Latest Advances in the Diagnosis and Treatment of Large Granular Lymphocytic Leukemia

International audienceLarge granular lymphocyte (LGL) leukemia has been recognized in the World Health Organization classifications among mature T cell and natural killer cell neoplasms and is divided into three categories. Chronic T cell leukemia and natural killer cell lymphocytosis can be considered as a similar spectrum of an indolent disease characterized by cytopenias and autoimmune conditions. The last category, aggressive natural killer cell LGL leukemia is very rare, related to Epstein-Barr virus, and seen mainly in young Asian people. Clonal LGL expansion arises from chronic antigenic stimulation sustained by interleukin-15 and platelet-derived growth factor cytokine signal. Those leukemic cells are resistant to apoptosis, mainly because of constitutive activation of survival pathways including Jak/Stat, MapK, Pi3k-Akt, RasRaf-1, MEK1/ERK, sphingolipid, and NFκB. Stat3 constitutive activation is the hallmark of this lymphoproliferative disorder. Socs3 is downregulated, but no mutation could be found to explain this status. However, several somatic mutations, including Stat3, Stat5b, and tumor necrosis factor alpha-induced protein 3, have been demonstrated recently in LGL leukemia; they are identified in half of patients and cannot explain by themselves LGL leukemogenesis. Recurrent infections as a result of chronic neutropenia, anemia, and autoimmune disorders are the main complications related to LGL leukemia. Despite an indolent presentation, 10% of patients die, mainly because of infectious complications. Current treatments are based on immunosuppressive therapies. A better mechanistic understanding of LGL leukemia will allow future consideration of a personalized therapeutic approach perhaps based on Jak/Stat inhibitors, which may offer better results than current immunosuppressive therapy

Large granular lymphocyte leukemia: An indolent clonal proliferative disease associated with an array of various immunologic disorders

International audienceLarge granular lymphocyte leukemia (LGLL) is a chronic lymphoproliferative disorder characterized by the proliferation of T or NK cytotoxic cells in the peripheral blood, the spleen and the bone marrow. Neutropenia leading to recurrent infections represents the main manifestation of LGLL. One specificity of LGLL is its frequent association with auto-immune disorders, among them first and foremost rheumatoid arthritis, and other hematologic diseases, including pure red cell aplasia and bone marrow failure. The large spectrum of manifestations and the classical indolent course contribute to the diagnosis difficulties and the frequency of underdiagnosed cases. Of importance, the dysimmune manifestations disappear with the treatment of LGLL as the blood cell counts normalize, giving a strong argument for a pathological link between the two entities. The therapeutic challenge results from the high rate of relapses following the first line of immunosuppressive drugs. New targeted agents, some of which are currently approved in autoimmune diseases, appear to be relevant therapeutic strategies to treat LGLL, by targeting key activated pathways involved in the pathogenesis of the disease, including JAK-STAT signaling