Sirolimus (Rapamune ) for Relapse Prevention in People With Severe Aplastic Anemia Responsive to Immunosuppressive Therapy

- Most acquired aplastic anemia ensues from immune-mediated destruction of hematopoietic
stem and progenitor cells

- Immunosuppression is the definitive treatment of patients with acquired aplastic anemia
who are not candidates for immediate hematopoietic stem cell transplantation.

- Horse ATG combined with the calcineurin inhibitor, cyclosporine (CsA), remains standard
as first-line immunosuppressive therapy (IST).

- Hematologic responses to transfusion independence occur in about two thirds of patients
with standard IST and in 80-90% of patients treated with IST in combination with the
growth factor eltrombopag.

- About 30% to 40% of patients relapse after discontinuation of cyclosporine. Many achieve
disease control after the reinitiation of CSA, but remain CSA dependent indefinitely.

- Evidence from mouse models of bone marrow failure indicates that conversion from
cyclosporine to the mTOR inhibitor, sirolimus (SRL), results in immune tolerance which
can endure the eventual withdrawal of SRL.

- We hypothesize that CSA to SRL conversion will significantly decrease the relapse rate
after immunosuppressive therapy for acquired aplastic anemia.

- This study will investigate the safety and efficacy of SRL for preventing relapse in
patients previously treated with IST who remain on CSA. The primary endpoint is rate of
relapse at 2 years following conversion from CSA to SRL, versus stopping CSA.

- Biological sampling of peripheral blood and bone marrow aspirates during treatment will
be used to investigate changes to lymphocyte phenotypes and cytokine profiles.

- INCLUSION CRITERIA:

1. Age greater than or equal to 2 years old

2. Weight greater than 12 kg

3. Previous diagnosis of SAA by bone marrow biopsy and cytogenics, treated with
lymphodepleting therapy ATG, cyclophosphamide or alemtuzumab that included
cyclosporine. The lymphodepleting therapy must have been administered at least 12
months prior.

4. Continuous treatment with cyclosporine for the previous 6 months (excluding minor
dose delays not exceeding more than 30 days).

5. Evidence of a hematologic response to an lymphodepletion-based regimen as
evidence of at least two of the following:

- Absolute neutrophil count greater than or equal to 500/uL

- Platelet count greater than or equal to 20,000/uL (without transfusion support)

- Absolute reticulocyte count greater than or equal to 60,000/uL (or hemoglobin 10 gm/dL
without transfusion support)

EXCLUSION CRITERIA:

1. Evidence of relapse of aplastic anemia due to cyclosporine withdrawal during the
previous 6 months

2. Prior use of sirolimus or other mTOR inhibitor within 12 weeks of study entry

3. Myelodysplastic syndrome or acute myeloid leukemia, according to WHO diagnostic
criteria (if baseline BM consistent with MDS after enrollment, patients will be
considered ineligible and immediately exit the study, and the subject can be replaced
with another subject)

4. Patients that are on CYP3A4 inhibitors and cannot replace these medications with other
equivalent medications for the period of study: protease inhibitors (ritonavir,
indinavir, nelfinavir, saquinavir), some macrolide antibiotics (clarithromycin,
telithromycin, erythromycin), azole anti-fungals (fluconazole, itraconazole,
ketoconazole), metroclopramide, felodipine, nifedipine, carbamazepine, phenobarbital,
grapefruit juice and St. John s Wort.

5. Anaphylactic or hypersensitivity reaction to sirolimus

6. Patients with infections not adequately responding to appropriate therapy as evidenced
by persistence of a clear source of infection that, in the view of the investigator,
would preclude safe treatment with sirolimus.

7. Current pregnancy, or unwillingness to take oral contraceptives or use the barrier
methods of birth control or practice abstinence to refrain from pregnancy if of
childbearing potential during the course of the study 8. Lactating women, due to the
potentially harmful effects on the nursing child.

9. Patients who have received live vaccines within the past 30 days

10. Patients with cancer who are actively receiving chemotherapeutic treatment or who take
drugs with hematological effects such as thrombopoietin receptor agonists (such as
eltrombopag), granulocyte-colony stimulating factor or erythroid stimulating agents.

11. Moribund status such that death within 7 to 10 days is likely. Comorbidities of such
severity that in the view of the Investigator it would likely preclude the patient's
ability to tolerate sirolimus.

12. Inability to understand the investigational nature of the study or to give informed
consent or without a legally authorized representative or surrogate that can provide
informed consent.