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Sirolimus for Autoimmune Disease of Blood Cells

This study is ongoing, but not recruiting participants.
Information provided by (Responsible Party):
Children's Hospital of Philadelphia Identifier:
First received: October 24, 2006
Last updated: March 16, 2017
Last verified: March 2017
Treatment for patients with autoimmune destruction of blood cells is poor. The part of the body that fights infections is called the immune system and white blood cells (WBCs) are part of the immune system. Normally, a person's body creates WBCs to fight infections and eliminates WBCs which have stopped helping the body function. Patients with autoimmune destruction of blood cells have difficulty eliminating old WBCs. The abnormal WBCs build up and can damage other healthy cells, which can lead to anemia, fatigue, jaundice, internal bleeding, infection, and cancer. Few effective medications exist for treatment for patients with autoimmune cytopenias and those commonly used are fraught with side effects. Nevertheless, as scientific understanding of autoimmune diseases has improved, more directed and less toxic therapies are becoming available. A number of groups have been studying the efficacy of a medication called sirolimus in patients with autoimmune diseases. This medicine has been FDA-approved for over 20 years. Sirolimus is a medicine used in children with other diseases. Sirolimus works, in part, by eliminating old and abnormal WBCs. Our group and others have shown that sirolimus is effective in mice with autoimmunity and in children with a rare condition called Autoimmune Lymphoproliferative Syndrome (ALPS). We believe sirolimus will help children with autoimmune cytopenias. We believe it will improve their symptoms and make them less sick. We propose to study sirolimus in children with chronic and/or refractory autoimmune cytopenias.

Condition Intervention Phase
Autoimmune Pancytopenia
Autoimmune Lymphoproliferative Syndrome (ALPS)
Evans Syndrome
Idiopathic Thrombocytopenic Purpura
Anemia, Hemolytic, Autoimmune
Autoimmune Neutropenia
Lupus Erythematosus, Systemic
Inflammatory Bowel Disease
Rheumatoid Arthritis
Drug: sirolimus
Phase 1
Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: No masking
Primary Purpose: Treatment
Official Title: Sirolimus for Patients With Chronic and/or Refractory Autoimmune Cytopenias: A Pilot Series

Resource links provided by NLM:

Further study details as provided by Children's Hospital of Philadelphia:

Primary Outcome Measures:
  • To define the toxicities of administration of oral sirolimus in children with autoimmune cytopenias [ Time Frame: 6 months ]

Secondary Outcome Measures:
  • To evaluate the efficacy of oral sirolimus in children with autoimmune cytopenias [ Time Frame: 6 months ]
  • To characterize the trough levels produced by administration of oral sirolimus in children with autoimmune cytopenias [ Time Frame: 6 months ]
  • To evaluate the effect of sirolimus on intracellular targets [ Time Frame: 6 months ]

Enrollment: 32
Study Start Date: December 2006
Estimated Study Completion Date: February 2020
Primary Completion Date: February 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Sirolimus treatment
Sirolimus treatment
Drug: sirolimus
Tablet or liquid; taken once or twice daily; dosage is based on establishing a serum trough of 5-15 ng/ml by high-performance liquid chromatography (initial loading dose of 3 mg/m2 then 2.5 mg/m2 with adjustment based on serum trough)
Other Names:
  • rapamycin
  • rapamune

Detailed Description:

Patients with autoimmune destruction of hematopoietic cells frequently have severe and debilitating disease requiring aggressive and frequent medical management. These patients are often treated with non-specific immunosuppressive medications with limited efficacy and untoward side-effect profiles. We have been investigating the use of an immunosuppressive and anti-cancer agent, sirolimus in patients with an autoimmune cytopenias syndrome: Autoimmune Lymphoproliferative Syndrome (ALPS). ALPS is a primary immune deficiency caused by mutations in the Fas apoptotic pathway, leading to abnormal lymphocyte survival. Clinical manifestations in patients with ALPS typically include autoimmune cytopenias, lymphadenopathy, hepatosplenomegaly, and a propensity to develop secondary malignancies. Thus, far we have found excellent results albeit the total number of patients treated is small.

Sirolimus is a signal transduction inhibitor with a tolerable side effect profile. Sirolimus has two properties making it an attractive agent to treat patients with autoimmune cytopenias syndromes, including ALPS. First, sirolimus induces apoptosis in normal and abnormal white blood cells, the cell type dysregulated in patients with autoimmune disease. In addition, sirolimus increases a T cell subset called Regulatory T cells (Tregs). Tregs are a cell population designed to suppress the immune system and control autoimmunity. These combined properties make sirolimus unique as compared with other immunosuppressive agents. Ample preclinical and clinical data exists demonstrating sirolimus in effective in patients with autoimmunity. Accordingly, we hypothesize sirolimus is a safe and efficacious medication for patients with autoimmune destruction of blood cells..

