Hematopoietic Stem Cell Transplantation in High Risk Patients With Fanconi Anemia

RATIONALE: A bone marrow or umbilical cord blood transplant may be able to replace blood-forming cells that were destroyed by chemotherapy. Giving combination chemotherapy before a donor stem cell transplant may make the transplant more likely to work. This may be an effective treatment for patients with high risk Fanconi's anemia. PURPOSE: This clinical trial is studying how well combination chemotherapy works in treating high risk patients who are undergoing a donor stem cell transplant for Fanconi's anemia.

OBJECTIVES: Primary Determine whether the incidence of neutrophil engraftment is acceptable in high-risk patients with Fanconi's anemia treated with busulfan, cyclophosphamide, fludarabine, and antithymocyte globulin followed by allogeneic hematopoietic stem cell transplantation. Secondary Determine the tolerability of mycophenolate mofetil in these patients. Determine the incidence of acute and chronic graft-vs-host disease in patients treated with this regimen. Determine the incidence of major infections in patients with a history of major infections treated with this regimen. Determine the incidence of relapse in patients with refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, or acute myeloid leukemia treated with this regimen Determine the probability of 1-year survival of patients treated with this regimen. OUTLINE: Patients are stratified according to donor/recipient HLA type (identical vs other). Cytoreductive combination chemotherapy: Patients receive busulfan intravenously (IV) over 2 hours twice daily on days -7 and -6 and cyclophosphamide IV over 2 hours and fludarabine IV over 30 minutes once daily on days -5 to -2. Graft failure prophylaxis: Patients receive methylprednisolone IV twice daily on days -5 to 30 and anti-thymocyte globulin IV over 4-6 hours twice daily on days -5 to -1. Graft-vs-host disease prophylaxis: Patients receive cyclosporine IV over 2 hours twice daily on days -3 to 100 (if patient has a matched sibling donor) or days -3 to 180 (if patient has another donor type). Patients also receive mycophenolate mofetil orally or IV twice daily on days -3 to 45. Allogeneic hematopoietic stem cell transplantation (HSCT): Patients undergo allogeneic HSCT (using bone marrow or umbilical cord blood) on day 0. Patients receive filgrastim (G-CSF) subcutaneously beginning on day 1 and continuing until blood counts recover. After completion of study treatment, patients are followed periodically for 3 years.

given 5 mcg/kg/day intravenously on Day 1 (continue until absolute neutrophil count (ANC) ≥2.5 x 10^9/L)

Busulfan 0.8 mg/kg intravenously (IV) every 12 hours on Days -7 and -6 (1.0 mg/kg IV if <4 years old)

Infused on Day 0 - Donor bone marrow or umbilical cord blood will be collected in the usual sterile manner using established parameters determined by the National Marrow Donor Program.

Chronic Graft-Versus-Host Disease is a severe long-term complication created by infusion of donor cellsinto a foreign host.

Chronic Graft-Versus-Host Disease is a severe long-term complication created by infusion of donor cellsinto a foreign host.

Acute Graft-Versus-Host Disease is a severe short-term complication created by infusion of donor cells into a foreign host.

Acute Graft-Versus-Host Disease is a severe short-term complication created by infusion of donor cells into a foreign host.

Patients with leukemia will have this done by BM biopsy and additional special studies such as cytogenetics or flow cytometry as appropriate.

Inclusion Criteria: Patients must be <45 years of age with a diagnosis of Fanconi anemia with: Biallelic BRCA2 mutations, or Aplastic anemia, or advanced myelodysplastic syndrome (MDS) (MDS with ≥5% blasts), or acute leukemia who are ineligible for total body irradiation. Aplastic anemia is defined as having at least one of the following (with or without cytogenetic abnormalities): platelet count <20 * 10^9, - absolute neutrophil count (ANC) <5 * 10^8/L, - Hgb <8 g/dL Patients must have an HLA-A, B, DRB1 identical or 1 antigen mismatched related or unrelated BM donor or have an HLA-A, B, DRB1 identical, 1 antigen or 2 antigen mismatched related or unrelated umbilical cord blood (UCB) donor. Patients and donors will be typed for HLA-A and B using serological level typing and for DRB1 using high resolution molecular typing. Adequate major organ function including: Cardiac: ejection fraction >45% Hepatic: no clinical evidence of hepatic failure (e.g. coagulopathy, ascites, no cirrhosis) Karnofsky performance status >70% or Lansky >50% Women of child bearing potential must be using adequate birth control and have a negative pregnancy test. Exclusion Criteria: Active CNS leukemia at time of HSCT. Active uncontrolled infection within one week of hematopoietic stem cell transplant (HSCT). Pregnant or lactating female. Donor Inclusion Criteria: Donor must be in good health based on review of systems and results of physical examination. Donor must have a normal hemoglobin, white count, platelet count and partial thromboplastin time (PTT), and a negative diepoxybutane (DEB) test. HIV-NAT negative, HTLV-1, HTLV-2 negative, Hepatitis B and C negative. Female donors of childbearing potential must have a negative pregnancy test. Unrelated donors must agree to peripheral blood stem cell (PBSC) donation Donor Exclusion Criteria: Donor is a lactating female.