Fludarabine-based Conditioning for Allogenetic Marrow Transplantation From HLA-Compatible Unrelated Donors in Severe Aplastic Anemia
The study is a prospective Phase I/II dose optimization study. All patients are given a fixed dose of ATG (either Thymoglobulin: 3 mg/kg IV daily x 3 or ATGAM 30 mg/kg IV daily x 3, on Days x4 to x2), Fludarabine (30 mg/m2 IV daily x 4, on Days x 5 to x2), and TBI (200 cGy from a linear accelerator at <= 20 cGy/min on Day x1). The starting CY dose will be 150 mg/kg (50 mg/kg intravenously daily, Days x4 to x2), and will be de-escalated depending on engraftment and toxicity. GVHD prophylaxis will consist of cyclosporine (CSA) 3 mg/kg/day by continuous infusion beginning at least 12 hours prior to marrow infusion (to be switched to oral administration as soon as clinically feasible). Patients will also receive Methotrexate (MTX) at the dose of 10 mg/m2 IV on Day 1 3, 6 and 11. The Phase I portion of the trial (maximum of 24-27 patients) tests each of four dose levels of CY for adequate safety and graft retention. The Phase II portion of the trial refines the dose selection and allocates an additional 54 patients to the optimal dose, at which two-year post-transplant survival will be assessed. The combined enrollment in Phase I and II will total 78- 81 patients. All of the weekly assessments and lab tests are part of standard of care for patients undergoing transplant. The only item that is not standard of care is the treatment dose of Cyclophosphamide (CTX). The infusion of the CTX will take approximately one hour on days -4 to -2. The infusions of CTX take no longer than when CTX is given as standard of care. Patient visits to clinic take approximately one hour per visit and are not lengthened by participation in the study. All labs and physical exams performed are part of standard of care for transplant patients. No additional labs or clinic time are required. Criteria for discontinuing subjects from the study are if the patient[Right Quote]s medical problem remains unchanged or becomes worse, the patient does not qualify to be in the study because the patient does not meet the study requirements, the patient needs a medical treatment not allowed in this study, the study treatments have a bad effect on the patient, the patient becomes pregnant and the study treatment could be harmful to the fetus, study doctor believes that participation in the research is no longer safe, the study doctor believes that other treatment may be more helpful, the sponsor or the FDA stops the research for the safety of the participants, the sponsor cancels the research, and the patient is unable to keep appointments and to follow the study doctor[Right Quote]s instructions.
Patients up to 65 years of age with a diagnosis of SAA and an available unrelated donor with a 7/8 or 8/8 for HLA-A, B, C (intermediate resolution) and DRB1 (high resolution). In addition, HLA-DQ typing is recommended but will not count in the match.. HLA-C typing is also required. If an HLA-C mismatch is present, no other mismatches are allowed. Patients with adequate organ function within 6 weeks of initiation of conditioning as measured by: Cardiac: left ventricular ejection fraction at rest must be > 40% or shortening fraction >20%. Hepatic: serum total bilirubin <2x, ALT and AST < 4x upper limit of normal (as per local laboratory) for age (with the exception of isolated hyperbilirubinemia due to Gilbert[Single Quote]s syndrome). Renal: serum creatinine < 2x upper limit of normal for age (as per local laboratory). For patients with serum creatinine above the normal range, a glomerular filtration rate (measured as per institutional practice, typically creatinine clearance) equal to or greater than 60 mL/min (corrected to 1.73m2 body surfact area) is required. For pediatric patients, other comparable methods for renal function estimation in keeping with local institutional practice are permitted. Pulmonary: FEV l, FVC and DLCO (corrected for Hgb) > 50% predicted. For patients where pulse oximetry is preformed, O2 saturation must be > 92%. The diagnosis of Fanconi anemia based on diepoxybutane (DEB) testing on peripheral blood or comparable testing on marrow must be excluded in patients less than 18 years old. Spanish speaking subjects will be eligible to participate in the study.