We plan to confirm our hypotheses by performing a pilot series in children with autoimmune cytopenias who are either refractory to standard therapy or have significant toxicity from standard treatments. Our primary aim is to define the toxicities of administration of oral sirolimus in children with autoimmune cytopenias. Our secondary aims are to evaluate the efficacy of sirolimus in children with autoimmune cytopenias, to determine the trough levels of sirolimus when used in these patients, and to evaluate the effects of sirolimus on intracellular targets of mammalian target of rapamycin (mTOR). We intend to enroll 50 children with autoimmune cytopenias and treat for a 6 month period, however, if we find sirolimus is effective, we anticipate these children will continue to take sirolimus for a longer period of time. We anticipate the results of this work will establish sirolimus is an effective and well tolerated medication and will lead directly to a larger national phase II clinical trial.


Ages Eligible for Study:   1 Year to 30 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Age > 12 months and < 30 years at the time of study entry
  • Diagnosis of autoimmune cytopenias requiring treatment with medications
  • At least one of the following: Autoimmune Neutropenia, Autoimmune Hemolytic Anemia, and/or Autoimmune Thrombocytopenia
  • Must be proven autoimmune by either a documented autoantibody (positive direct anti globulin test, positive anti-neutrophil, and/or anti-platelet antibody) and/or a documented clinical response to immunosuppression
  • Autoimmune Cytopenias can be idiopathic (Idiopathic Thrombocytopenic Purpura (ITP), Autoimmune Hemolytic Anemia (AIHA), Autoimmune Neutropenia (AIN), or Evans syndrome) or secondary to one of following conditions: Lupus, Rheumatoid Arthritis (RA), ALPS (Autoimmune Lymphoproliferative Syndrome), or Inflammatory bowel disease (IBD)
  • Patients must have chronic disease diagnosed by either a documented cytopenia syndrome (Lupus, ALPS, RA, or IBD), or by having Evans syndrome defined as idiopathic destruction of multiple blood cell types, and/or by having disease >6 months
  • Patients must be refractory to or unable to tolerate standard front-line therapies for autoimmune cytopenias (corticosteroids and/or IVIG)
  • Patients may be taking second-line agents for autoimmune cytopenias (mycophenolate mofetil, cyclosporine, tacrolimus, mercaptopurine, and/or methotrexate) at time of study entry; however, attempts should be made to wean these agents. Patients may not stay on a combination of sirolimus and a calcineurin inhibitor for greater than 4 weeks
  • Informed consent/assent MUST be obtained prior to initiating treatment
  • Patient must be able to consume oral medication in the form of tablets or solution

Exclusion Criteria:

  • Pregnancy or breast feeding
  • Uncontrolled infection
  • Known allergy to Sirolimus or its components
  • Patients with a documented malignancy on therapy or not in remission
  • Patients who do not meet organ function requirements listed in protocol
  • Patients with a documented history of severe combined immunodeficiency or human immunodeficiency virus infection (HIV)
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Please refer to this study by its identifier: NCT00392951

United States, Pennsylvania
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States, 19104
Sponsors and Collaborators
Children's Hospital of Philadelphia
Principal Investigator: David T. Teachey, MD Children's Hospital of Philadelphia
  More Information

Publications automatically indexed to this study by Identifier (NCT Number):
Responsible Party: Children's Hospital of Philadelphia Identifier: NCT00392951     History of Changes
Other Study ID Numbers: 2006-7-4873
Study First Received: October 24, 2006
Last Updated: March 16, 2017

Keywords provided by Children's Hospital of Philadelphia:
Lymph Nodes
Hemolytic Anemia
Immune Thrombocytopenia

Additional relevant MeSH terms:
Autoimmune Lymphoproliferative Syndrome
Arthritis, Rheumatoid
Inflammatory Bowel Diseases
Purpura, Thrombocytopenic
Lupus Erythematosus, Systemic
Purpura, Thrombocytopenic, Idiopathic
Anemia, Hemolytic
Anemia, Hemolytic, Autoimmune
Pathologic Processes
Joint Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Connective Tissue Diseases
Autoimmune Diseases
Immune System Diseases
Gastrointestinal Diseases
Digestive System Diseases
Intestinal Diseases
Leukocyte Disorders
Hematologic Diseases processed this record on April 25, 2017