Autoimmune lymphoproliferative syndrome

Editor-In-Chief: David Teachey, MD [mailto:TEACHEYD@email.chop.edu]

Overview
Autoimmune lymphoproliferative syndrome is a form of lymphoproliferative disorder. It affects lymphocyte apoptosis. Autoimmune Lymphoproliferative Syndrome (ALPS) is a rare disorder of abnormal lymphocyte survival caused by defective Fas mediated apoptosis. Normally, after infectious insult, the immune system down-regulates by increasing Fas expression on activated B and T lymphocytes and Fas-ligand on activated T lymphocytes. Fas and Fas-ligand interact to trigger the caspase cascade, leading to cell apoptosis. Patients with ALPS have a defect in this apoptotic pathway, leading to chronic non-malignant lymphoproliferation, autoimmune disease, and secondary cancers.

Clinical Manifestations
Lymphoproliferation: The most common clinical manifestation of ALPS is lymphoproliferation, affecting 100% of patients. Autoimmune disease: The second most common clinical manifestation and one that most often requires treatment.
 * Lymphadenopathy: >90% of patients present with chronic non-malignant lymphadenopathy. It can be mild to severe, affecting multiple nodal groups. Most commonly presents with massive non-painful hard cervical lymphadenopathy
 * Splenomegaly: >80% of patients present with clinically identifiable splenomegaly. It can be massive.
 * Hepatomegaly: 30-40% of patients have enlarged livers.
 * Lymphoproliferation tends to present at a young age (median 11.5 months) and may improve with age.
 * Autoimmune cytopenias: Most common. Can be mild to very severe. Can be intermittent or chronic.
 * Autoimmune Hemolytic Anemia
 * Autoimmune Neutropenia
 * Autoimmune Thrombocytopenia
 * Other: Can affect any organ system similar to systemic lupus erythematosis (most rare affecting <5% of patients)
 * Nervous: Autoimmune cerebellar ataxia; Guillain-Barre; Transverse myelitis
 * GI: Autoimmune esophagitis, gastritis, colitis, hepatitis, pancreatitis
 * Derm: Urticaria
 * Pulmonary: Bronchiolitis obliterans
 * Renal: Autoimmune glomerulonephritis, nephrotic syndrome
 * Cancer: Secondary neoplasms affect approximately 10% of patients. True prevalence unknown as <20 reported cases of cancer. Most common EBER+ Non-Hodgkin's and Hodgkin's lymphoma
 * Unaffected family members with genetic mutations are also at increased risk of developing cancer

Laboratory Manifestations

 * Elevated peripheral blood Double Negative T cells (DNTs)
 * Required for diagnosis
 * Immunophenotype: CD3+/CD4-/CD8-/TCRalpha/beta+
 * Measured by flow cytometry: Normal values <2.5% total T cells; <1% of total lymphocytes in peripheral blood
 * Marked elevations >5% virtually pathognomic for ALPS
 * Mild elevations also found in other autoimmune diseases
 * Thought to be cytotoxic T lymphocytes that have lost CD8 expression
 * ?Unknown if driver of disease or epiphenomenon
 * May be falsely elevated in setting of lymphopenia or falsely decreased with immunosuppressive treatment
 * Defective in vitro Fas mediated apoptosis
 * Required for diagnosis under old definition. Now can be used to make diagnosis; however, not required to make diagnosis.
 * Time and labor intensive assay.
 * T cells from patient and normal control supported in culture for >10 days with mitogen stimulation and IL-2 expansion and then exposed to anti-Fas IgM monoclonal antibody
 * ALPS patient T cells: Do not die with anti-Fas monoclonal antibody exposure. Normal T cells from unaffected patient do.
 * False negative in somatic Fas variant ALPS and FasL variant ALPS
 * Genetic mutations in ALPS causative genes (see below)
 * Biomarkers
 * Polyclonal hypergammaglobulinemia
 * Elevated serum FASL
 * Elevated plasma IL-10 and/or IL-18
 * Elevated plasma or serum vitamin B12
 * Autoantibodies: Non-specific. Can have antibodies to blood cells (DAT, anti-neutrophil, anti-platelet). Also, can have positive ANA, RF, ANCA.

