Fludarabine, Cyclophosphamide, and Total-Body Irradiation Followed By Donor Bone Marrow Transplant in Treating Patients With Sickle Cell Anemia and Other Blood Disorders

• Transplant-related mortality at day 100 and 1 year after bone marrow transplantation (BMT) [ Time Frame: 1 year after bone marrow transplant ] [ Designated as safety issue: No ]
• Risk-stratified estimates of 2-year progression-free survival [ Time Frame: 2 years from bone marrow transplant ] [ Designated as safety issue: No ]

• Transplant-related mortality at day 100 and 1 year after bone marrow transplantation (BMT)
• Risk-stratified estimates of 2-year progression-free survival

• Time to recovery of circulating neutrophils and platelets after chemotherapy [ Time Frame: 60 days from bone marrow transplant ] [ Designated as safety issue: No ]
• Donor chimerism at 30, 60, 180, and 365 days after bone marrow transplant [ Time Frame: 1 year from bone marrow transplant ] [ Designated as safety issue: No ]
• Development of graft-vs-host disease [ Time Frame: 1 year from bone marrow transplant ] [ Designated as safety issue: No ]

• Time to recovery of circulating neutrophils and platelets after chemotherapy
• Donor chimerism at 30, 60, and 180 days after BMT
• Development of graft-vs-host disease

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. Donors receive filgrastim (G-CSF) subcutaneously beginning on day -5 to day -1.
• 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 25 patients will be accrued for this study.

• Biological: G-CSF
  Donors will receive subcutaneous injections in the stomach (or other fatty area of the body) of G-CSF at 10 μg/kg/day for 5 consecutive days until the day of the harvest, the day we collect bone marrow for the transplant.
  Other Name: Filgrastim®
• Drug: cyclophosphamide
  Cyclophosphamide (CTX) 14.5 mg/kg intravenously for 2 days before and after transplant.
• Drug: fludarabine phosphate
  Fludarabine 30 mg/M2 intravenously for 5 days before bone marrow transplant
• Drug: mycophenolate mofetil
  Mycophenolate mofetil 15 mg/kg by mouth three times a day daily for 30 days beginning 5 days after bone marrow transplant.
• Drug: Sirolimus
  The first dose of Sirolimus is 6 mg and is taken by mouth 5 days after bone marrow transplant. On the 6th day after bone marrow transplant, the dose of Sirolimus is 2 mg by mouth daily for 1 year.
• Procedure: Allogeneic bone marrow transplantation
  An allogeneic bone marrow transplant is a procedure that involves taking bone marrow from a donor and giving it to a recipient.
• Radiation: total-body irradiation
  Radiation of the total body will be administered the day before bone marrow transplant.
• Drug: Levetiracetam
  Levetiracetam 500 mg orally twice a day 6 days before transplant and for 1 year after transplant. Levetiracetam prevents seizures.
  Other Name: Keppra

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