scholarly journals Felty’s Syndrome

2021 ◽  
Author(s):  
Vadim Gorodetskiy
Keyword(s):  
T Cell ◽  
Treatment Options ◽  
Correct Diagnosis ◽  
Clinical Manifestations ◽  
Elongation Factor ◽  
Tumor Burden ◽  
Lymphocytic Leukemia ◽  
Diagnostic Challenge ◽  
Felty's Syndrome ◽  
Felty’S Syndrome

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.

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

2020 ◽  
Author(s):  
Vadim R. Gorodetskiy ◽  
Yulia V. Sidorova ◽  
Natalia A. Kupryshina ◽  
Vladimir I. Vasilyev ◽  
Natalya A. Probatova ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cell ◽  
Somatic Mutations ◽  
Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Felty's Syndrome ◽  
Large Granular Lymphocytic Leukemia ◽  
Felty’S Syndrome ◽  
T Cell Clonality ◽  
Cell Clonality

Abstract 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.

scholarly journals 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

2020 ◽  
Author(s):  
Vadim Romanovich Gorodetskiy ◽  
Yulia Vladimirovna Sidorova ◽  
Natalia Alexandrovna Kupryshina ◽  
Vladimir Ivanovich Vasilyev ◽  
Natalya Alexandrovna Probatova ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cell ◽  
Laboratory Data ◽  
Gene Mutations ◽  
Lymphocytic Leukemia ◽  
Felty's Syndrome ◽  
Large Granular Lymphocytic Leukemia ◽  
Felty’S Syndrome ◽  
T Cell Clonality ◽  
Cell Clonality

AbstractT-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.

Unusual T cell proliferations and neutropenia in rheumatoid arthritis: comparison with classical Felty's syndrome

2009 ◽  
Vol 33 (4) ◽  
pp. 342-350 ◽  
Author(s):  
David C. Linch ◽  
Adrian C. Newland ◽  
Alan L. Tumbull ◽  
Lesley J. Knott ◽  
Alan MacWhannel ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cell ◽  
Felty's Syndrome ◽  
Felty’S Syndrome ◽  
Cell Proliferations

Preclinical Analyses Support Clinical Investigation of Combined Anti-CD19 CAR-T Cell, JCAR017 with Ibrutinib for the Treatment of Chronic Lymphocytic Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3231-3231 ◽  
Author(s):  
Jim Qin ◽  
Alex Baturevych ◽  
Sherri Mudri ◽  
Ruth Salmon ◽  
Michael Ports
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
Tumor Burden ◽  
Lymphocytic Leukemia ◽  
Initial Growth ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T

