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

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Brief Title

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

Official Title

A Randomized Trial of Sirolimus (Rapamune(R)) for Relapse Prevention in Patients With Severe Aplastic Anemia Responsive to Immunosuppressive Therapy

Brief Summary


      People with severe aplastic anemia (SAA) do not make enough red and white blood cells, and/or
      platelets. Their body's immune system stops the bone marrow from making these cells. The
      treatment cyclosporine leads to better blood counts. But when this treatment is stopped, the
      disease may return in 1 in 3 people. The drug sirolimus may help by suppressing the immune


      To evaluate and compare the usefulness of sirolimus in preventing aplastic anemia from
      returning after cyclosporine is stopped, compared with stopping cyclosporine alone.


      People ages 2 and older with SAA who:

      Have responded to immunosuppressive therapy that includes cyclosporine, and continue to take

      Are not taking drugs with hematologic effects


      Participants will be screened with:

      Medical history

      Physical exam

      Blood and urine tests

      Bone marrow biopsy: The area above the hipbone will be numbed. A thin needle will remove

      some bone marrow.

      Participants will be randomly assigned to a group. All will stop cyclosporine. Group 1 will
      take sirolimus by mouth at the same time each day for 3 months with close monitoring. Group 2
      will not receive the study drug but will be monitored closely.

      Participants will have clinical tests for the first 3 months:

      Weekly blood test

      Monthly fasting blood test

      For group 1, measurements of sirolimus in the blood every 1 2 weeks

      Participants will have clinic visits at 3 months, 12 months, and annually for 5 years after
      the study starts. They may have another visit if their SAA returns. These will include:

      Blood and urine tests

      Bone marrow biopsy

Detailed Description

      -  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.

Study Phase

Phase 2

Study Type


Primary Outcome

To determine if the rate of relapse at 24 months after CSA discontinuation can be improved by conversion to sirolimus in severe aplastic anemia patients who have responded to IST.

Secondary Outcome

 Safety and tolerability of sirolimus.


Severe Aplastic Anemia



Study Arms / Comparison Groups

Description:  sirolimus


* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information

Recruitment Status


Estimated Enrollment


Start Date

December 19, 2016

Completion Date

August 31, 2023

Primary Completion Date

August 31, 2023

Eligibility 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 cytogenetics, 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)


          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.




2 Years - N/A

Accepts Healthy Volunteers



Bhavisha A Patel, M.D., (301) 827-2988, [email protected]

Location Countries

United States

Location Countries

United States

Administrative Informations



Organization ID


Secondary IDs


Responsible Party


Study Sponsor

National Heart, Lung, and Blood Institute (NHLBI)

Study Sponsor

Bhavisha A Patel, M.D., Principal Investigator, National Heart, Lung, and Blood Institute (NHLBI)

Verification Date

September 9, 2022