• Number of Patients Alive at Three Years (Survival) [ Time Frame: 3 years ] [ Designated as safety issue: No ]
• Number of Patients With Succcessful Engraftment After Transplantation [ Time Frame: 42 Days ] [ Designated as safety issue: No ]
• Number of Patients With Grade 2-4 Acute Graft Versus Host Disease [ Time Frame: 100 Days ] [ Designated as safety issue: Yes ]
• Number of Patients With Chronic Graft Versus Host Disease [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
• Number of Patients With Disease Recurrence [ Time Frame: 2 years ] [ Designated as safety issue: No ]

• To provide the potential for curative therapy of Kostman's neutropenia, Shwachman's neutropenia, Diamond-Blackfan anemia and severe osteopetrosis by unrelated donor (URD) bone marrow or cord blood transplantation.
• To evaluate the rate of engraftment after transplantation of non-genotypic identical marrow or cord blood cells using a using a “non-myeloablative” preparative regimen consisting of busulfan, fludarabine, ATG and irradiation.
• To determine the incidence of acute and chronic graft-versus-host disease (GVHD), disease recurrence and three year survival in patients receiving transplantation with non-genotypic matched marrow or cord blood.
• To characterize the pharmacokinetic parameters in patients receiving 2 mg/kg/dose of IV busulfan twice daily.

The researchers hypothesize that it will be possible to perform unrelated bone marrow or cord blood transplants in a safer manner by using less intensive therapy yet still achieve an acceptable level of donor cell engraftment for non-malignant congenital bone marrow failure disorders.

Prior to transplantation, subjects will receive the drugs busulfan (orally or through the catheter), as well as fludarabine and anti-thymocyte globulin (ATG) via the catheter. Busulfan, fludarabine and ATG will be given with Total Lymphoid Irradiation (TLI) to help the new donor bone marrow take and grow after transplantation.

Those patients receiving donor marrow will have the T cells (a type of white blood cell in the donor marrow) removed to lower the risk that the new marrow will react to their body, a condition called Graft-Versus-Host-Disease (GVHD). After bone marrow transplantation, subjects will receive drugs to help prevent GVHD, including cyclosporin and mycophenolate mofetil (MMF).

Blood samples are taken at day 28, day 60, day 100, 1 year and as required by medical status yearly for five years after transplant to evaluate how well the new marrow is growing. A bone marrow biopsy is required at day 21, at day 100 and 1 year.

• Diamond-Blackfan Anemia
• Kostmann's Neutropenia
• Shwachman-Diamond Syndrome

• Procedure: Stem cell transplant
• Drug: Busulfan, fludarabine and anti-thymocyte globulin (ATG)
• Procedure: Total lymphoid irradiation

Inclusion Criteria:

• Patients eligible for transplantation under this protocol will be <35 years of age, and will be diagnosed with:

  • a bone marrow failure syndrome unresponsive to available therapy, including but not limited to Diamond-Blackfan anemia, Shwachman Diamond syndrome or Kostmann's neutropenia but exclusive of aplastic anemia.

• Diamond Blackfan Anemia:

  • Patients must show evidence of steroid resistance requiring equivalent of >6 transfusions yearly despite steroid therapy.
  • Evidence of developing aplasia or myelodysplasia will also be criteria for transplantation.

• Kostmann's Neutropenia, Shwachman-Diamond syndrome:

  • Patients must have been previously diagnosed as having a clinical picture characteristic of Shwachman-Diamond syndrome (exocrine pancreatic insufficiency, growth retardation, metaphyseal dysostosis, neutropenia), or must have a bone marrow aspirate consistent with Kostmann's neutropenia, with no evidence of acute leukemia.
  • Patients must have failed therapy with G-CSF, as determined by an inability to maintain an absolute neutrophil count (ANC) >750 cells/ml(3), or manifesting recurrent infections despite G-CSF administration resulting in life threatening infections or repeated hospitalizations (<4 /year).

Exclusion Criteria:

• Patients >35 years of age
• Karnofsky score <70%
• Hepatic dysfunction as determined by bilirubin >3.0, ALT >150, or active hepatitis
• Pulmonary function tests with FVC and FEV <70%; O2 saturation <94%
• Renal dysfunction with GFR <30% of predicted.
• Cardiac compromise, with left ejection fraction <45%.
• Severe, stable neurologic impairment.
• HIV positivity.
• Pregnant or lactating females