Treatment with sirolimus results in complete responses in patients with autoimmune lymphoproliferative syndrome

Abstract

We hypothesized that sirolimus, an mTOR inhibitor, may be effective in patients with autoimmune lymphoproliferative syndrome (ALPS) and treated patients who were intolerant to or failed other therapies. Four patients were treated for autoimmune cytopenias; all had a rapid complete or near complete response. Two patients were treated for autoimmune arthritis and colitis, demonstrating marked improvement. Three patients had complete resolution of lymphadenopathy and splenomegaly and all patients had a reduction in double negative T cells, a population hallmark of the disease. Based on these significant responses, we recommend that sirolimus be considered as second-line therapy for patients with steroid-refractory disease.

Fig. 1

Sirolimus improves lymphoproliferation, autoimmune cytopenias and double negative T cells in patients with ALPS. Four patients were treated with sirolimus for autoimmune cytopenias. Panels depict changes in platelet count (A), ANC (B) and haemoglobin (C). Patients 1 and 3 had autoimmune pancytopenia. Patient 2 only had autoimmune thrombocytopenia. Patient 4 had autoimmune neutropenia and thrombocytopenia. The x-axis depicts time in weeks with data for every 2-week time points if available. NOTE change in scale after 16 weeks demarcated by vertical purple line. Week 0 (zero) is the time sirolimus was initiated. Arrows depict the time points when steroids were stopped. Panel D depicts peripheral blood DNTS (Double negative T cells; T cell phenotype: CD3⁺, CD4⁻, CD8⁻, TCRa/b⁺). DNTs were collected prior to initiating sirolimus and on therapy. All patients demonstrated significant reduction in DNTs. Post-treatment data point represents time 4–8 weeks after steroids stopped except for Patient 5 who had his level obtained on low dose steroids (5 mg every other day). Panel E depicts Fluorodeoxyglucose (FDG) PET–CT imaging, demonstrating a marked improvement in lymphadenopathy and splenomegaly in Patient 1 with ALPS after 3 months of treatment with sirolimus. Improvement was demonstrated in size of lymph nodes and spleen and in FDG-uptake. Upper panels represent pre-treatment (marked by arrows) and lower panels represent post-treatment.