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 with clonal expansions in blood LGLs, often without a clearly identifiable cause. Patients with these diseases 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 LGLL 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 patients with T-LGLL 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 or 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. Prospective studies are examining the role of these agents in LGLL.
DEFINITION AND HISTORY
Large granular lymphocytic leukemia (LGLL) was initially described in the 1970s,1,2 and in 1985 further characterized,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 WHO [World Health Organization] Classification of Tumours of the Haematopoietic 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+) LGLs without a clearly identifiable cause.4 The corresponding NK cell type of LGLL (sCD3–, CD16+), 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 represents 2 to 3 percent 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 of the neoplastic NK cells. ...