Latest Advances in the Diagnosis and Treatment of Large Granular Lymphocytic Leukemia

Moignet, Aline; Lamy, Thierry

doi:10.1200/edbk_200689

Cited by 80 publications

(104 citation statements)

References 62 publications

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“…However, during the disease course in 60% of cases therapy is needed, mostly for cytopenia-related manifestations, symptomatic patients showing clinical features often related to neutropenia (2). Currently, no specific treatment is available for LGL disorders and the current therapy is based on immunosuppressive drugs (i.e., Methotrexate, Cyclophosphamide or Cyclosporine A) giving unsatisfying responses (6,7).…”

Section: Introductionmentioning

confidence: 99%

Insights Into Genetic Landscape of Large Granular Lymphocyte Leukemia

et al. 2020

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Large granular lymphocyte leukemia (LGLL) is a chronic proliferation of clonal cytotoxic lymphocytes, usually presenting with cytopenias and yet lacking a specific therapy. The disease is heterogeneous, including different subsets of patients distinguished by LGL immunophenotype (CD8+ Tαβ, CD4+ Tαβ, Tγδ, NK) and the clinical course of the disease (indolent/symptomatic/aggressive). Even if the etiology of LGLL remains elusive, evidence is accumulating on the genetic landscape driving and/or sustaining chronic LGL proliferations. The most common gain-of-function mutations identified in LGLL patients are on STAT3 and STAT5b genes, which have been recently recognized as clonal markers and were included in the 2017 WHO classification of the disease. A significant correlation between STAT3 mutations and symptomatic disease has been highlighted. At variance, STAT5b mutations could have a different clinical impact based on the immunophenotype of the mutated clone. In fact, they are regarded as the signature of an aggressive clinical course with a poor prognosis in CD8+ T-LGLL and aggressive NK cell leukemia, while they are devoid of negative prognostic significance in CD4+ T-LGLL and Tγδ LGLL. Knowing the specific distribution of STAT mutations helps identify the discrete mechanisms sustaining LGL proliferations in the corresponding disease subsets. Some patients equipped with wild type STAT genes are characterized by less frequent mutations in different genes, suggesting that other pathogenetic mechanisms are likely to be involved. In this review, we discuss how the LGLL mutational pattern allows a more precise and detailed tumor stratification, suggesting new parameters for better management of the disease and hopefully paving the way for a targeted clinical approach.

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Section: Introductionmentioning

confidence: 99%

Insights Into Genetic Landscape of Large Granular Lymphocyte Leukemia

et al. 2020

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“…There have been many reported cases of T-LGL leukemia associated with underlying autoimmune disorders, malignancy, bone marrow failure, solid organ transplantation, or use of certain drugs. [2][3][4][5][6]13 In general, it is reported to be an indolent type of leukemia and the…”

Section: Discussionmentioning

confidence: 99%

Clonal T‐cell large granular lymphocyte proliferations in childhood and young adult immune dysregulation conditions

Savaşan

Al-Qanber

Buck

et al. 2020

Pediatric Blood & Cancer

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Background Proliferation of large granular lymphocytes (LGL) and T‐cell LGL (T‐LGL) in peripheral blood along with demonstration of clonality are the hallmarks of a heterogeneous group of disorders, including T‐LGL leukemia or T‐LGL lymphocytosis. They are often associated with neutropenia and responsive to immunosuppression. The true nature of this entity is not well understood. Some cases are reported as reactive phenomena with very limited experience in pediatric population. Methods Hematology/Oncology Flow Cytometry Laboratory database has been reviewed retrospectively. Patients with identifiable distinct CD5‐dim T‐cell population and positive clonal T‐cell receptor rearrangement were included in the analysis. Clinical and laboratory data were then reviewed. Results Sixteen cases of children and young adults with increased peripheral blood clonal T‐LGL population characterized by dim CD5 expression with wide range of underlying immune dysregulation/stimulation disorders were reviewed. Extended follow up with repeat testing suggested the reactive nature of persistent clonal T‐LGL proliferations in this group. Conclusions Our observations indicate that clonal T‐LGL proliferations in children and young adults are reactive in nature and some can be persistent with an indolent course with unknown consequentiality. Clonal T‐LGL cells could be targeting the most prominent immunogenic stressor(s) involved as a control mechanism.

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“…[12,22] For T-LGLL, the current diagnostic requirements have lowered this threshold to > 0.4 or 0.5 × 10 9 /L provided that a clonal T-LGL population is found with an appropriate clinical context. [23][24][25] Recent studies have shown that 49% of patients with T-LGLL have no absolute lymphocytosis and 36% of patients have blood LGLs < 1 × 10 9 /L. [9] As the clinical manifestations of RAassociated T-LGLL are often identical to those in which one would suspect an FS, it may be di cult to differentiate RA-associated T-LGLL with a low LGL count (0.4-2.0 × 10 9 /L) from FS.…”

Section: Discussionmentioning

confidence: 99%

Comparison of somatic STAT3 and STAT5b gene mutations between Felty's syndrome and T-cell large granular lymphocytic leukemia with rheumatoid arthritis

Gorodetskiy¹,

Sidorova²,

Купрышина³

et al. 2020

Preprint

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Objectives Approximately 15% of patients with T-cell large granular lymphocytic leukemia (T-LGLL) have rheumatoid arthritis (RA). RA-associated T-LGLL with low large granular lymphocyte counts (aleukemic presentation) and Felty's syndrome (FS) have indistinguishable clinical presentations. These disorders are distinguished by T-cell clonality which is observed in T-LGLL but not in FS. Activating somatic mutations in the signal transducer and activator of transcription 3 (STAT3) and 5 (STAT5b) genes are involved in T-LGLL pathogenesis; however, the prevalence of these mutations in FS is unknown.Methods Based on the rearrangements of T-cell receptor (TCR) gamma and beta genes according to the BIOMED-2 protocol, we examined T-cell clonality in 81 patients with RA and unexplained neutropenia. We stratified these patients by the presence or absence of T-cell clonality, respectively, into 2 groups: RA-associated T-LGLL (56 patients) and FS (25 patients). Allele-specific TaqMan Real-Time polymerase chain reaction assay was employed to detect point somatic mutations in STAT3 and STAT5b genes in each group.Results Mutations of the STAT3 gene were detected in none of the 24 cases of FS and in 22 of 56 cases of RA-associated T-LGLL (39%) (p < 0.001). No mutation of the STAT5b gene was detected in any of the patients in each group.Conclusions Although further data are needed, our results suggest that activating somatic mutations in STAT3 and STAT5b genes are not involved in the pathogenesis of FS.

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Latest Advances in the Diagnosis and Treatment of Large Granular Lymphocytic Leukemia

Cited by 80 publications

References 62 publications

Insights Into Genetic Landscape of Large Granular Lymphocyte Leukemia

Insights Into Genetic Landscape of Large Granular Lymphocyte Leukemia

Clonal T‐cell large granular lymphocyte proliferations in childhood and young adult immune dysregulation conditions

Comparison of somatic STAT3 and STAT5b gene mutations between Felty's syndrome and T-cell large granular lymphocytic leukemia with rheumatoid arthritis

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