Sirolimus and Cyclosporine for Treatment-Resistant Aplastic Anemia

The most successful treatment for aplastic anemia is bone marrow transplantation. However,
few patients are eligible for this procedure. For others, treatment usually consists of
immunosuppressive agents, such as antithymocyte globulin (ATG) and cyclosporine.
Unfortunately, even with immunosuppressive therapy, relapse is common. New combinations of
medications may offer alternative and more effective treatment options. Sirolimus and
cyclosporine are two drugs routinely used to suppress the immune system and prevent
rejection in patients who have received organ transplants. While cyclosporine has been
proven effective for treating aplastic anemia, sirolimus has not been tested for this
disease. This study will evaluate the safety and efficacy of sirolimus in combination with
cyclosporine for treating individuals with aplastic anemia that has not responded to other
treatments.

This study will last at least 6 months. Participants will first be screened to verify
diagnosis of aplastic anemia. The screening will include a physical examination, blood test,
bone marrow biopsy from the pelvic bone, and review of medications and medical history.
Individuals who are eligible will then start the first treatment period. Participants will
receive two medications: cyclosporine will be taken twice a day and sirolimus will be taken
once a day. Depending on side effects, the doses of either drug may be temporarily stopped
or lowered. On Day 1, blood will be drawn and females will undergo a pregnancy test.
Subsequent study visits will occur weekly for the first month, every 2 weeks for 2 months,
and then once a month for the remainder of the study. Each visit will include a physical
examination, vital sign assessment, and review of side effects and medications. Blood tests
will be performed weekly for the first 3 weeks, and then every 2 weeks.

After 6 months of treatment, if a participant has shown improvements in disease status
without major side effects, the treatment will continue. Over time the doses may be lowered.
If a participant has not improved while on the study medication, treatment will stop at 6
months. Whenever treatment is discontinued, the participant will again undergo a physical
examination, blood tests, and bone marrow biopsy.

Inclusion Criteria:

- Diagnosis of moderate or severe aplastic anemia with bone marrow cellularity of less
than 25%

- Falls within one of the following descriptions at the time of the original diagnosis:

1. For severe aplastic anemia, fulfills any two of the following three criteria:
absolute neutrophil count less than 500/uL; absolute reticulocyte count less
than 60,000/uL; and platelet count less than 20,000/uL

2. For moderate aplastic anemia, fulfills any two of the following three criteria:
absolute neutrophil count less than 1200/ul; hemoglobin less than 8 g/dL with
corrected reticulocyte count less than 1%; and platelet count less than
60,000/uL (Note: Participants who have progressed from moderate to severe
aplastic anemia prior to study entry will be classified as having severe
aplastic anemia)

- Diagnosis of refractory aplastic anemia, as defined by a failure to achieve at least
a partial response to ATG within 6 months of treatment. Individuals who had a prior
response to ATG but who have relapsed and not responded to salvage ATG are eligible.
Individuals with relapsed disease who are not candidates for salvage ATG because they
experienced a serious or life-threatening complication prior to ATG are also
eligible.

- A Karnofsky performance status of at least 60%

- Adequate organ function, as defined by creatine levels less than 1.5 times the upper
limit normal (ULN), and liver function tests (AST, bilirubin) less than 2 times the
ULN

- Women of childbearing age must be willing to use effective contraception throughout
the study

Exclusion Criteria:

- Received ATG treatment less than 6 months prior to study entry

- Candidate for related allogeneic stem cell transplantation

- Active uncontrolled infection

- History of myelodysplastic syndrome or bone marrow cytogenetic abnormalities

- History of Fanconi's anemia or other congenital form of aplastic anemia

- Treatment with an investigational agent within 1 month of study entry

- HIV infection

- Pregnant or breastfeeding