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Sirolimus for Patients With Chronic and/or Refractory Autoimmune Cytopenias: A Pilot Series

Phase 1/Phase 2
1 Year
30 Years
Open (Enrolling)
Autoimmune Pancytopenia, Autoimmune Lymphoproliferative Syndrome (ALPS), Evans Syndrome, Idiopathic Thrombocytopenic Purpura, Anemia, Hemolytic, Autoimmune, Autoimmune Neutropenia, Lupus Erythematosus, Systemic, Inflammatory Bowel Disease, Rheumatoid Arthritis

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Trial Information

Sirolimus for Patients With Chronic and/or Refractory Autoimmune Cytopenias: A Pilot Series

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

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.

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

- 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)

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

To define the toxicities of administration of oral sirolimus in children with autoimmune cytopenias

Outcome Time Frame:

6 months

Safety Issue:


Principal Investigator

David T. Teachey, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Children's Hospital of Philadelphia


United States: Institutional Review Board

Study ID:




Start Date:

December 2006

Completion Date:

December 2014

Related Keywords:

  • Autoimmune Pancytopenia
  • Autoimmune Lymphoproliferative Syndrome (ALPS)
  • Evans Syndrome
  • Idiopathic Thrombocytopenic Purpura
  • Anemia, Hemolytic, Autoimmune
  • Autoimmune Neutropenia
  • Lupus Erythematosus, Systemic
  • Inflammatory Bowel Disease
  • Rheumatoid Arthritis
  • ALPS
  • Autoimmune
  • Cytopenias
  • Treatment
  • Sirolimus
  • Rapamycin
  • Lymph Nodes
  • Spleen
  • Hemolytic Anemia
  • Immune Thrombocytopenia
  • Neutropenia
  • ITP
  • Lupus
  • Anemia
  • Anemia, Hemolytic
  • Anemia, Hemolytic, Autoimmune
  • Arthritis
  • Arthritis, Rheumatoid
  • Autoimmune Diseases
  • Inflammatory Bowel Diseases
  • Intestinal Diseases
  • Lupus Erythematosus, Systemic
  • Neutropenia
  • Pancytopenia
  • Purpura
  • Purpura, Thrombocytopenic
  • Purpura, Thrombocytopenic, Idiopathic
  • Thrombocytopenia
  • Hemolysis
  • Autoimmune Lymphoproliferative Syndrome



Children's Hospital of Philadelphia Philadelphia, Pennsylvania  19104