Hematopoietic Stem Cell Transplantation in High Risk Patients With Fanconi Anemia

• Incidence of Acute and Chronic Graft-Versus-Host Disease [ Time Frame: Day 42 and 1 Year ] [ Designated as safety issue: No ]
• Incidence of Relapse [ Time Frame: 1 Year ] [ Designated as safety issue: No ]
• Incidence of Major Infections [ Time Frame: Day 1 through End of Treatment ] [ Designated as safety issue: Yes ]
• Transplant-Related Toxicity [ Time Frame: Day 100 ] [ Designated as safety issue: Yes ]
• Overall Survival [ Time Frame: 1 Year ] [ Designated as safety issue: No ]
  cumulative proportion surviving
• Incidence of Chronic Graft-Versus-Host Disease [ Time Frame: Day 42 and 1 Year ] [ Designated as safety issue: No ]

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.

• Biological: anti-thymocyte globulin
  Given 15 mg/kg/day intravenously every 12 hours on Days -5 through -1.
  Other Name: ATG
• Biological: filgrastim
  given 5 mcg/kg/day intravenously on Day 1 (continue until absolute neutrophil count (ANC) ≥2.5 x 10^9/L)
  Other Name: G-CSF
• Drug: busulfan
  Busulfan 0.8 mg/kg intravenously (IV) every 12 hours on Days -7 and -6 (1.0 mg/kg IV if <4 years old)
• Drug: cyclophosphamide
  10 mg/kg intravenously (IV) on Days -5 through -2.
  Other Name: Cytoxan
• Drug: fludarabine phosphate
  35 mg/m^2 intravenously (IV) on Days -5 through -2.
  Other Name: Fludara
• Drug: methylprednisolone
  1 mg/kg intravenously (IV) every 12 hours on Days -5 through -1.
• Biological: Hematopoietic stem cell transplantation
  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.
  Other Name: HSCT

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.