The purpose of this study is to determine whether the use of lower doses of busulfan and the elimination of cyclosporine will further reduce transplant-related side effects for patients with Fanconi Anemia (FA). Patients will undergo a transplant utilizing mis-matched related or matched unrelated donors following a preparative regimen of busulfan, fludarabine, anti-thymocyte globulin and cyclophosphamide.
Patients must have a diagnosis of Fanconi anemia
Platelet count <20 x 109/L or platelet transfusion dependence*
ANC <1000 x 109/L
Hgb <8 gm/dl or red cell transfusion dependence*
Active CNS leukemia
Female patients who are pregnant (positive serum or urine HCG) or breast-feeding.
Active uncontrolled viral, bacterial or fungal infection
Patient seropositive for HIV-I/II; HTLV -I/II
Parallel
Busulfan
DrugA standard dose of busulfan, associated with excellent outcomes in our previous trial will be used for young patients with marrow aplasia (arm A). A higher dose of busulfan will be used in younger patients with MDS and AML (arm B) to maximize disease control. A lower dose of busulfan will be used in older patients (arm C) to minimize toxicity.
Cyclophosphamide
DrugArms A, B and C - Cytoxan will be given as a 1-2 hour infusion for 4 days. The dose will be adjusted according to patients ideal body weight for obese patients.
Fludarabine
DrugArms A, B and C - Fludarabine will be given IV over 30 minutes daily for 4 days. The dose will be adjusted according to renal function according to Institutional guidelines.
rabbit ATG
DrugArms A, B and C - 4 doses will be given prior to transplant to promote engraftment.
G-CSF
DrugAll patients will also receive G-CSF post-transplant to foster engraftment.
Peripheral blood stem cell
Biological/VaccineThe source of stem cells for all patients will be peripheral blood stem cells (PBSC) induced and mobilized by treatment of the donor with G-CSF for 4-6 days. T-cell depletion will be uniformly performed by positive CD34 selection with the use of the Miltenyi system (CliniMACS device).
Graft Failure or Rejection
Primary non-engraftment is diagnosed when the patient fails to achieve an ANC \>=500/mm3 at any time in the first 28 days post-transplant. If (1) after achievement of an absolute neutrophil count (ANC) \>=500/mm3, the ANC declines to \<500/mm3 for more than 3 consecutive days in the absence of relapse, or, (2) there is absence of donor cells in the marrow and/or blood as demonstrated by chimerism assay in the absence of relapse, a diagnosis of secondary graft failure is made. The patient is not evaluable for graft failure or rejection if recurrence of host MDS is detected concurrently.
Post-transplant severe morbidity and mortality
The occurrence of severe post-transplant regimen-related severe morbidity (grade IV toxicity) and/or mortality will be the second endpoint of this study. In the context of the agents or agent-combination used for cytoreduction used, particular attention will be given to toxicity involving (1) the liver, (2) the lungs, (3) the oral mucosa and gastrointestinal tract, and (4) the central nervous system.
Graft Versus Host Disease
Patients will be observed for acute and/or chronic graft versus host disease (GvHD). Standard clinical criteria for the grading of acute and chronic GvHD will be done according to IBMTR guidelines.
Leukemic Relapse
For patients with MDS or AML, relapse will be analyzed as to type and genetic origin of the MDS/leukemic cells.
Secondary malignancies
Patients will be followed for 5 years through annual contact with their treatment center in order to track the risk of developing a secondary malignancy.
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Children's Hospital Medical Center, Cincinnati
Lead sponsor
Memorial Sloan Kettering Cancer Center
Collaborator
Fred Hutchinson Cancer Center
Collaborator
