Unrelated Donor Transplant Versus Immune Therapy in Pediatric Severe Aplastic Anemia

A major challenge in treating pediatric Severe Aplastic Anemia (SAA) is the determination of
best primary therapy for patients who lack a fully matched related donor for HSCT. Good
survival outcomes have been seen with IST, but initial and late failures, CSA dependence,
persistent cytopenias and secondary Myelodysplastic Syndrome (MDS) / Acute Myeloid Leukemia
(AML) in a portion of patients leave considerable room for improvement. MUD HSCT survival in
SAA has markedly improved, but a direct comparison of this approach with IST is necessary to
determine whether this approach is feasible and will lead to better Event Free Survival. This
trial will address the feasibility of randomization, test whether patients can be evaluated
in a timely fashion and safely begin therapy with MUD HSCT or IST, and give a preliminary
assessment of the safety of up-front MUD HSCT. If successful, this trial will lead to a
future prospective trial comparing directly IST to MUD HSCT in this disease.

Inclusion Criteria:

1. Confirmed diagnosis of idiopathic SAA, defined as:

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

- Two out of three of the following (in peripheral blood): neutrophils <0.5 x109/L,
platelets <20 x109/L, reticulocyte count <60 x109/L with hemoglobin <8g/dL.

2. Age ≤25 years old.

3. No suitable fully matched related donor available (minimum 6/6 match for Human
Leukocyte antigen (HLA) -A and B at intermediate or high resolution and DRB1 at high
resolution using DNA based typing).

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

5. Signed informed consent for the randomized trial by patient and/or legal guardian.

6. Adequate organ function defined as in the judgment of the investigator, there is not
irreversible organ damage that would preclude the patient from meeting the organ
function inclusion criteria for HSCT listed in section 2.3.4 by the intended time of
HSCT (6-8 weeks after randomization) or preclude patients from receiving horse ATG.

Exclusion Criteria:

1. Inherited bone marrow failure syndromes (IBMFS). The diagnosis of Fanconi anemia must
be excluded by diepoxybutane (DEB) or equivalent testing on peripheral blood or
marrow. Telomere length testing should be sent on all patients to exclude Dyskeratosis
congenita, but if results are delayed or unavailable and there are no clinical
manifestations of DC, patients may enroll. If patients have clinical characteristics
suspicious for Shwachman Diamond syndrome, this syndrome must be excluded by
pancreatic isoamylase testing or gene mutation analysis. Note: pancreatic isoamylase
testing is not accurate in children less than 3 years.

2. Clonal cytogenetic abnormalities or fluorescence In Situ Hybridization (FISH) pattern
consistent with pre-myelodysplastic syndrome (pre-MDS) or MDS on marrow examination
(see section 4.2.3.1 for details of the required MDS FISH panel).

3. Known severe allergy to horse ATG.

4. Prior allogeneic stem cell transplant.

5. Prior solid organ transplant.

6. Infection with human immunodeficiency virus (HIV).

7. Active Hepatitis B or C. This should be excluded in patients where there is clinical
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 cervical carcinoma
in situ.