Abstract Chronic lymphocytic leukemia (CLL) drives systemic immune suppression and T cell dysfunction in patients, highlighting an important consideration in this setting for the manufacturing and efficacy of adoptive cell therapies using autologous T cells. In clinical studies, anti-CD19 CAR-T cells produce durable and complete responses in leukemic and some lymphomatous B cell malignancies. While preconditioning with cyclophosphamide (Cy) and fludarabine (Flu) has improved CAR-T responses in CLL patients, reported complete response rates still have been below 50%; additional therapeutic strategies likely will be required. Ibrutinib, an irreversible inhibitor of BTK, has been approved as a frontline treatment option for patients with CLL. The potent off-BTK activity of ibrutinib on ITK and TEC family kinases could affect CAR T cell biology. Recent work highlighted the ability of ibrutinib to restore CLL patient T cell functionality, enhance CAR-T production and potentially improve clinical efficacy. Additional preclinical work demonstrated improved tumor clearance when anti-CD19 CAR T cells were combined with ibrutinib in several murine tumor models. A preclinical evaluation of the combination between the anti-CD19 CAR-T product, JCAR017, and ibrutinib was performed to determine feasibility for clinical use in CLL. JCAR017 is a second generation CAR-T cell product candidate that contains a 41BB costimulatory endo-domain and is currently in phase 1 trials for non-Hodgkin lymphoma (NHL). A series of in vitro studies assessed the functional activity of JCAR017 cells (derived from 3 healthy donors), in combination with ibrutinib (500-0.05nM), across a dose range covering the cMax and cMin. Cytolytic activity was monitored by co-culturing CAR-T cells with ibrutinib-resistant K562 CD19 tumor cells at an effector-to-target ratio of 2.5:1. Ibrutinib, at concentrations tested, did not inhibit the cytolytic function of JCAR017 cells. For cells derived from some donors, addition of ibrutinib appeared to increase % target killing. To address ibrutinib effects on JCAR017 activation, cell surface markers and cytokines were tracked over 4 days following stimulation with irradiated K562 CD19 cells. We observed no significant effect on JCAR017 surface expression of CD25, CD38, CD39, CD95, CD62L, CCR7, or CD45RO, or of EGFRt, a surrogate transduction marker. With addition of ibrutinib, we observed a modest decrease in the percentage of cells expressing CD69, CD107a and PD-1. With 5 and 50nM of ibrutinib, there was a 19.5% (p<0.01) average increase in IFNγ production. At supraphysiological concentrations (500nM) we observed a 20% (p<0.05) decrease in IL-2 production, suggesting ibrutinib at high concentrations may dampen T cell activation. CAR-T cell expansion after repeated antigen stimulation has been shown to be a predictor of in vivo efficacy. JCAR017 cells stimulated every 3-4 days with irradiated target cells in the presence of ibrutinib showed no inhibition of initial growth. However, after 5 rounds of stimulation, JCAR017 + ibrutinib cells from 1 donor had enhanced proliferation compared to control, untreated cells (p<0.05). Interestingly, after 5 rounds of serial stimulation, we observed an increased proportion of CD4+CXCR3+CRTh2- Th1 cells with 500nM ibrutinib treatment compared to control (p<0.01). We assessed the in vivo anti-tumor activity of JCAR017 in combination with ibrutinib using NSG mice injected with 5x105 Nalm6-luciferase cells. After tumor engraftment, a suboptimal dose (5x105) of JCAR017 cells was transferred to mice and ibrutinib (25 mg/kg qd) was administered for the duration of the study. Ibrutinib treatment alone had no effect on tumor burden compared to vehicle treatment. Mice treated with a suboptimal JCAR017 dose + ibrutinib showed decreased tumor burden (p<0.05) and increased median survival from 44 days to >80 days (p<0.001) compared to the group receiving the suboptimal JCAR017 dose + vehicle. Similar effects were seen in replicate studies using JCAR017 cells produced from multiple donors. Ex vivo evaluation for CAR-T quantitation and immunophenotyping was also performed. Taken together, the results suggest that ibrutinib enhances intrinsic JCAR017 activity and may improve outcomes in CLL patients treated with anti-CD19 CAR T therapy, irrespective of BTK mutational status. A Phase 1b study of JCAR017 in combination with ibrutinib for BTKi R/R CLL is planned. Disclosures Qin: Juno Therapeutics: Employment. Baturevych:Juno Therapeutics: Employment. Mudri:Juno Therapeutics: Employment, Equity Ownership. Salmon:Juno Therapeutics: Employment. Ports:Juno Therapeutics: Employment.

scholarly journals Large Granular Lymphocytic Leukemia: A Report of Response to Rituximab

2017 ◽  
Vol 2017 ◽  
pp. 1-3
Author(s):  
Uroosa Ibrahim ◽  
Sara Parylo ◽  
Shiksha Kedia ◽  
Shafinaz Hussein ◽  
Jean Paul Atallah
Keyword(s):  
T Cell ◽  
Cytotoxic T Cells ◽  
Treatment Options ◽  
Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Peripheral Blood Flow ◽  
Low Grade ◽  
Morphological Examination ◽  
Purine Analogues ◽  
First Line Therapy

