A Trial Comparing Unrelated Donor BMT with IST for Pediatric and Young Adult Patients with Severe Aplastic Anemia (TransIT, BMT CTN 2202)

Inclusion Criteria:

To be eligible to participate in the randomized trial, an individual must meet all the following criteria:

1. Provision of signed and dated informed consent form for the randomized trial bypatient and/or legal guardian.

2. Age ≤25 years old at time of randomized trial consent.

3. Confirmed diagnosis of idiopathic SAA, defined as:

4. Bone marrow cellularity <25%, or <30% hematopoietic cells.

5. Two of three of the following (in peripheral blood): neutrophils <0.5 x 10^9/L,platelets <20 x 10^9/L, absolute reticulocyte count <60 x 10^9/L or hemoglobin <8 g/dL.

6. No suitable fully matched related donor available (minimum 6/6 match for HLA-A and Bat intermediate or high resolution and DRB1 at high resolution using DNA basedtyping).

7. At least 2 unrelated donors noted on NMDP search who are well matched (9/10 or 10/10for HLA-A, B, C, DRB1, and DQB1 using high resolution).

8. In the treating physician's opinion, no obvious contraindications precluding themfrom BMT or IST.

Exclusion Criteria:

1. Presence of Inherited bone marrow failure syndromes (IBMFS). The diagnosis ofFanconi anemia must be excluded by diepoxybutane (DEB) or equivalent testing onperipheral blood or marrow. Telomere length testing should be sent on all patientsto exclude Dyskeratosis Congenita (DC), but if results are delayed or unavailableand there are no clinical manifestations of DC, patients may enroll. If patientshave clinical characteristics suspicious for Shwachman-Diamond syndrome, thisdisorder should be excluded by pancreatic isoamylase testing or gene mutationanalysis (note: pancreatic isoamylase testing is not useful in children <3). Othertesting per center may be performed to exclude IBMFS.

2. Clonal cytogenetic abnormalities or Fluorescence In-Situ Hybridization (FISH)pattern consistent with pre- myelodysplastic syndrome (pre-MDS) or MDS on marrowexamination.

3. Known severe allergy to ATG.

4. Prior allogeneic or autologous stem cell transplant.

5. Prior solid organ transplant.

6. Infection with human immunodeficiency virus (HIV).

7. Active Hepatitis B or C. This only needs to be excluded in patients where there isclinical suspicion of hepatitis (e.g., elevated LFTs).

8. Female patients who are pregnant or breast-feeding.

9. Prior malignancies except resected basal cell carcinoma or treated cervicalcarcinoma in situ.

10. Disease modifying treatment prior to study enrollment, including but not limited touse of androgens, eltrombopag, romiplostim, or immune suppression. Note: Supportivecare measures such as G-CSF, blood transfusion support and antibiotics are allowable