T-Cell Large Granular Lymphocytic Leukemia with Atypical Immunophenotypes: A Single Center Retrospective Analysis of 17 Cases

2021 ◽  
Author(s):  
Jing-jing Guo ◽  
Lei Cao ◽  
Hua-yuan Zhu ◽  
Yi Miao ◽  
Xin-yi Du ◽  
...  
Keyword(s):  
T Cell ◽  
Cytotoxic T Cells ◽  
Cell Receptor ◽  
Pure Red Cell Aplasia ◽  
Lymphocytic Leukemia ◽  
Small Subset ◽  
Large Granular Lymphocytic Leukemia ◽  
Cytotoxic Molecules ◽  
Similar Survival ◽  
Stat3 Mutations

Abstract Purpose T-cell large granular lymphocytic leukemia (T-LGLL) is characterized by expansion of cytotoxic T cells expressing αβ T cell receptor (TCR), CD2, surface CD3, CD8, CD57 as well as cytotoxic molecules. Atypical immunophenotypes of T-LGLL, including γδ TCR and CD4, reported in a small subset, remains to be well-defined. Methods We retrospectively analyzed immunophotypes and clinicopathologic features of 96 T-LGLL cases. Results We found a total of 17 cases with atypical immunophenotypes including 9 TCRγδ + cases and 8 CD4+ TCRαβ + cases. Pure red cell aplasia was less common in atypical immunophenotypes patients compared to that of typical immunophenotypes [0/17 (0%) vs. 26/79 (32.9%), p=0.005]. STAT3 mutations were also less frequent in atypical immunophenotypes cases, although accompanied with marginal significance (p=0.086). Conclusion Patients with atypical immunophenotypes showed a similar survival outcome to that of typical T-LGLL immunophenotypes. Additional efforts were needed to better understand the pathogenesis of these rare atypical immunophenotypes T-LGLL cases.

scholarly journals T-Cell Large Granular Lymphocytic Leukemia with Extremely Rare Immunophenotype (CD4/CD8 Double-Positive) Followed by Multiple Myeloma Diagnosis

2020 ◽  
Vol 2020 ◽  
pp. 1-7
Author(s):  
Dina Soliman ◽  
Sherin Sallam ◽  
Susanna Akiki ◽  
Deena Mudawi ◽  
Feryal Ibrahim
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
T Cell ◽  
Viral Infections ◽  
Cytotoxic T Cells ◽  
Flow Cytometric Analysis ◽  
Lymphocytic Leukemia ◽  
Double Positive ◽  
Large Granular Lymphocytic Leukemia ◽  
First Case

T-cell large granular lymphocytic leukemia is characterized by clonal expansion of a CD3+/CD57+ subpopulation, which are typically CD8+ positive cytotoxic T- cells, and can only be diagnosed if there is a persistent, greater than 6 months, elevation of LGL in the blood (usually 2–20 × 109/L), in the absence of an identifiable cause. T-LGLL has been associated with reactive conditions such as autoimmune diseases and viral infections and has also been reported in association with hematologic and non-hematologic malignancies. We report a case of asymptomatic CD4/CD8 double-positive T-LGLL. Flow cytometry on peripheral blood revealed a subpopulation of CD4/CD8 double-positive T cells expressing CD57 and cTIA. Clonality was established by flow cytometric analysis of T-cell receptor V(â) region repertoire which showed that >70% of the cells failed to express any of the tested V(â) regions. Clonality was further confirmed by PCR with the detection of clonal TCR beta and TCR gamma gene rearrangements. Six months later, she presented with persistent lower back pain and diagnosed with IgG kappa multiple myeloma. CD4/CD8 double-positive T-large granular leukemia is the first case reported in the literature. This rare phenotype is either underreported or a truly rare clinical entity. More studies are warranted to characterize the pathogenesis and clinical characteristics of this group of patients and to further assess the relationship between multiple myeloma and T-LGLL as a cause-and-effect relationship or simply related to the time at which diagnosis has been made.

scholarly journals T-cell Large Granular Lymphocytic Leukemia Manifesting in Patients with HIV-1 Infection: Cases Series and Review of the Literature

2018 ◽  
Vol 10 (1) ◽  
pp. e2018036
Author(s):  
Ashley M Rose ◽  
Leidy Isenalumhe ◽  
Magali VanDenBergh ◽  
Lubomir Sokol
Keyword(s):  
T Cell ◽  
B Cell ◽  
B Cell Lymphoma ◽  
Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Large Granular Lymphocytic Leukemia ◽  
Initiation Of Therapy ◽  
Criteria For Diagnosis ◽  
Immunodeficiency Syndrome ◽  
Hiv 1

We report five patients with human immunodeficiency virus-1/acquired immunodeficiency syndrome (HIV-1/AIDS) who developed T-cell large granular lymphocytic leukemia (T-LGLL). None of the patients fulfilled criteria for diagnosis of diffuse infiltrative lymphocyte syndrome (DILS) or HIV-associated CD8+ lymphocytosis syndrome at the time of diagnosis of LGLL. The immunophenotype of malignant T-cells was identical in three patients with co-expression of CD3, CD8, CD57, and T-cell receptor (TCR) alpha/beta. Three out of five patients were also diagnosed with clonal disorders of B-cell origin including diffuse large B-cell lymphoma, Burkitt’s lymphoma, and monoclonal gammopathy of undetermined significance (MGUS).  Two patients developed cytopenias due to T-LGLL prompting initiation of therapy. Our study suggests that chronic viral infection with HIV can contribute to evolution of T-LGLL. Clinical and laboratory characteristics of T-LGLL associated with HIV-1/AIDS resemble those of immunocompetent  patients.

