Advances in the Diagnosis and Treatment of Large Granular Lymphocytic Leukemia

Cheon, HeeJin; Dziewulska, Karolina; Moosic, Katharine B.; Olson, Kristine C.; Gru, Alejandro A.; Feith, David J.

doi:10.1007/s11899-020-00565-6

Cited by 48 publications

(59 citation statements)

References 67 publications

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“…Historically, a definitive diagnosis of LGLL can be made if the LGL count is persistently greater than 2 × 10 9 /L in peripheral blood for more than 6 months [16,17]. However, T-LGLL can currently be diagnosed if the LGL count exceeds 0.4 or 0.5 × 10 9 /L, provided that a clonal T-cell population is found with an appropriate clinical context (cytopenia and/or an autoimmune disease) [18][19][20]. Bone marrow involvement is present in at least 75% of T-LGLL cases, though it is often subtle and difficult to detect morphologically.…”

Section: Introductionmentioning

confidence: 99%

Analysis of a single-institution cohort of patients with Felty's syndrome and T-cell large granular lymphocytic leukemia in the setting of rheumatoid arthritis

et al. 2020

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T-cell large granular lymphocytic leukemia (T-LGLL) is a lymphoproliferative disorder characterized by a persistent increase in the number of large granular lymphocytes (LGLs), neutropenia, and splenomegaly. Clinical manifestations of T-LGLL in the setting of rheumatoid arthritis (RA) are often identical to those in which one would suspect Felty's syndrome (FS). These disorders are distinguished by the presence of T-cell clonality, which is present in T-LGLL but not in FS. Mutations in the signal transducer and activator of transcription 3 (STAT3) and 5b (STAT5b) genes can be used as molecular markers of T-LGLL, but their prevalence in FS is unknown.Eighty-one patients with RA and unexplained neutropenia or/and an increase in the number of LGLs above 2 × 109/L were stratified into RA-associated T-LGLL (N = 56) or FS (N = 25) groups based on the presence or absence of T-cell clonality. STAT3 and STAT5b gene mutations were assessed in each group by means of allele-specific polymerase chain reaction assays. Clinical, immunological, laboratory data and the results of immunophenotyping of blood and bone marrow lymphocytes were also evaluated.Mutations of the STAT3 gene and an increase in the number of LGLs above 2 × 109/L were detected in RA-associated T-LGLL, but not in FS (39% vs 0% and 21% vs 0%, respectively). Mutations in the STAT5b gene were not observed in either group. Expression of CD57, CD16, and CD5−/dim on CD3+CD8+ T-lymphocytes was observed in both RA-associated T-LGLL and FS.STAT3 gene mutations or LGL counts over 2 × 109/L in RA patients are indicative of T-LGLL.

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Section: Introductionmentioning

confidence: 99%

Analysis of a single-institution cohort of patients with Felty's syndrome and T-cell large granular lymphocytic leukemia in the setting of rheumatoid arthritis

et al. 2020

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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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“…A peculiar feature of T-LGL leukemia is its association with RA, which occurs in 17-28% of patients with T-LGL leukemia [32,33]. Historically, a definitive diagnosis of T-LGL leukemia required the increase in the number of LGLs in peripheral blood greater than 2 × 10 9 /L, but it is now recognized that a lower count (range, 0.4-2 × 10 9 /L) may be compatible with the diagnosis [34][35][36].…”

Section: Diagnosis and Differential Diagnosismentioning

confidence: 99%

Felty’s Syndrome

Gorodetskiy¹

2021

Rare Diseases - Diagnostic and Therapeutic Odyssey

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Felty’s syndrome (FS) is an uncommon subset of seropositive rheumatoid arthritis (RA) complicated by neutropenia with or without splenomegaly. The pathogenesis of neutropenia in FS is still not fully understood, but it is believed that the principal cause is neutrophil survival defect. Autoantibodies against peptidylarginine deiminase type 4 deiminated histones, glucose-6-phosphate isomerase, and eukaryotic elongation factor 1A-1 antigen may contribute to neutropenia development in FS patients. Splenic histology in FS shows non-specific findings and spleen size do not correlate with neutropenia. Cases of T-cell large granular lymphocytic leukemia with low tumor burden in blood and concomitant RA are clinically indistinguishable from FS and present a diagnostic challenge. Examination of T-cell clonality, mutations in signal transducer and activator of transcription 3 gene, and the number of large granular lymphocytes in the blood can establish a correct diagnosis. Optimal approaches to therapy for FS have not been developed, but the use of rituximab seems promising. In this chapter, the epidemiology, pathogenesis, clinical manifestations, differential diagnosis, and treatment options for FS are discussed.

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Advances in the Diagnosis and Treatment of Large Granular Lymphocytic Leukemia

Cited by 48 publications

References 67 publications

Analysis of a single-institution cohort of patients with Felty's syndrome and T-cell large granular lymphocytic leukemia in the setting of rheumatoid arthritis

Analysis of a single-institution cohort of patients with Felty's syndrome and T-cell large granular lymphocytic leukemia in the setting of rheumatoid arthritis

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

Felty’s Syndrome

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