Fludarabine-Based Conditioning for Allogeneic Marrow Transplantation in Aplastic Anemia

Inclusion Criteria:

1. 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.
2. 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
3. Patient and/or legal guardian able to provide signed informed consent.
4. Matched unrelated donor must consent to provide marrow allograft.
5. 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%
6. 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:

1. Clonal cytogenetic abnormalities associated with MDS or AML on marrow examination.
2. Diagnosis of other "congenital" aplastic anemias such as: Diamond-Blackfan; Shwachman-Diamond; congenital megakaryocytosis.
3. Symptomatic or uncontrolled cardiac failure or coronary artery disease.
4. Karnofsky performance status < 60% or Lansky < 40% for patients < 16 years of old.
5. 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.
6. Seropositive for the human immunodeficiency virus (HIV).
7. Pregnancy (positive ß-HCG) or breastfeeding.
8. Presence of large accumulation of ascites or pleural effusions, which would be a contraindication to the administration of methotrexate for GVHD prophylaxis.
9. Known severe or life-threatening allergy or intolerance to ATG or cyclosporine/tacrolimus.
10. Planned administration of alemtuzumab (Campath-1H) or other investigational agents as alternative agent for GVHD prophylaxis.
11. Concomitant enrollment in a Phase I study.
12. 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.
13. Prior allogeneic marrow or stem cell transplantation.
14. 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.