Clinical Features, Pathogenesis, and Treatment of Large Granular Lymphocyte Leukemias

Oshimi, Kazuo

doi:10.2169/internalmedicine.56.8881

Cited by 31 publications

(39 citation statements)

References 123 publications

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“…ANKL has been categorized as a distinct entity since the third WHO classification and has been also classified as a large granular lymphocyte (LGL) leukemia based on its morphological features ( 3 , 11 ). ANKL is further mentioned as a leukemic type of mature NK cell lymphoproliferative disorder, another type of which was designated chronic lymphoproliferative disorders of NK cell (CLPD-NK) in WHO 2017 classification, provisionally.…”

Section: Terminologymentioning

confidence: 99%

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Aggressive NK-Cell Leukemia

Ishida

2018

Front. Pediatr.

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Aggressive NK cell leukemia (ANKL) is a rare malignant lymphoproliferative disorder of mature NK cells closely associated with Epstein-Barr virus (EBV) and more common in East Asia than in other areas. Significant variations exist in the morphology of ANKL tumor cells, from typical large granular lymphocyte morphology to highly atypical features with basophilic cytoplasm containing azurophilc granules. The main involved sites are hepatosplenic lesions, bone marrow and peripheral blood, and nasal or skin lesions are infrequent. A fever and liver dysfunction with an often rapidly progressive course are the main clinical symptoms, including hemophagocytic syndrome and disseminated intravascular coagulation. Although the outcome had been dismal for decades, with a median survival of less than three months, the introduction of combined chemotherapy including L-asparaginase and allogeneic hematopoietic cell transplantation has helped achieve a complete response and potential cure for some patients. With the advent of next-generation sequencing technologies, molecular alterations of ANKL have been elucidated, and dysfunctions in several signaling pathways, including the JAK/STAT pathway, have been identified. Novel target approaches to managing these abnormalities might help improve the prognosis of patients with ANKL.

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Section: Terminologymentioning

confidence: 99%

“…Aggressive NK cell leukemia (ANKL) is a rare malignant lymphoproliferative disease of mature NK cell type ( 1 – 3 ). ANKL is prevalent among Eastern Asian populations compared with Western countries and develops mainly in the relatively young ( 4 – 6 ).…”

Section: Introductionmentioning

confidence: 99%

Aggressive NK-Cell Leukemia

Ishida

2018

Front. Pediatr.

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“…Most LGLL cases derive from TCRαβ + CD4 − CD8 + T lymphocytes (TCD8 + ), less frequently from TCRαβ + CD4 + CD8 −/+lo T cells (TCD4 + ), TCRγδ + T cells (Tγδ + ) or NK cells, and rarely from other cytotoxic cells (i.e., TCRαβ + CD4 -CD8 −/+lo double-negative T cells -Tαβ + DN-) [4]. T-LGLL and CLPD-NK usually show an indolent clinical course [4,5], which is often associated with autoimmune conditions-e.g., cytopenias-and recurrent infections, that require therapeutic interventions [5][6][7][8][9][10]. In a few cases (<5%) transformation to aggressive leukemia has been reported [5,[7][8][9][10][11].…”

Section: Introductionmentioning

confidence: 99%

“…This is mostly due to the absence in a significant fraction of patients of tumor-associated phenotypic and/or molecular markers of clonality that would allow clear cut distinction among expansions of clonal vs. reactive/oligoclonal T cells [6,12,13], together with the lack of an universal marker of clonality for NK cells [14]. In addition, clonal/oligoclonal LGLs are also frequently detected in blood of asymptomatic subjects, either transiently (i.e., after allogeneic hematopoietic stem cell transplantation or solid organ transplantation) or persistently (i.e., in the elderly) [9,10,15]. So far, no reliable predictors of (indolent vs. aggressive) disease behavior have been established for T-LGLL and CLPD-NK.…”

Section: Introductionmentioning

confidence: 99%

STAT3 and STAT5B Mutations in T/NK-Cell Chronic Lymphoproliferative Disorders of Large Granular Lymphocytes (LGL): Association with Disease Features

