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

A Phase II Trial of Non-Myeloablative Conditioning and Transplantation of Partially HLA-Mismatched and HLA-Matched Bone Marrow for Patients With Sickle Cell Anemia and Other Hemoglobinopathies

RATIONALE: Giving low doses of chemotherapy, such as fludarabine and cyclophosphamide, and total-body irradiation before a donor bone marrow transplant helps stop the growth of abnormal cells. It also helps stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving sirolimus and mycophenolate mofetil after transplant may stop this from happening.

PURPOSE: This phase II trial is studying how well giving fludarabine and cyclophosphamide together with total-body irradiation followed by a donor bone marrow transplant works in treating 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