Sirolimus for Autoimmune Disease of Blood Cells
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.
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 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 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.
Study Design
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Conditions
Autoimmune Cytopenias
Intervention
sirolimus
Location
Children's Hospital of Philadelphia
Philadelphia
Pennsylvania
United States
19104
Status
Recruiting
Source
Children's Hospital of Philadelphia
Results (where available)
Links
- Source: http://clinicaltrials.gov/show/NCT00392951
- Information obtained from ClinicalTrials.gov on July 15, 2010
Medical and Biotech [MESH] Definitions
Sirolimus
A macrolide compound obtained from Streptomyces hygroscopicus that acts by selectively blocking the transcriptional activation of cytokines thereby inhibiting cytokine production. It is bioactive only when bound to IMMUNOPHILINS. Sirolimus is a potent immunosuppressant and possesses both antifungal and antineoplastic properties.
Nervous System Autoimmune Disease, Experimental
Experimental animal models for human AUTOIMMUNE DISEASES OF THE NERVOUS SYSTEM. They include GUILLAIN-BARRE SYNDROME (see NEURITIS, AUTOIMMUNE, EXPERIMENTAL); MYASTHENIA GRAVIS (see MYASTHENIA GRAVIS, AUTOIMMUNE, EXPERIMENTAL); and MULTIPLE SCLEROSIS (see ENCEPHALOMYELITIS, AUTOIMMUNE, EXPERIMENTAL).
Thyroiditis, Autoimmune
Inflammatory disease of the THYROID GLAND due to autoimmune responses leading to lymphocytic infiltration of the gland. It is characterized by the presence of circulating thyroid antigen-specific T-CELLS and thyroid AUTOANTIBODIES. The clinical signs can range from HYPOTHYROIDISM to THYROTOXICOSIS depending on the type of autoimmune thyroiditis.
Polyendocrinopathies, Autoimmune
Autoimmune diseases affecting multiple endocrine organs. Type I is characterized by childhood onset and chronic mucocutaneous candidiasis (CANDIDIASIS, CHRONIC MUCOCUTANEOUS), while type II exhibits any combination of adrenal insufficiency (ADDISON'S DISEASE), lymphocytic thyroiditis (THYROIDITIS, AUTOIMMUNE;), HYPOPARATHYROIDISM; and gonadal failure. In both types organ-specific ANTIBODIES against a variety of ENDOCRINE GLANDS have been detected. The type II syndrome differs from type I in that it is associated with HLA-A1 and B8 haplotypes, onset is usually in adulthood, and candidiasis is not present.
Demyelinating Autoimmune Diseases, Cns
Conditions characterized by loss or dysfunction of myelin (see MYELIN SHEATH) in the brain, spinal cord, or optic nerves secondary to autoimmune mediated processes. This may take the form of a humoral or cellular immune response directed toward myelin or OLIGODENDROGLIA associated autoantigens.
Clinical Trials
The Efficacy and Safety of Alemtuzumab in Auotoimmune Cytopenias
The majority of cases of autoimmune cytopenias, which includes immune thrombocytopenia (ITP), autoimmune hemolytic anemia, autoimmune neutropenia (AIN) and pure red cell aplasia, will resp...
Alemtuzumab and Rituximab in the Treatment of Refractory Autoimmune Cytopenias
The purpose of this study is to determine whether the combination of low doses of alemtuzumab and rituximab are effective in the treatment of patients with autoimmune cytopenias who has fa...
The purpose of this study is to determine the safety and efficacy of an ocular sirolimus (rapamycin) formulation compared to Placebo on the signs and symptoms of dry eye in the CAE Model.
Sirolimus as Therapeutic Approach to Uveitis
The purpose of this study is to find out about the safety and effectiveness of the study drug, sirolimus, in patients with uveitis and to utilize the potential effectiveness of sirolimus,...
Study Evaluating Sirolimus and Cyclosporine in Kidney Transplant Recipients
To assess equivalence in the rates of functional graft survival at 12 months after transplantation in patients receiving continuous therapy with cyclosporine (CsA, Sandimmune, Neoral) and...
PubMed Articles
Treatment of autoimmune cytopenias remains unsatisfactory for patients refractory to first-line management. We evaluated the safety and efficacy of low-dose rituximab plus alemtuzumab in patients with...
Sirolimus immunosuppression for graft-versus-host disease prophylaxis and therapy: an update.
PURPOSE OF REVIEW: Sirolimus is being used increasingly as an immunosuppressant in allogeneic hematopoietic stem cell transplantation. This article reviews recent results in sirolimus-based graft-vers...
Sirolimus therapy may cause cardiac tamponade.
The side-effects associated with the immunosuppressive drug sirolimus are numerous and constitute a major limitation for its use in renal transplantation. In this study, we describe two cases of renal...
We report our experience on rituximab-cyclophosphamide-dexamethasone (RCD) combination therapy for the treatment of autoimmune disorders (AIDs) in 48 chronic lymphocytic leukemia (CLL) patients. Overa...
We analyzed the prevalence, characteristics, clinical correlates, and prognostic significance of autoimmune cytopenia in patients with CLL. Seventy of 960 (7 %) unselected patients had autoimmune cyto...
