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.