Non-Myeloablative Bone Marrow Transplant for Patients With Sickle Cell Anemia and Other Blood Disorders

OBJECTIVES:

- Determine the transplant-related mortality and progression-free survival of patients
with severe hemoglobinopathies receiving nonmyeloablative conditioning comprising
fludarabine phosphate, cyclophosphamide, and total-body irradiation followed by
partially HLA-mismatched bone marrow transplantation from first-degree relatives or
HLA-matched donors.

- Characterize donor hematopoietic chimerism at 30, 60, and 180 days after transplantation
in these patients.

- Determine the hematologic and non-hematologic toxicity of this regimen in these
patients.

OUTLINE:

- Preparative regimen: Patients receive fludarabine phosphate IV over 30 minutes on days
-6 to -2 and cyclophosphamide IV over 1-2 hours on days -6 and -5. Patients also undergo
total-body irradiation on day -1.

- Bone marrow transplantation: Patients undergo allogeneic bone marrow transplantation on
day 0. Patients then receive cyclophosphamide IV over 1-2 hours on days 3 and 4.

- Graft-versus-host disease prophylaxis: Patients receive sirolimus orally daily on days
5-365 and oral mycophenolate mofetil 3 times a day on days 5-35.

After completion of study treatment, patients are followed periodically.

PROJECTED ACCRUAL: A total of 50 patients will be accrued for this study.

DISEASE CHARACTERISTICS:

- Diagnosis of 1 of the following sickle cell anemias (Hb SS):

- Hb S/β° thalassemia

- Hb S/β+ thalassemia

- Hb SC disease

- Hb SE disease

- Hb SD disease

- Hemoglobin SO-Arab disease

- Hb S/hereditary persistence of fetal hemoglobin

- Meets 1 of the following criteria:

- History of invasive pneumococcal disease

- Stroke or CNS event lasting > 24 hours

- MRI changes indicative of brain parenchymal damage

- Evidence of cerebrovascular disease by magnetic resonance angiography

- Acute chest syndrome requiring exchange transfusion or hospitalization

- Recurrent vaso-occlusive pain crisis (> 2 per year for the last 2 years)

- Stage I or II sickle lung disease

- Sickle retinopathy

- Osteonecrosis

- Red cell alloimmunization (> 2 antibodies) during long-term transfusion

- Constellation of dactylitis in the first year of life AND a baseline hemoglobin <
7 g/dL and leukocytosis (WBC > 13.4/mm^3) in the absence of infection during the
second year of life

- Pitted RBC count > 3.5% during the first year of life

- Ineligible for or refused bone marrow transplantation from an HLA-matched sibling
donor

- Partially mismatched (at least haploidentical) first-degree relative donor available

- No minor (donor anti-recipient) ABO incompatibility if an ABO compatible donor is
available

PATIENT CHARACTERISTICS:

- ECOG performance status (PS) 0-1 OR Karnofsky or Lansky PS 70-100%

- LVEF ≥ 35%

- FEV_1 and forced vital capacity ≥ 40% predicted

- Direct bilirubin < 3.1 mg/dL

- No moderate to severe pulmonary hypertension by ECHO

- No debilitating medical or psychiatric illness that would preclude study participation

- No HIV positivity

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

- No prior transfusions from donor

- No immunosuppressive agents, including steroids as antiemetics, within 24 hours after
the last dose of post-transplantation cyclophosphamide