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INTRODUCTION

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SUMMARY

Indolent clonal proliferations of large granular lymphocytes (LGLs) can arise from either T cells or natural killer (NK) cells. These diseases show overlapping clinical, morphologic, immunophenotypic, and genetic features. T-cell large granular lymphocytic leukemia (T-LGLL) and the related provisional 2008 World Health Organization entity, chronic lymphoproliferative disorders of NK cells (CLPD-NK), are similarly defined as persistent (>6 months) and clonal expansions in blood LGLs, often without a clearly identifiable cause. These patients are typically older, present with single lineage or multilineage cytopenias, and often have clinical and laboratory features of autoimmunity or immune dysfunction. Autoimmune neutropenia, thrombocytopenia, hemolytic anemia, and occasionally pure red cell aplasia may occur. Patients with T-LGLL frequently have elevated rheumatoid factor and clinical hallmarks of rheumatoid arthritis. The diagnosis of LGL leukemia requires a high degree of suspicion and careful examination of the blood film, because a significant fraction of patients do not have an absolute lymphocytosis, although the proportion of LGLs is usually increased. Most patients with T-LGLL and fewer with CLPD-NK have chronic neutropenia, and approximately half of T-LGLL patients have neutrophil counts less than 0.5 × 109/L. Anemia is observed in approximately half of patients with T-LGLL. Morbidity and mortality usually result from recurrent infections secondary to chronic neutropenia, transfusion-related iron overload, and less frequently from disease acceleration and transformation into a more aggressive T/NK leukemia or lymphoma. The treatment approach generally consists of immune modulatory or immune suppressive drugs, such as weekly oral methotrexate, cyclophosphamide, cyclosporine, prednisone, and alemtuzumab.

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Acronyms and Abbreviations

AICD, activation-induced cell death; ANKL, aggressive NK cell leukemia; CD, cluster of differentiation; CDR3, complementarity determining region 3; CLPD-NK, chronic lymphoproliferative disorders of NK cells; CMV, cytomegalovirus; CTL, cytotoxic T lymphocyte; EBV, Epstein-Barr virus; FS, Felty syndrome; HLA, human leukocyte antigen; HSTCL, hepatosplenic T-cell lymphoma; HTLV, human T-cell leukemia virus; IL, interleukin; KIR, killer immunoglobulin-like receptor; LGL, large granular lymphocyte; LGLL, large granular lymphocytic leukemia; NK, natural killer cell; NK-LGL, natural killer cell–large granular lymphocyte; PDGF, platelet-derived growth factor; PI3K, phosphatidylinositol 3′-kinase; RF, rheumatoid factor; STAT, signal transducer and activator of transcription; TCR, T-cell receptor; T-LGLL, T-cell large granular lymphocytic leukemia; WHO, World Health Organization.

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DEFINITION AND HISTORY

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Large granular lymphocytic leukemia (LGLL) was initially described in the 1970s,1,2 and further characterized in 1985,3 as a clonal disorder of cytotoxic cluster of differentiation (CD)8+ T-cells involving blood, marrow, liver, and spleen, and clinically manifesting as an indolent proliferation of large granular lymphocytes (LGLs). Normally LGLs comprise 10 to 15 percent of blood mononuclear cells and may be either surface CD3+ (T-cell) or surface CD3– (natural killer [NK] cell). The absolute number of LGLs in the blood of normal subjects is 0.2 to 0.4 × 109/L. According to the 2008 World Health Organization (WHO) Classification of Tumors of the Hematopoietic and Lymphoid Tissues, T-cell large granular lymphocytic leukemia (T-LGLL) is defined as a ...

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