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
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.