Intervention: Fludarabine
Trial phase: Phase 1 | Phase 2
ATC code: L01BB05
SMILES: Nc1nc(F)nc2c1ncn2C1OC(CO)C(O)C1O
Sex: All
Age groups: Child | Adult | Older Adult
Healthy volunteers: No
Participants at risk: 3
Group description: Fludarabine only (no Cyclophosphamide administered)
Eligibility criteria:
Inclusion Criteria:

Patients up to 65 years of age at time of registration with a diagnosis of SAA; SAA is defined as follows:

Bone marrow cellularity less than 25% or marrow cellularity less than 50% but with less than 30% residual hematopoietic cells
Two out of three of the following (in peripheral blood): neutrophils less than 0.5 x 10^9/L; platelets less than 20 x 10^9/L; reticulocytes less than 20 x 10^9/L
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 a marrow allograft

Patients with adequate organ function as measured by:

Cardiac: left ventricular ejection fraction at rest must be greater than 40% or shortening fraction greater than 20%
Hepatic: serum bilirubin less than 2x upper limit of normal for age as per local laboratory) (with the exception of isolated hyperbilirubinemia due to Gilbert's syndrome), alanine transaminase (ALT) and aspartate transaminase (AST) less than 4x upper limit of normal for age (as per local laboratory)
Renal: serum creatinine less than 2x upper limit of normal for age (as per local laboratory)
Pulmonary: Forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and carbon monoxide diffusing capacity (DLCO) (corrected for Hb) greater than 50% predicted; for patients in which pulse oxymetry is performed, O2 saturation greater than 92%
Diagnosis of Fanconi anemia must be excluded in patients younger than 18 years of age by diepoxybutane testing on peripheral blood or comparable testing on marrow.

Exclusion Criteria:

Clonal cytogenetic abnormalities associated with myelodysplastic syndrome (MDS) or acute myeloid leukemia (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 less than 60% or Lansky less than 40% for patients younger than 16 years old
Uncontrolled bacterial, viral or fungal infections (currently taking medication and progression of clinical symptoms)
Seropositive for the human immunodeficiency virus (HIV)
Pregnant (positive total 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; the definition of match is in Section 2.2.1; the crossmatch would only apply to mismatches at HLA-A or B, not DRB1 or HLA-C
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 less than 5 years previously will not be allowed unless approved by the Medical Monitor or Protocol Chair; cancer treated with curative intent more than 5 years previously will be allowed