Large granular lymphocytic (LGL) leukemia is a rare form of low grade leukemia characterized by large cytotoxic T cells or natural killer cells on morphological examination. Immunosuppressive therapy is employed as first-line therapy. Treatment options in refractory cases include the anti-CD52 antibody alemtuzumab and purine analogues. We report a rare case that responded to the anti-CD20 monoclonal antibody rituximab. A 77-year-old female presented with complaints of fatigue, fever, and chills of 3 months’ duration. A CBC showed that pancytopenia with an absolute neutrophil count (ANC) was 0. Peripheral blood flow cytometry detected increased number of T cell large granular lymphocytes and T cell receptor rearrangement study detected a clonal T cell population. Bone marrow biopsy showed peripheral T cell lymphoma, most consistent with T-large granulocytic leukemia. The patient was treated with prednisone and oral cyclophosphamide for four months with no response. Thereafter, she received four weekly infusions of rituximab with improvement in her blood counts. A response to rituximab in refractory cases such as ours has been reported and may guide us towards exploring other immune-based therapeutics in this rare disease.

scholarly journals Agranulocytosis in Felty’s syndrome: a case from clinical practice

2018 ◽  
Vol 99 (5) ◽  
pp. 833-835
Author(s):  
A A Tulichev ◽  
E O Efremova
Keyword(s):  
Rheumatic Diseases ◽  
Successful Treatment ◽  
Clinical Presentation ◽  
Clinical Laboratory ◽  
Correct Diagnosis ◽  
Diagnostic Methods ◽  
Felty's Syndrome ◽  
Treatment And Prevention ◽  
Felty’S Syndrome ◽  
Hematological Manifestations

Differential diagnosis of articular syndrome is one of the leading issues of primary medical sanitary care. Timely and correct diagnosis of rheumatic diseases made by an internist in an out-patient setting is a cornerstone of successful treatment and prevention of possible complications. The masks of clinical course, subtle symptoms, as well as pathomorphosis of the disease make the accurate diagnosis difficult to establish. Among rheumatic diseases more and more often isolated hematological manifestations are observed on the onset of the disease. Among them the leading place is taken by Felty’s syndrome. Being a form of seropositive rheumatoid arthritis, it is often associated with cytopenia. The aim of the article is to draw attention to the problem of timely diagnosis of Felty’s syndrome. The presented clinical case of Felty’s syndrome with agranulocytosis was based on clinical, laboratory, instrumental data obtained on examination of a patient. The features of the course, diagnostic methods and treatment methods of the pathology are discussed. The treatment efficacy of corticosteroids and cytostatics, similarities in clinical presentation and course of the syndrome with lymphoproliferative diseases and liver cirrhosis are presented. According to the obtained data a conclusion was made about the need for early diagnosis and complex examination in case of Felty’s syndrome for successful treatment of the nosology.

scholarly journals Restoration of the immune function as a complementary strategy to treat Chronic Lymphocytic Leukemia effectively

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Carol Moreno ◽  
Cecilia Muñoz ◽  
María José Terol ◽  
José-Ángel Hernández-Rivas ◽  
Miguel Villanueva
Keyword(s):  
Immune System ◽  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
Immune Function ◽  
Treatment Options ◽  
Tumor Burden ◽  
Lymphocytic Leukemia ◽  
Secondary Neoplasms ◽  
Cell Therapies ◽  
Clinical Consequences

AbstractChronic Lymphocytic Leukemia (CLL) is a hematological malignancy characterized by uncontrolled proliferation of B-cells and severe immune dysfunction. Chemo(immuno)therapies (CIT) have traditionally aimed to reduce tumor burden without fully understanding their effects on the immune system. As a consequence, CIT are usually associated with higher risk of infections, secondary neoplasms and autoimmune disorders. A better understanding of the biology of the disease has led to the development of therapeutic strategies which not only act against malignant B-cells but also reactivate and enhance the patient’s own anti-tumor immune response. Here, we review the current understanding of the underlying interplay between the malignant cells and non-malignant immune cells that may promote tumor survival and proliferation. In addition, we review the available evidence on how different treatment options for CLL including CIT regimens, small molecular inhibitors (i.e, BTK inhibitors, PI3K inhibitors, BCL-2 inhibitors) and T-cell therapies, affect the immune system and their clinical consequences. Finally, we propose that a dual therapeutic approach, acting directly against malignant B-cells and restoring the immune function is clinically relevant and should be considered when developing future strategies to treat patients with CLL.

