Large Granular Lymphocytic Leukemia: Clinical Features, Molecular Pathogenesis, Diagnosis and Treatment

Simple Summary The insights gleaned from available evidence contribute to our understanding that clonal LGL arises from chronic antigenic stimulation by a virus. The findings discussed here provide insights into the molecular pathogenesis of the disease. The current treatment is immunosuppressive monotherapy, and there is no standard first-line regimen for the disease. Unfortunately, these therapies have limited efficacy in eradicating the LGL clone and sustain satisfactory long-term remission. The discovery of novel therapeutic targets and large clinical trials could potentially lead to improved response.Abstract Large granular lymphocytic (LGL) leukemia is a lymphoproliferative disorder characterized by persistent clonal expansion of mature T- or natural killer cells in the blood via chronic antigenic stimulation. LGL leukemia is associated with specific immunophenotypic and molecular features, particularly STAT3 and STAT5 mutations and activation of the JAK-STAT3, Fas/Fas-L and NF-kappa B signaling pathways. Disease-related deaths are mainly due to recurrent infections linked to severe neutropenia. The current treatment is based on immunosuppressive therapies, which frequently produce unsatisfactory long-term responses, and for this reason, personalized approaches and targeted therapies are needed. Here, we discuss molecular pathogenesis, clinical presentation, associated autoimmune disorders, and the available treatment options, including emerging therapies.