Sirolimus for Autoimmune Disease of Blood Cells
Sirolimus for Autoimmune Disease of Blood Cells
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.
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.
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)