Jump-starting the T cells in CLL

Blood ◽  
2013 ◽  
Vol 121 (20) ◽  
pp. 4016-4017 ◽  
Author(s):  
James B. Johnston
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
Tumor Burden ◽  
Lymphocytic Leukemia ◽  
Immune Synapse

In this issue of Blood, Shanafelt and colleagues demonstrate that T-cell immune synapse function can be increased in chronic lymphocytic leukemia (CLL), both by reducing tumor burden with immunochemotherapy and by lenalidomide.1

scholarly journals Performance of anti-CD19 chimeric antigen receptor T cells in genetically defined classes of chronic lymphocytic leukemia

2020 ◽  
Vol 8 (1) ◽  
pp. e000471 ◽  
Author(s):  
Veronika Mancikova ◽  
Helena Peschelova ◽  
Veronika Kozlova ◽  
Aneta Ledererova ◽  
Adriana Ladungova ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
Tumor Burden ◽  
Lymphocytic Leukemia ◽  
Car T Cells ◽  
Cell Engraftment ◽  
Car T

BackgroundWhile achieving prolonged remissions in other B cell-derived malignancies, chimeric antigen receptor (CAR) T cells still underperform when injected into patients with chronic lymphocytic leukemia (CLL). We studied the influence of genetics on CLL response to anti-CD19 CAR T-cell therapy.MethodsFirst, we studied 32 primary CLL samples composed of 26 immunoglobulin heavy-chain gene variable (IGHV)-unmutated (9ATM-mutated, 8TP53-mutated, and 9 without mutations inATM,TP53,NOTCH1orSF3B1) and 6IGHV-mutated samples without mutations in the above-mentioned genes. Then, we mimicked the leukemic microenvironment in the primary cells by ‘2S stimulation’ through interleukin-2 and nuclear factor kappa B. Finally, CRISPR/Cas9-generatedATM-knockout andTP53-knockout clones (four and seven, respectively) from CLL-derived cell lines MEC1 and HG3 were used. All these samples were exposed to CAR T cells. In vivo survival study in NSG mice using HG3 wild-type (WT),ATM-knockout orTP53-knockout cells was also performed.ResultsPrimary unstimulated CLL cells were specifically eliminated after >24 hours of coculture with CAR T cells. ‘2S’ stimulated cells showed increased survival when exposed to CAR T cells compared with unstimulated ones, confirming the positive effect of this stimulation on CLL cells’ in vitro fitness. After 96 hours of coculture, there was no difference in survival among the genetic classes. Finally, CAR T cells were specifically activated in vitro in the presence of target knockout cell lines as shown by the production of interferon-γ when compared with control (CTRL) T cells (p=0.0020), but there was no difference in knockout cells’ survival. In vivo, CAR T cells prolonged the survival of mice injected with WT,TP53-knockout andATM-knockout HG3 tumor cells as compared with CTRL T cells (p=0.0485, 0.0204 and <0.0001, respectively). When compared withATM-knockout,TP53-knockout disease was associated with an earlier time of onset (p<0.0001), higher tumor burden (p=0.0002) and inefficient T-cell engraftment (p=0.0012).ConclusionsWhile in vitro no differences in survival of CLL cells of various genetic backgrounds were observed, CAR T cells showed a different effectiveness at eradicating tumor cells in vivo depending on the driver mutation. Early disease onset, high-tumor burden and inefficient T-cell engraftment, associated withTP53-knockout tumors in our experimental setting, ultimately led to inferior performance of CAR T cells.

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