Clinical Trial: Sirolimus for Autoimmune Disease of Blood Cells
Study Status: Active, not recruiting
Recruit Status: Active, not recruiting
Study Type: Interventional
Official Title: Sirolimus for Patients With Chronic and/or Refractory Autoimmune Cytopenias: A Pilot Series
Brief 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 Summary:
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
Sponsor: Children's Hospital of Philadelphia
Current Primary Outcome: To define the toxicities of administration of oral sirolimus in children with autoimmune cytopenias [ Time Frame: 6 months ]
Original Primary Outcome: To define the toxicities of administration of oral sirolimus in children with ALPS
Current Secondary Outcome:
- 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 ]
Original Secondary Outcome:
- To evaluate the efficacy of oral sirolimus in children with ALPS
- To characterize the trough levels produced by administration of oral sirolimus in children with ALPS.
- To evaluate the effect of sirolimus on intracellular targets
Information By: Children's Hospital of Philadelphia
Dates:
Date Received: October 24, 2006
Date Started: December 2006
Date Completion: February 2020
Last Updated: March 16, 2017
Last Verified: March 2017
