Cytoxan, Fludara, and Antithymocyte Globulin Conditioning Followed By Stem Cell Transplant in Treating Fanconi Anemia

OBJECTIVES:

Primary

• To determine the probability of engraftment in patients with Fanconi anemia treated with cyclophosphamide, fludarabine phosphate, and antithymocyte globulin followed by HLA-genotypically identical sibling donor hematopoietic stem cell transplantation that is T-cell depleted.

Secondary

• To evaluate the incidence of acute graft-versus-host disease (GVHD) and chronic GVHD in patients treated with this regimen.
• To evaluate the incidence of regimen-related toxicity in these patients.
• To evaluate the 1-year survival of patients treated with this regimen.
• To evaluate the incidence of late secondary malignancies (e.g., squamous cell carcinoma of the head and neck or cervix) in patients treated with this regimen.

OUTLINE:

• Preparative cytoreductive therapy: Patients receive cyclophosphamide IV over 2 hours on days -6 to -3 and fludarabine phosphate IV over 30 minutes and anti-thymocyte globulin IV over 4-6 hours on days -6 to -2.
• T-cell depleted donor hematopoietic stem cell transplantation: Patients undergo T-cell depleted donor bone marrow or umbilical cord blood stem cell transplantation on day 0. Patients also receive filgrastim (G-CSF) IV beginning on day 1 and continuing until blood counts recover.
• Graft-versus-host disease prophylaxis: Patients receive cyclosporine IV over 2 hours or orally every 8-12 hours beginning on day -3 and continuing until day 100, followed by a taper. Patients will receive Mycophenolate Mofetil (MMF) therapy beginning on day -3 through day +30 or for 7 days after engraftment, whichever day is later, if no acute GVHD. Engraftment is defined as 1st day of 3 consecutive days of absolute neutrophil count [ANC] > 0.5 x 10^9/L.

After completion of study therapy, patients are followed periodically.

Inclusion criteria

• Patients must be <60 years of age with a diagnosis of Fanconi Anemia (FA).
• Patients must have an HLA-A, B, DRB1 identical sibling donor. Patients and donors will be typed for HLA-A and B using serological or molecular techniques and for DRB1 using high resolution molecular typing.
• Patients with FA must have moderately severe aplastic anemia (AA), early myelodysplastic syndrome (MDS) with no excess blasts with or without chromosomal abnormalities.

• In patients <18 years of age, moderately severe aplastic anemia is defined as having at least one of the following:

• platelet count <40 x 10^9/L
• absolute neutrophil count (ANC) <10 x 10^8/L
• Hgb <9 g/dL
• In patients 18-60 years of age, moderately severe aplastic anemia is defined as having at least one of the following:

• platelet count <20 x 10^9/L
• absolute neutrophil count ANC <5 x 10^8/L
• Hgb <8 g/dL
• Early myelodysplastic syndrome, with multilineage dysplasia with < 5% blasts, with or without chromosomal anomalies.
• Adequate major organ function including:

• Cardiac: ejection fraction >45%
• Hepatic: no clinical evidence of hepatic failure (e.g. coagulopathy, ascites)
• Karnofsky performance status >70% or Lansky >50%
• Women of child bearing age must be using adequate birth control and have a negative pregnancy test.

Exclusion criteria

• Active bacterial infection within one week of hematopoietic cell transplant (HCT)
• Active fungal infection at time of HCT.
• Late MDS with greater than 5% blasts in bone marrow.
• Acute myelogenous leukemia (AML) or history of AML
• Malignant solid tumor (e.g. squamous cell carcinoma of the head/neck/cervix) within 2 years of HCT.
• Pregnant or lactating female.