Sirolimus (Rapamune ) for Relapse Prevention in People With Severe Aplastic Anemia Responsive to Immunosuppressive Therapy

Description

* Most acquired aplastic anemia ensues from immune-mediated destruction of hematopoietic stem and progenitor cells.
* Immunosuppression is the definitive treatment of patients with acquired aplastic anemia who are not candidates for immediate hematopoietic stem cell transplantation.
* Horse ATG combined with the calcineurin inhibitor, cyclosporine (CsA), remains standard as first-line immunosuppressive therapy (IST).
* Hematologic responses to transfusion independence occur in about two thirds of patients with standard IST and in 80-90% of patients treated with IST in combination with the growth factor eltrombopag.
* About 30% to 40% of patients relapse after discontinuation of cyclosporine.Many achieve disease control after the reinitiation of CSA, but remain CSA dependent indefinitely.
* Evidence from mouse models of bone marrow failure indicates that conversion from cyclosporine to the mTOR inhibitor, sirolimus (SRL), results in immune tolerance which can endure the eventual withdrawal of SRL.
* We hypothesize that CSA to SRL conversion will significantly decrease the relapse rate after immunosuppressive therapy for acquired aplastic anemia.
* This study will investigate the safety and efficacy of SRL for preventing relapse in patients -previously treated with IST who remain on CSA. The primary endpoint is rate of relapse at 2 years following conversion from CSA to SRL, versus stopping CSA.
* Biological sampling of peripheral blood and bone marrow aspirates during treatment will be used to investigate changes to lymphocyte phenotypes and cytokine profiles.