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 Treatment for CD57-negative γδ T-cell large granular lymphocytic leukemia with pure red cell aplasia: A case report

2021 ◽  
Vol 9 (26) ◽  
pp. 7818-7824
Author(s):  
Ping-Ping Xiao ◽  
Xu-Yan Chen ◽  
Zhi-Gao Dong ◽  
Jin-Mei Huang ◽  
Qing-Qing Wang ◽  
...  
Keyword(s):  
Case Report ◽  
T Cell ◽  
Pure Red Cell Aplasia ◽  
Lymphocytic Leukemia ◽  
Red Cell ◽  
Γδ T Cell ◽  
Red Cell Aplasia ◽  
Large Granular Lymphocytic Leukemia

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.

T-cell large granular lymphocytic leukemia evolution post-transplant: The Cleveland Clinic experience.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e19072-e19072
Author(s):  
Hassan Awada ◽  
Jibran Durrani ◽  
Fahrettin Covut ◽  
Bicky Thapa ◽  
Reda Z. Mahfouz ◽  
...  
Keyword(s):  
T Cell ◽  
Viral Genome ◽  
Cleveland Clinic ◽  
Lymphocytic Leukemia ◽  
Solid Organ ◽  
Post Transplantation ◽  
Post Transplant ◽  
Large Granular Lymphocytic Leukemia ◽  
Stat3 Mutations

e19072 Background: T-cell large granular lymphocytic leukemia (LGLL) has been reported after solid organ transplantation (SOT) and hematopoietic stem cell transplantation (HSCT); yet its underlying pathophysiological evolution has been poorly explained. Methods: We retrospectively screened a cohort of 243 LGLL patients at Cleveland Clinic for disease development post-transplantation and postulated several possible responsible pathophysiological mechanisms. Results: Five percent (n = 12) of the patients had a history of transplant. Of these, 67% (n = 8) had SOT (kidney, liver or heart) while 33% (n = 4) had HSCT. Twenty-five percent were females while 75% were males. The median age was 56 years (range: 15-65). The median time from transplant to diagnosis was 7 years. Conventional cytogenetic showed normal karyotype in 89% of the patients. TCR gene re-arrangement by PCR was detected in all tested individuals. Targeted deep sequencing identified somatic STAT3 mutations in 17% (n = 2) of the cases. Fifty percent (n = 6) had EBV DNA, IgM and/or IgG post-transplant. Forty-two percent (n = 5) had CMV DNA, IgM and/or IgG; of which 80% (n = 4) were post-transplant and 20% (n = 1) pre-transplant. The median survival from disease diagnosis was 64.3 months (8.37-232.9). Indeed, T-LGL clonal expansion resulted from long-term stimulation by viral antigens including EBV and CMV causing continuous cytotoxic T cell immune response or by “oncomodulation” as explained in 83% of patients. The latter theory suggests that CMV infects tumor cells and modulates their malignant properties, without direct transformation. Immunosuppression in setting of pre-transplant exposure to CMV, caused reactivation of the latent oncogenic viral genome as seen in 8% of patients. In 17% of cases that were seronegative for viral genome, graft allo-antigenic stimulation has triggered long-term recipient LGLL expansion from antigenic mismatch. Somatic STAT3 mutations, which are highly expressed in leukemic LGL, has led to aberrant signaling and transformation (17%). Conclusions: Our study highlights the complex nature of LGLL evolution post SOT and HSCT and points out confounding mechanisms. Certainly, investigating pre- vs. post-transplantation baseline, clinical and molecular characteristics is warranted to deeply understand this phenomenon.

The clinical significance of STAT3 mutation, LDH and β2-MG in T-cell large granular lymphocytic Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3483-3483 ◽  
Author(s):  
Zhi-Yuan Qiu ◽  
Lei Fan ◽  
Li Wang ◽  
Chun Qiao ◽  
Yu-Jie Wu ◽  
...  
Keyword(s):  
T Cell ◽  
Conflicts Of Interest ◽  
Univariate Analysis ◽  
Flow Cytometric Analysis ◽  
Lymphocytic Leukemia ◽  
Mutation Status ◽  
Large Granular Lymphocytic Leukemia ◽  
Significant Difference ◽  
Stat3 Mutation ◽  
Stat3 Mutations

