Hematopoietic Stem Cell Transplantation in High Risk Patients With Fanconi 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.

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.