Large Granular Lymphocytic Leukemia: From Immunopathogenesis to Treatment of Refractory Disease

Simple Summary Large Granular Lymphocytic Leukemia (LGLL) is a clonal disorder of cytotoxic T-cells. Because of the variety of clinical presentations ranging from the mere presence of lymphocytosis to cytopenias and autoimmune conditions, this rare lymphoma may require treatment to control such manifestations. Although first-line treatments are more established, refractory cases are often managed based on the experience of the attending physician. Herein, we review the pathways involved in the pathogenesis of LGLL, including refractory cases, inferring clues as to the potentially actionable targets. Large Granular Lymphocyte Leukemia (LGLL) is a rare, chronic lymphoproliferative disorder of effector cytotoxic T-cells, and less frequently, natural killer (NK) cells. The disease is characterized by an indolent and often asymptomatic course. However, in roughly 50% of cases, treatment is required due to severe transfusion-dependent anemia, severe neutropenia, or moderate neutropenia with associated recurrent infections. LGLL represents an interesting disease process at the intersection of a physiological immune response, autoimmune disorder, and malignant (clonal) proliferation, resulting from the aberrant activation of cellular pathways promoting survival, proliferation, and evasion of apoptotic signaling. LGLL treatment primarily consists of immunosuppressive agents (methotrexate, cyclosporine, and cyclophosphamide), with a cumulative response rate of about 60% based on longitudinal expertise and retrospective studies. However, refractory cases can result in clinical scenarios characterized by transfusion-dependent anemia and severe neutropenia, which warrant further exploration of other potential targeted treatment modalities. Here, we summarize the current understanding of the immune-genomic profiles of LGLL, its pathogenesis, and current treatment options, and discuss potential novel therapeutic agents, particularly for refractory disease.