• To find out the best dose of cyclophosphamide that can be given with fludarabine, antithymocyte globulin (ATG), and low-dose total body irradiation (TBI) to patients before a bone marrow transplant. [ Time Frame: 3 Years ] [ Designated as safety issue: No ]
  

Inclusion Criteria:

• Patients up to 65 years of age at time of registration with a diagnosis of severe aplastic anemia (SAA). SAA is defined as follows: - Bone marrow cellularity < 25%, or marrow cellularity < 50% but with < 30% residual hematopoietic cells. Two out of three of the following (in peripheral blood): neutrophils < 0.5 x 10^9/L; platelets < 20 x 10^9/L; reticulocytes < 20 x 10^9/L. SAA diagnostic criteria may be applied to assessment at initial diagnosis or to the follow-up assessments.
• Patient must have an available unrelated donor with a 7/8 or 8/8 match for HLA-A, B, C and DRB1 antigen. Typing is by DNA techniques: intermediate resolution for A, B and C, and high resolution for DRB1. HLA-DQ typing is recommended but will not count in the match
• Patient and/or legal guardian able to provide signed informed consent.
• Matched unrelated donor must consent to provide marrow allograft.
• Patients with adequate organ function as measured by: a) cardiac: left ventricular ejection fraction at rest must be > 40% or shortening fraction > 20% b) hepatic: serum total bilirubin < 2x upper limit of normal for age as per local laboratory; ALT and AST < 4x upper limit of normal for age as per local laboratory; c) renal: serum creatinine < 2x upper limit of normal for age (as per local laboratory). d) pulmonary FEV1, FVC and DLCO (corrected for Hb) > 50% predicted. For pts where pulse oxymetry is performed, O2 saturation > 92%
• The diagnosis of Fanconi anemia must be excluded in patients younger than 18 years of age by diepoxybutane (DEB) testing on peripheral blood or comparable testing or marrow.

Exclusion Criteria:

• Clonal cytogenetic abnormalities associated with MDS or AML on marrow examination.
• Diagnosis of other "congenital" aplastic anemias such as: Diamond-Blackfan; Shwachman-Diamond; congenital amegakaryocytosis.
• Symptomatic or uncontrolled cardiac failure or coronary artery disease.
• Karnofsky performance status < 60% or Lansky < 40% for patients < 16 years of old.
• Uncontrolled bacterial, viral or fungal infections (currently taking medication and progression of clinical symptoms). Patients with fevers despite broad-spectrum antimicrobials but no clinical or hemodynamic evidence of sepsis will be allowed.
• Seropositive for the human immunodeficiency virus (HIV).
• Pregnancy (positive ß-HCG) or breastfeeding.
• Presence of large accumulation of ascites or pleural effusions, which would be a contraindication to the administration of methotrexate for GVHD prophylaxis.
• Known severe or life-threatening allergy or intolerance to ATG or cyclosporine/tacrolimus.
• Planned administration of alemtuzumab (Campath-1H) or other investigational agents as alternative agent for GVHD prophylaxis.
• Concomitant enrollment in a Phase I study.
• Positive patient anti-donor lymphocyte crossmatch in HLA-A or B mismatched transplants (test recommended but not mandatory). The definition of match is in Section 2.2.1.
• Prior allogeneic marrow or stem cell transplantation.
• Patients with prior malignancies except resected basal cell carcinoma or treated carcinoma in-situ. Cancer treated with curative intent < 5 years previously will not be allowed unless approved by the Medical Monitor or Protocol Chair. Cancer treated with curative intent > 5 years previously will be allowed.