Classification
Old nomenclature Revised nomenclature (2010)
 * IA - Fas
 * IB - Fas ligand
 * IIA - Caspase 10
 * IIB - Caspase 8
 * III - unknown
 * IV - Neuroblastoma RAS viral oncogene homolog
 * ALPS-FAS: Fas. Germline FAS mutations. 70% of patients. Autosomal dominant. Dominant negative and haploinsufficient mutations described.
 * ALPS-sFAS: Fas. Somatic FAS mutations in DNT compartment. 10% of patients
 * ALPS-FASL: Fas ligand. Germline FASL mutations. 3 reported cases
 * ALPS-CASP10: Caspase 10. Germline CASP10 mutation. 2% of patients
 * ALPS-U: Undefined. 20% of patients
 * CEDS: Caspase 8 deficiency state. No longer considered a subtype of ALPS but distinct disorder
 * RALD: NRAS, KRAS. Somatic mutations in NRAS and KRAS in lympocyte comparment. No longer considered a subtype of ALPS but distinct disesase

Diagnostic Algorithm
Old criteria
 * Required
 * Chronic non-malignant lymphoproliferation
 * Elevated peripheral blood DNTs
 * Defective in vitro Fas mediated apoptosis

New criteria
 * Required
 * Chronic non-malignant lymphoproliferation (>6 months lymphadenopathy and/or splenomegaly)
 * Elevated peripheral blood DNTs
 * Accessory
 * Primary Accessory
 * Defective in vitro Fas mediated apoptosis
 * Somatic or germline mutation in ALPS causative gene (FAS, FASL, CASP10)
 * Secondary Accessory
 * Elevated biomarkers
 * Plasma sFASL >200pg/ml
 * Plasma IL-10 >20pg/ml
 * Plasma or serum vitamin B12 >1500ng/L
 * Plasma IL-18 >500pg/ml
 * Immunohistochemical findings on biopsy consistent with ALPS as determined by experienced hematopathologist
 * Autoimmune cytopenias and polyclonal hypergammaglobulinemia
 * Family history of ALPS or non-malignant lymphoproliferation
 * Definitive diagnosis: Required plus one primary accessory criteria
 * Probable diagnosis: Required plus one secondary accessory criteria
 * Definitive and Probable ALPS should be TREATED THE SAME and patients counseled that they have ALPS if definitive or probable

Treatment

 * Mostly commonly directed at autoimmune disease
 * Maybe needed to treat bulky lymphoproliferation
 * First line therapies
 * Corticosteroids
 * Very active but toxic with chronic use
 * IVIgG
 * Not as effective as in other immune cytopenia syndromes
 * Second line therapies
 * Mycophenolate mofetil (cellcept)
 * Inactivates inosine monophosphate
 * Active in most patients
 * Most studied medicine in clinical trials
 * Some patients have complete resolution of autoimmune disease
 * Some patients have partial responses
 * Some patients relapse
 * Does not affect lymphoproliferation or reduce DNTs
 * Well-tolerated: Side effects: Diarrhea, neutropenia
 * Does not require therapeutic drug monitoring
 * No drug-drug interactions
 * Can cause hypogammaglobulinemia (transient) requiring IVIgG replacement
 * Consider PCP prophylaxis but usually not needed
 * Sirolimus (rapamycin, rapamune)
 * mTOR (mammalian target of rapamycin) inhibitor
 * Active in most patients
 * Second most studied agent in clinical trials
 * Most patients have complete resolution of autoimmune disease (>90%)
 * Most patients have complete resolution of lymphoproliferation, including lymphadenopathy and splenomegaly (>90%)
 * Some patients have near complete response (disease flares with viral illness)
 * A few patients have had partial responses (most commonly patient with non-cytopenia autoimmune disease)
 * Most patients have elimination of peripheral blood DNTs
 * mTOR/Akt/PI3K pathway may be activated in abnormal ALPS cells: mTOR inhibitors may be targeted therapy
 * May not be as immune suppressive in normal lymphocytes as other agents. Some patients have had improvement in immune function with transition from cellcept to rapamycin
 * Not reported to cause hypogammaglobulinemia
 * Hypothetically, may have lower risk of secondary cancers as opposed to other immune suppressants
 * Always a risk with any agent in pre-cancerous syndrome as immune suppression can decreased tumor immunosurvellence
 * mTOR inhibitors active against lymphomas, especially EBV+ lymphomas. Thus, THEORETICALLY could eliminate malignant clones.
 * Requires therapeutic drug monitoring
 * Goal serum trough 5-15ng/ml
 * Drug-drug interactions
 * Well tolerated: Side effects: mucositis, diarrhea, hyperlipidemia, delayed wound healing
 * Consider PCP prophylaxis but usually not needed
 * Other agents:
 * Fansidar, mercaptopurine: More commonly used in Europe. Good ancedotal data
 * Rituximab: AVOID. Can cause life long hypogammaglobulinemia
 * Splenectomy: AVOID. >30% risk of pneumococcal sepsis even with vaccination and antibiotic prophylaxis