Sirolimus for Autoimmune Disease of Blood Cells
Condition: Autoimmune Pancytopenia; Autoimmune Lymphoproliferative Syndrome (ALPS); Evans Syndrome; Idiopathic Thrombocytopenic Purpura; Anemia, Hemolytic, Autoimmune; Autoimmune Neutropenia; Lupus Erythematosus, Systemic; Inflammatory Bowel Disease; Rheumatoid Arthritis
MeSH terms: Inflammatory Bowel Diseases; Neutropenia; Purpura; Purpura, Thrombocytopenic; Purpura, Thrombocytopenic, Idiopathic; Pancytopenia; Anemia, Hemolytic; Autoimmune Lymphoproliferative Syndrome; Anemia, Hemolytic, Autoimmune; Lupus Erythematosus, Systemic; Syndrome; Hemolysis
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      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.
    

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.
    

Intervention name(s): sirolimus
Intervention type(s): Drug
Intervention description(s): 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 intervention name(s): rapamycin; rapamune
Intervention MeSH terms: Sirolimus
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: ALPS; Autoimmune; Cytopenias; Treatment; Sirolimus; Rapamycin; Lymph Nodes; Spleen; Hemolytic Anemia; Immune Thrombocytopenia; Neutropenia; ITP; Lupus