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INTRODUCTION

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 2016 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, alemtuzumab, and more recently peptides that inhibit inflammatory cytokines such as interleukin-15. Prospective studies are ongoing to define the respective role of these agents in LGLL.

DEFINITION AND HISTORY

Large granular lymphocytic leukemia (LGLL) was initially described in the 1970s1,2 and further characterized in 19853 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% of blood mononuclear cells and may be either surface CD3 positive (T-cell) or surface CD3 negative (natural killer [NK] cell). The absolute number of LGLs in the blood of normal subjects is 0.2–0.4 × 109/L. According to the 2016 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 persistent (>6 months) and usually clonal expansion of surface CD3 (sCD3+) LGL without a clearly identifiable cause.4 The corresponding NK cell type of LGLL (sCD3–, CD16+, CD56+), referred to as chronic lymphoproliferative disorders of NK cells (CLPD-NK), was included as a provisional diagnosis in the 2008 WHO classification and is similarly defined.5 LGLL represent 2% to 3% of mature lymphocytic leukemias.4 CLPD-NK should be distinguished from the acute and often fulminant aggressive NK cell leukemia (ANKL),6 which is associated with Epstein-Barr virus (EBV) infection ...

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