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

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

Background:

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 system.

Objective:

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

Eligibility:

People ages 2 and older with SAA who:

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

Are not taking drugs with hematologic effects

Design:

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

Study Overview

• Status: Active, not recruiting
• Conditions: Severe Aplastic Anemia
• Intervention / Treatment: Drug: Sirolimus

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 Type: Interventional
• Enrollment (Actual): 84
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

• 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 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)

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sirolimus; sirolimus	Drug: Sirolimus; Sirolimus will be started on day 1 for subjects in the Sirolimus arm. A baseline CBC will be obtained within one week of randomization, or on Day 0. Thereafter, CBC will be monitored on a weekly basis for subjects in both arms. In the event of relapse (see definition of outcomes Section 6.7), the patient shall return to the NIH CRC for evaluation to include bone marrow biopsy and aspirate to exclude clonal evolution to MDS. Assessment will include (i) flow cytometry phenotyping of peripheral blood mononuclear cells for regulatory T-cells (Tregs, e.g. CD4+ CD25high FOXP3+) and regulatory dendritic cells (DCregs) and (ii) proteomics assay (research labs).
No Intervention: Standard of Care; no intervention

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Rate of relapse in both arms	24 months

Secondary Outcome Measures

Outcome Measure	Time Frame
Safety and tolerability of sirolimus.	3 mo

Collaborators and Investigators

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

Publications and helpful links

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): December 19, 2016
• Primary Completion (Actual): September 4, 2025
• Study Completion (Estimated): June 30, 2030

Study Registration Dates

• First Submitted: December 1, 2016
• First Submitted That Met QC Criteria: December 1, 2016
• First Posted (Estimated): December 2, 2016

Study Record Updates

• Last Update Posted (Estimated): January 16, 2026
• Last Update Submitted That Met QC Criteria: January 15, 2026
• Last Verified: January 6, 2026

More Information

Terms related to this study

• Keywords: Rapamycin; Immune Tolerance; Relapse Prevention
• Additional Relevant MeSH Terms: Bone Marrow Failure Disorders; Hematologic Diseases; Bone Marrow Diseases; Anemia; Hemic and Lymphatic Diseases; Anemia, Aplastic; Organic Chemicals; Macrolides; Lactones; Sirolimus
• Other Study ID Numbers: 170019; 17-H-0019

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: This is a new requirement and the sharing of IPD is not discussed in the protocol.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No