1.73 m2 by radionuclide GFR.

               -  Hepatic function: Serum conjugated (direct) bilirubin < 2 x upper limit of normal
                  for age as per local laboratory and ALT and AST < 5 x upper limit of normal as
                  per local laboratory. Patients with hyperbilirubinemia as a consequence of
                  hyperhemolysis, or who experience a sudden, profound change in the serum
                  hemoglobin after a RBC transfusion, are not excluded.

               -  For participants with a suitable donor who meet eligibility criteria and are
                  willing to proceed to HCT, if they have received chronic transfusion therapy for
                  ≥ 1 year and have clinical evidence of iron overload by serum ferritin or MRI, an
                  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

          4. Suitable Donor: To undergo transplantation on this study, participants must have an
             adult first degree relative who shares at least 1 human leukocyte antigen (HLA)
             haplotype with the participant, does not have SCD or other hemoglobinopathy, and is in
             good health; if these criteria are met, they will be allowed to serve as donors.
             Relatives with sickle cell trait are not excluded as donors. When more than 1 donor is
             available, the donor with the fewest HLA allele mismatches will be chosen, unless the
             patient had donor anti-HLA antibodies or there was a medical reason to exclude the
             donor. If donor anti-HLA antibodies are detected, the next best related match will be
             chosen. Umbilical cord blood or peripheral blood stem cell donors will not be
             accepted.

        Exclusion Criteria:

          -  Availability of HLA matched sibling or 8 of 8 HLA-A, B, C and DRB1 matched unrelated
             donor

          -  Presence of donor specific antibodies in the patient

          -  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). The presence of bridging fibrosis will be an exclusion criterion.

          -  Uncontrolled bacterial, viral or fungal infection in the 6 weeks before enrollment

          -  Seropositivity for HIV

          -  Previous hematopoietic cell transplantation (HCT)

          -  Participation in a clinical trial in which the patient received an investigational
             drug or device or off-label use of a drug or device within 3 months of enrollment

          -  Demonstrated lack of compliance with prior medical care

          -  Unwilling to use approved contraception for at least 6 months after transplant

          -  A history of substance abuse in the last 5 years that interferes with care

          -  Pregnant or breast-feeding females at the time of consideration for HCT

        Donor Selection Criteria:

        Preference will be given to related marrow donors who are 2-4 (out of 8) HLA antigen
        mismatched and towards whom the recipient does not have donor specific antibodies. Donors
        will sign an informed consent disclosing that the marrow donation will be used by a patient
        participating in this study. The donor must be matched with the recipient for at least 4 of
        8 HLA alleles (HLA -A, -B, -C and -DRB1 by allele-level DNA methodology). The target total
        nucleated cell count (TNC) is 3.5-8.0 x 108/kg of recipient weight. Marrow will be
        collected without mobilization. Mobilized peripheral blood stem cell (HPC-A) collections
        will not be permitted. Donors must undergo hemoglobinopathy screening by electrophoresis;
        donors who have a hemoglobinopathy will be excluded but trait condition is acceptable.