Muñoz-García

Jara‐Acevedo

Caldas

et al. 2020

Cancers

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STAT3 and STAT5B (STAT3/STAT5B) mutations are the most common mutations in T-cell large granular lymphocytic leukemia (T-LGLL) and chronic lymphoproliferative disorders of NK cells (CLPD-NK), but their clinical impact remains unknown. We investigated the frequency and type of STAT3/STAT5B mutations in FACS-sorted populations of expanded T/NK-LGL from 100 (82 clonal; 6 oligoclonal; 12 polyclonal) patients, and its relationship with disease features. Seventeen non-LGL T-CLPD patients and 628 age-matched healthy donors were analyzed as controls. STAT3 (n = 30) and STAT5B (n = 1) mutations were detected in 28/82 clonal T/NK-LGLL patients (34%), while absent (0/18, 0%) among oligoclonal/polyclonal LGL-lymphocytosis. Mutations were found across all diagnostic subgroups: TCD8+-LGLL, 36%; CLPD-NK, 38%; TCD4+-LGLL, 7%; Tαβ+DP-LGLL, 100%; Tαβ+DN-LGLL, 50%; Tγδ+-LGLL, 44%. STAT3-mutated T-LGLL/CLPD-NK showed overall reduced (p < 0.05) blood counts of most normal leukocyte subsets, with a higher rate (vs. nonmutated LGLL) of neutropenia (p = 0.04), severe neutropenia (p = 0.02), and cases requiring treatment (p = 0.0001), together with a shorter time-to-therapy (p = 0.0001), particularly in non-Y640F STAT3-mutated patients. These findings confirm and extend on previous observations about the high prevalence of STAT3 mutations across different subtypes of LGLL, and its association with a more marked decrease of all major blood-cell subsets and a shortened time-to-therapy.

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“…Most patients remain asymptomatic and are diagnosed incidentally on routine blood test. [4] It has been reported to accompany some autoimmune diseases. [5] However, to date, there has been no report of T-LGL leukemia and anti-GBM disease.…”

Section: Introductionmentioning

confidence: 99%

Recurrent anti-GBM disease with T-cell large granular lymphocytic leukemia

Zhang¹,

Guan²,

Zhu

et al. 2019

Medicine

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Rationale: Anti-glomerular basement membrane disease (anti-GBM disease) is a rare small vessel vasculitis caused by autoantibodies directed against the glomerular and alveolar basement membranes. Anti-GBM disease is usually a monophasic illness and relapse is rare after effective treatment. This article reports a case of coexistence of recurrent anti-GBM disease and T-cell large granular lymphocytic (T-LGL) leukemia. Patient concerns: A 37-year-old man presented with hematuria, edema, and acute kidney injury for 2 months. Diagnosis: Anti-GBM disease was diagnosed by renal biopsy, in which crescentic glomerulonephritis was observed with light microscopy, strong linear immunofluorescent staining for immunoglobulin G on the GBM and positive serum anti-GBM antibody. Given this diagnosis, the patient was treated with plasmapheresis, steroids, and cyclophosphamide for 4 months. The anti-GBM antibody titer was maintained to negative level but the patient remained dialysis-dependent. One year later, the patient suffered with a relapse of anti-GBM disease, after an extensive examination, he was further diagnosed T-LGL leukemia by accident. Interventions: The patient received cyclosporine A therapy for T-LGL leukemia. Outcomes: After treatment with cyclosporine A, serum anti-GBM antibody became undetectable. During the 16 months follow-up, anti-GBM titer remained normal and abnormal T-lymphocytes in the bone marrow and peripheral blood were also decreased. Lessons: T-LGL leukemia is an indolent lymphoproliferative disorder that represents a monoclonal expansion of cytotoxic T cells, which has been reported to be accompanied by some autoimmune diseases. This is the first report of coincidence of T-LGL leukemia and anti-GBM disease, and suggests there are some relationships between these 2 diseases. Clinical physicians should exclude hematological tumors when faced with recurrent anti-GBM disease.

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Clinical Features, Pathogenesis, and Treatment of Large Granular Lymphocyte Leukemias

Cited by 31 publications

References 123 publications

Aggressive NK-Cell Leukemia

Aggressive NK-Cell Leukemia

STAT3 and STAT5B Mutations in T/NK-Cell Chronic Lymphoproliferative Disorders of Large Granular Lymphocytes (LGL): Association with Disease Features

Recurrent anti-GBM disease with T-cell large granular lymphocytic leukemia

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