Chapter 93: Large Granular Lymphocytic Leukemia

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.

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; CR, complete remission; CTL, cytotoxic T lymphocyte; Cy, cyclophosphamide; EBV, Epstein-Barr virus; ECOG, Eastern Cooperative Oncology Group; FDA, Federal Drug Administration; FS, Felty syndrome; HIV, human immunodeficiency virus; 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; MDS, myelodysplasia; MTX, methotrexate; NGS, next generation sequencing; NK, natural killer cell; NK-LGL, natural killer cell–large granular lymphocyte; ORR, overall response rate; PCR, polymerase chain reaction; PDGF, platelet-derived growth factor; PI3K, phosphatidylinositol 3'-kinase; PR, partial remission; RA, rheumatoid arthritis; RF, rheumatoid factor; sCD3, surface CD3; STAT, signal transducer and activator of transcription; TCR, T-cell receptor; T-LGLL, T-cell large granular lymphocytic leukemia; WHO, World Health Organization.