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Study Description

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 have 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 dose 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.

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Study Inclusion/Exclusion Criteria


  • Acquired moderate or severe aplastic anemia with bone marrow cellularity <25%, failure to respond durably to at least one course of ATG, and any of the following at the time of the original diagnosis:

  •   º Severe AA fulfills any two of the following criteria: absolute neutrophil count <500/µL, absolute reticulocyte count <60,000/µL,and platelet count <20,000/µL

      º Moderate AA fulfills any two of the following criteria: absolute neutrophil count <1200/µL, hemoglobin <8 g/dL with corrected reticulocyte count <1%, and platelet count <60,000/µL

      º Patients who have progressed from moderate to severe AA prior to enrollment in the study will be classified as severe AA.
  • Refractory AA is defined as persistent disease that fulfills the criteria for moderate or severe AA at least 6 months after ATG treatment. Patients cannot have achieved a partial response within the previous 3 months. Patients with relapsed disease who are not candidates for salvage ATG because they do not meet the criteria for severe disease, or they previously experienced a serious or life-threatening complication of the most recent prior ATG, are also eligible.
  • Karnofsky performance status of >=60%
  • Adequate organ function defined by creatinine <1.5x the ULN, and liver function tests (AST, bilirubin) <2x the ULN
  • Patients must be aged >=21 years and be able to give informed consent


  • Patient has received ATG treatment less than 6 months ago
  • Patient is a candidate for related allogeneic stem cell transplantation
  • Patients taking cyclosporine prior to enrollment are not excluded
  • 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 enrollment
  • HIV infection
  • Pregnancy or breast feeding. Women of childbearing age must use adequate birth control measures

Study History

Background for the Study

Aplastic anemia

Acquired aplastic anemia (AA) is an uncommon disorder characterized by peripheral blood pancytopenia and bone marrow hypoplasia. Although the onset of occasional cases can be temporally associated with the intake of certain medications, antecedent hepatitis, or exposure to benzene, the etiology of most cases is unknown.(1) Several lines of evidence support the hypothesis that AA is due to autoimmune suppression and destruction of hematopoietic stem cells. First, there appears to be an inherited predisposition to AA based on the human leukocyte antigen (HLA) haplotype, a characteristic shared by other autoimmune disorders. An increased frequency of the HLA DR2 antigen has been observed in AA patients.(2-4) A wide variety of other autoimmune disorders including systemic lupus erythematosus, pernicious anemia, immune thrombocytopenic purpura, Goodpasture syndrome, multiple sclerosis and ulcerative colitis have been associated with an increased frequency of the HLA DR2 antigen.(2) Second, AA patients have activated circulating T lymphocytes which are capable of suppressing the growth of normal bone marrow cells.(5,6) These cells may mediate their suppressive effects by local elaboration of interferon-γ in the bone marrow.(6-8) Finally, many AA patients respond to treatment with immunosuppressive agents such as antithymocyte globulin (ATG) and cyclosporine.(9-11)

Allogeneic bone marrow transplantation is curative in a high percentage of severe AA patients who are eligible to undergo this procedure. However, only a minority of patients with severe AA has an HLA compatible sibling donor and is young enough to have a transplant. The remaining AA patients are usually treated with ATG and cyclosporine. Responses are observed in approximately 65% of patients, but relapses eventually occur in 36-38% of responders.(12-13) Patients who fail to respond to initial immunosuppressive therapy have a poor long-term outcome with fewer than 20% surviving for five years.(14) Hematopoietic growth factors including granulocyte-macrophage colony-stimulating factor, granulocyte colony-stimulating factor, interleukin-3, and interleukin-6 have been used in clinical trials for the treatment of AA.(15-23) Although several growth factors are capable of improving neutrophil counts in AA patients, this effect is not sustained when treatment is discontinued. In addition, growth factors cannot routinely induce tri-lineage hematopoietic recovery in AA. Therefore, new therapies are needed for AA patients who fail to respond to immunosuppressive therapy.


Sirolimus (Rapamune®) is a macrolide originally isolated from Streptomyces hygroscopicus. It is a potent immunosuppressive medication like cyclosporine and FK-506 that interfere with signaling systems in T lymphocytes.(24,25) These agents bind to a ubiquitous family of proteins known as immunophilins and inhibit their enzymatic activity. The immunophilins are subdivided into cyclophilins and FK-506 binding proteins (FKBP). Sirolimus binds to FKBP-12 to form a complex that interacts with a kinase called mammalian target of rapamycin (mTOR), blocking its activity. This, in turn, results in inhibition of downstream proteins, including p70 S6 kinase and the eukaryotic initiation factor (elF)-4E-binding protein, PHAS-I (phosphorylated heat and acid-stable protein). (26,27) Inhibition of these key signaling pathways results in inefficient translation of mRNAs important for cell-cycle progression through G1 phase.(28-30)

Two randomized trials have demonstrated that the addition of sirolimus to cyclosporine and glucocorticoids significantly reduced the rate of graft rejection in renal transplant patients.(31,32) There was no difference between the effectiveness of the 2 mg and 5 mg sirolimus daily doses. Sirolimus administration was associated with more frequent elevations in serum cholesterol and triglycerides, and decreased creatinine clearance compared to cyclosporine alone in these studies.

The rationale for the use of sirolimus in AA is based on the well-established effectiveness of immunosuppressive therapy for the treatment of this disorder. In addition, combined immunosuppressive therapy is more effective than treatment with a single agent.(13) Because sirolimus and cyclosporine have complimentary immunosuppressive activities and no overlapping toxicities, this drug combination may also be useful in AA patients who have failed to respond durably to ATG. The safety of sirolimus and cyclosporine in AA patients, and preliminary response data using this combination will be obtained in this study.

  • Study Activated May 15, 2006
  • First Accrual July 20, 2006
  • Study Closed on July 17, 2009

Selected Publications
Diseases/Traits Related to Study (MeSH terms)
Authorized Data Access Requests
Study Attribution
  • Principal Investigator
    • Ronald Paquette, MD. University of California, Los Angeles, Division of Hematology/Oncology, Los Angeles, CA, USA.
  • Funding Source
    • U54 RR19397-01. National Institutes of Health, Bethesda, MD, USA.