Cyclophosphamide as a first-line therapy in LGL leukemia

Large granular lymphocyte (LGL) leukemia is a T or NK clonal disorder characterized by the tissue invasion of marrow, spleen and liver. Clinical presentation is dominated by recurrent infections associated with neutropenia, anemia, splenomegaly and autoimmune diseases, particularly rheumatoid arthritis. 1 , 2 , 3 , 4 Recently, STAT3 and STAT5 mutations have been detected in T-LGL and in NK-LGL leukemias. 5 , 6 , 7 , 8 These somatic mutations, coupled to other intrinsic and extrinsic mechanisms, are likely to induce constitutive activation of the JAK/STAT pathway thus contributing to maintenance of leukemic LGL survival. 9 These findings strongly suggest a common specific pathogenic pattern in T-LGL and NK-LGL leukemias and provide justification for consideration of the same treatment options. Indications for treatment are severe or symptomatic neutropenia, symptomatic or transfusion-dependent anemia or associated autoimmune diseases requiring therapy. There is no standard treatment for patients with LGL leukemia. All the largest series published in the literature (collecting data on more than 40 patients) are retrospective. Data are very heterogeneous and treatment outcome per single agent is available for very few patients. Immunosuppressive therapy remains the foundation of treatment including single agents that is, methotrexate, oral cyclophosphamide or cyclosporine. On the basis of an initial study showing very good overall response rate (ORR) using methotrexate, this drug has remained the most recommended option in LGL leukemia. 10 Oral low dose cyclophosphamide was first used in pure red cell aplasia associated with LGL leukemia. 11 , 12 In a French series, cyclophosphamide was shown to be also efficient in neutropenic patients and for those who failed methotrexate. 13 Those results suggested that cyclophosphamide used as first-line therapy could be an interesting alternative to methotrexate.