Complete Responses in Patients with Autoimmune Lymphoproliferative Syndrome (ALPS) Using the mTOR Inhibitor Sirolimus (rapamycin)
Authors: Teachey Davi d T. , Greiner Robert J , Schwabe Dirk , Bleesing Jack , Manno Catherine Scott , Sullivan Kathleen , Wechsler Daniel S. , Grupp Stephan A. 
Published: April 2020

Abstract
Autoimmune lymphoproliferative syndrome (ALPS) is a rare disorder of abnormal lymphocyte survival caused by defective Fas-mediated apoptosis. Patients with ALPS develop lymphadenopathy, hepatosplenomegaly, and increased number of a T cell population normally found in low numbers in peripheral blood called double negative T cells (DNTs, T cell phenotype CD3+/4−/8−, TCRalpha/beta +). Patients frequently develop severe autoimmune disease, primarily manifested as autoimmune cytopenias. Some patients with ALPS need long-term treatment and these patients have limited therapeutic options. Sirolimus, an mTOR inhibitor, has been shown to induce apoptosis in normal and malignant lymphocytes. Because ALPS is caused by defective lymphocyte apoptosis, we hypothesized that sirolimus would be effective by inducing apoptosis in these abnormal cells, controlling the lymphoproliferation that is the hallmark of the disease. We previously tested this hypothesis using murine models of ALPS, and have now opened a phase I/II clinical trial testing sirolimus in patients with ALPS. Six children with ALPS (2 type IA; 4 type III) were started on treatment with sirolimus, targeting a serum trough level of 5–15ng/ml. 4 patients were treated for clinically significant autoimmune cytopenias that either failed standard therapies or in whom these therapies, including high dose corticosteroids, were not tolerated. The two other patients also had autoimmune cytopenias; however, the indication for treatment was autoimmune arthritis and colitis with steroid intolerance. Four of the patients had previously failed treatment with mycophenolate mofetil and not all six could tolerate corticosteroids. One patient had failed treatment with rituximab, methotrexate, cyclosporine, tacrolimus, anti-TNFalpha agents, and cyclophosphamide. Another patient had failed treatment with mercaptopurine and plaquenil. Five of 6 patients had complete resolution of autoimmune cytopenias and normalization of blood counts within 4 weeks of initiating therapy with sirolimus. One of six patients had persistent Grade 1 thrombocytopenia (plt count &gt;100,000/mm3 but less than 150,000/mm3). Four patients had resolution of lymphadenopathy and splenomegaly (3 complete; 1 partial with a greater than 90% reduction). Patients have been treated for 3, 3, 4, 15, 26, and 36 months, respectively. The two patients with co-morbid autoimmune arthritis and colitis showed response in these symptoms as well. All six patients had a greater than 50% reduction in DNTs. Serial PET/CTs were performed on one patient that demonstrated a complete resolution of diffuse PET-avid disease after 3 months. No patient developed any significant toxicity. One patient had developed EBV reactivation while being treated with a combination of high dose steroids, mycophenolate mofetil, and plaquenil-the EBV load went to zero after conversion to sirolimus, which may represent the effect of an mTOR inhibitor on EBV-transformed B cells. We found sirolimus significantly reduced the lymphoproliferative state and improved autoimmunity in patients with ALPS who had failed other therapies. We will continue to test sirolimus in a clinical trial; however, based on the significant improvement we found with this series we would argue that sirolimus be considered as second line therapy for patients with steroid-refractory or steroid-intolerant disease.