Abstract Background T-cell large granular lymphocytic leukemia (T-LGLL) is a rare lymphoproliferative disorder of cytotoxic T cells (CTLs) and often associated with autoimmune disorders. The signal transducer and activator of transcription 3 (STAT3) is an oncogene, and its activation plays a key role in cell signaling transduction pathways in many types of cancer. The aim of the current study was to analyze the characteristics of T-LGLL. Methods We did this by determining the mutation status of STAT3 in 28 patients presenting with T-LGLL and evaluating STAT3 status in association with serum level of lacticdehydrogenase (LDH) and β2-microglobulin (β2-MG). Flow cytometric analysis for immunophenotype and TCR variable β-chain (Vβ) was performed in the patients. Results FC-Vβ analysis was performed in 26 patients, and 22 (84.6%) patients had a restricted Vβ reactivity pattern, with predominance of a single Vβ mAb reactivity. There was no significant difference between serum LDH levels, gender, age or symptoms at diagnosis (P=0.062), lymphocytosis, anemia (P=0.057), thrombocytopenia, splenomegaly, LGL count or STAT3 mutation status. However, high β2-MG levels (P=0.005), neutropenia (P=0.018) and pure red blood cell aplasia (PRCA) (P=0.001) all displayed a significant association with STAT3 mutations. In univariate analysis, treatment-free survival (TFS) was affected by STAT3 mutation status (P=0.008) and β2-MG (P=0.006). In multivariate analysis, only anemia (P<0.001) was found to be an independent risk factor of shorter TFS. Conclusions We found an incidence of STAT3 mutations of 21.4% in patients presenting with T-LGLL and two mutations, E616V and V671F, had not been previously reported. Our results further demonstrate the remarkable correlation of STAT3 mutation with anemia, neutropenia and β2-MG. β2-MG and LDH is commonly used laboratory indicators, and detecting of them is helpful in estimating clinical characteristics and guiding treatment. We conclude from our data that FC-Vβ analysis is a fast and relatively economical alternative approach that can be used as a powerful tool in screening patients with suspected T-LGLL. Our study not only confirmed some of the previously reported observations, but it also provided new information on clinical associations, laboratory findings, prognostic factors, therapy and outcome in these patients. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Clinicobiological Characteristics and Outcomes of Patients with T-Cell Large Granular Lymphocytic Leukemia and Chronic Lymphoproliferative Disorder of Natural Killer Cells from a Single Institution

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3900
Author(s):  
Andrea Rivero ◽  
Pablo Mozas ◽  
Laura Jiménez ◽  
Mónica López-Guerra ◽  
Dolors Colomer ◽  
...  
Keyword(s):  
T Cell ◽  
Nk Cells ◽  
Natural Killer ◽  
Solid Tumors ◽  
Lymphoproliferative Disorder ◽  
Lymphocytic Leukemia ◽  
Spanish Population ◽  
Large Granular Lymphocytic Leukemia ◽  
Mutational Status ◽  
Stat3 Mutations

T-cell large granular lymphocytic leukemia (T-LGLL) and chronic lymphoproliferative disorder of natural killer (NK) cells are two infrequent diseases characterized by clonal expansions of cytotoxic T lymphocytes and NK cells, respectively. Somatic mutations of STAT3 are involved in the pathogenesis of these entities. We describe the clinicobiological features, mutational status of STAT3/STAT5B, treatment and outcome of 131 patients. Neutropenia was the most frequent finding at diagnosis, followed by anemia. Concurrent hematological disorders were diagnosed in 37% of patients and autoimmune conditions and solid tumors in 17% and 15%, respectively. All patients who needed treatment belonged to the CD8+CD57+ group. Remarkably, patients included in the CD4+ group had a higher association with solid tumors (p = 0.037). STAT3 mutations were found in 17% of patients, mainly Y640F and D661Y mutations. Patients carrying STAT3 mutations more frequently presented with anemia, neutropenia, high LDH, high large granular lymphocyte counts and need for treatment (p = 0.0037). Methotrexate was the most frequently used agent (72% of cases). The overall response rate to all treatments was 50%. The 10-year overall survival of this series was 78%, with no differences according to the mutational status of STAT3. We compared the survival of these patients with the general Spanish population and no differences were found, confirming the indolent nature of these hematological malignancies. Our study further extends findings documented by others on the clinical behavior of the disease and the impact of STAT3, and for the first time analyzes survival compared to a matched general Spanish population.

scholarly journals A non-cytotoxic regimen of decitabine to treat refractory T-cell large granular lymphocytic leukemia

2021 ◽  
Author(s):  
Misam Zawit ◽  
CARMELO GURNARI ◽  
Simona Pagliuca ◽  
Hassan Awada ◽  
Jaroslaw Maciejewski ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Elderly Patients ◽  
Frail Elderly ◽  
Cytotoxic T Cells ◽  
Clonal Expansion ◽  
Lymphocytic Leukemia ◽  
Large Granular Lymphocytic Leukemia ◽  
Cytotoxic Therapies

T-cell large granular lymphocytic leukemia (T-LGL) is a chronic malignancy characterized by clonal expansion of cytotoxic T-cells possibly complicated by cytopenias of one or more myeloid lineages. By describing a multiply-refractory T-LGL case, this report highlights the importance of molecular-targeted and non-cytotoxic therapies in the context of frail elderly patients.

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