This phase II trial studies how well total-body irradiation (TBI) works when given together with fludarabine phosphate and cyclophosphamide followed by donor bone marrow transplant, mycophenolate mofetil, and cyclosporine in treating patients with Fanconi anemia (FA). Giving low doses of chemotherapy, such as fludarabine phosphate and cyclophosphamide, and TBI before or after a donor bone marrow transplant helps stop the growth of abnormal cells. It may also stop the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune cells and help destroy any remaining cancer cells (graft-versus-tumor effect). Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving mycophenolate mofetil and cyclosporine after the transplant may stop this from happening.
PRIMARY OBJECTIVES: I. Identify doses of total-body irradiation (TBI) that lead to sufficient probability of donor engraftment (\> 5% donor cluster of differentiation \[CD\]3 chimerism) by day +200. II. Evaluate the probability of severe acute graft-versus-host disease. SECONDARY OBJECTIVES: I. Evaluate the probabilities of overall survival, regimen-related toxicity (RRT), and recurrent hematopoietic malignancy in those patients with a prior underlying history of such. II. Examine the degree to which mixed chimerism provides for amelioration of symptoms (i.e., infections due to neutropenia, hemorrhage due to thrombocytopenia) associated with bone marrow failure. III. Determine if the FA complementation group and % initial mosaicism predict engraftment and RRT outcomes. OUTLINE: Patients are assigned to 1 of 4 treatment arms. NOTE: Patients no longer receive pre-transplant cyclophosphamide as of February 2009. After completion of study treatment, patients are followed up at 6 months and then annually thereafter.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
6
Undergo allogeneic bone marrow transplant
Given IV
Given IV or PO
Given IV
Correlative studies
Given PO
Undergo allogeneic stem cell transplant
Undergo TBI
Children's Hospital and Research Center at Oakland
Oakland, California, United States
Vanderbilt University/Ingram Cancer Center
Nashville, Tennessee, United States
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
Seattle, Washington, United States
Children's Hospital of Wisconsin
Milwaukee, Wisconsin, United States
Universidade Federal do Paraná
Curitiba, Paraná, Brazil
Number of Patients Who Engraft at Each Dose of TBI Used
Number of subjects who engrafted. Engraftment defined as greater than 95% donor chimerism.
Time frame: Up to Day 200
Incidence of Grades III-IV Acute GVHD
Number of subjects who developed maximum grade acute graft-vs-host disease aGVHD Stages Skin: 1. \- a maculopapular eruption involving \< 25% BSA 2. \- a maculopapular eruption involving 25 - 50% BSA 3. \- generalized erythroderma 4. \- generalized erythroderma with bullous formation and often with desquamation Liver: 1. \- bilirubin 2.0 - 3.0 mg/100 mL 2. \- bilirubin 3 - 5.9 mg/100 mL 3. \- bilirubin 6 - 14.9 mg/100 mL 4. \- bilirubin \> 15 mg/100 mL Gut: Diarrhea is graded 1 - 4 in severity. Nausea and vomiting and/or anorexia caused by GVHD is assigned as 1 in severity. The severity of gut involvement is assigned to the most severe involvement noted. Patients with visible bloody diarrhea are at least stage 2 gut and grade 3 overall. aGVHD Grades Grade III: Stage 2 - 4 gastrointestinal involvement and/or +2 to +4 liver involvement, with or without a rash Grade IV: Pattern and severity of GVHD similar to grade 3 with extreme constitutional symptoms or death
Time frame: Up to Day 100
Incidence of Transplant-related Mortality
Number of subjects who expired due to transplant-related mortality
Time frame: Up to Day 200
Incidence of Adverse Events
Number of subjects who developed reportable AEs, assessed using adapted version of the Common Toxicity Criteria
Time frame: Up to Day 100
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