Using the Genetics of the Autoimmune Lymphoproliferative Syndrome to Guide Therapy

Abstract SCI-7

Autoimmune Lymphoproliferative Syndrome (ALPS) is a disorder of abnormal lymphocyte survival caused by defective Fas-mediated apoptosis. Patients with ALPS may present with lymphoproliferation (lymphadenopathy and hepatosplenomegaly), autoimmune disease (most commonly autoimmune cytopenias), and secondary malignancies (typically EBER+ non-Hodgkin lymphoma). Eighty percent of ALPS patients have an identifiable genetic mutation in FAS (TNFRSF6), FASL (TNFSF6), or CASP10. These mutations can be germline or somatic with localization to the double negative T cell (DNT) compartment. DNTs (cell phenotype TCRα/β+, CD3+, CD4−, CD8−) are an atypical T cell population found in elevated quantities in peripheral blood and lymphoid tissue in ALPS patients. The diagnostic criteria for ALPS were modified in 2010 based on the results of an international consensus conference and include meeting a constellation of clinical findings, elevated DNTs, abnormal biomarkers (elevated vitamin B12, IL-10, and sFasL), in vitro evidence of defective Fas-mediated apoptosis, and mutations (somatic or germline) in Fas pathway genes. Patients with idiopathic autoimmune cytopenia syndromes (ITP, AIHA, and Evans Syndrome) and rheumatologic conditions (SLE) may have similar clinical presentations as ALPS. Our group demonstrated that approximately 45% of children diagnosed with Evans syndrome may in fact have a forme fruste of ALPS as confirmed by genetic and functional testing. Diagnosing ALPS with genetic confirmation is extremely important, because patients with idiopathic immune cytopenias should receive different treatment than ALPS patients. While first line therapy for both uses IVIgG and corticosteroids, two second-line treatments routinely used for refractory and/or chronic idiopathic autoimmune cytopenias are relatively contradicted in ALPS patients. Splenectomy has been associated with pneumococcal sepsis despite appropriate vaccination and antibiotic prophylaxis in ALPS patients. It is hypothesized that ALPS patients have increased difficulty fighting encapsulated organisms and splenectomy should be avoided. Rituximab (anti-CD20 monoclonal antibody) has been shown to cause profound and potentially life-long hypogammaglobulinemia similar to common variable immunodeficiency when used in ALPS patients and should also be avoided. In contrast, other agents used less commonly in idiopathic autoimmune cytopenias have demonstrated remarkable success in ALPS. Mycophenolate mofetil (MMF) improves autoimmune cytopenias in some refractory ALPS patients and is often used as second line treatment. Recently, we demonstrated that the mTOR inhibitor sirolimus (rapamycin) is extremely effective in ALPS both in preclinical models and in children. We have found complete responses in most patients treated with sirolimus to date. Unlike other agents, we found that sirolimus improved both autoimmune disease and lymphoproliferation, as well as specifically targeting the abnormal DNTs. No other agent, including corticosteroids, has been demonstrated to eliminate DNTs. Our preliminary data suggest that the DNTs have intrinsic abnormalities in mTOR signaling, potentially driving the autoimmune disease; and, therefore, we have a possible biologic explanation for the profound effects. Ongoing work will determine if the mTOR signaling abnormalities are specific to FAS-mutant ALPS or whether they are also found in other genetic ALPS variants that result in abnormal Fas-mediated apoptosis.