Clinical characteristics and treatment outcomes of Asian patients with T-cell large granular lymphocytic Leukemia: a single-center analysis of 67 cases.

Large granular lymphocytic (LGL) leukemia is a clonal lymphoproliferative disorder of LGLs derived from cytotoxic T lymphocytes or natural killer cells. However, the clinical features and treatment responses are still not fully understood because of the rarity of the disease. To describe and assess a cohort of patients with T-cell large granular lymphocytic leukemia (T-LGLL). Single-center, retrospective, observational study. We retrospectively collected the clinical data of patients diagnosed with T-LGLL at Seoul National University Hospital since 2006. We included 67 patients in this study. The median age at diagnosis was 60 years. Additionally, 37 patients (55%) were symptomatic, and 25 (37%) had splenomegaly; 54 patients (81%) required treatment. Cyclophosphamide (n = 35), methotrexate (n = 25), and cyclosporin A (n = 19) were used most frequently for treatment, and their overall response rates were similar: cyclophosphamide (77%), methotrexate (64%), and cyclosporin A (63%). Splenomegaly was associated with an increased response rate to first-line therapy and a decreased complete response rate. Thrombocytopenia was associated with decreased response rates to cyclophosphamide, methotrexate, cyclosporin A, and steroids. In contrast, a high LGL number (> 2000/µL) in the peripheral blood smear was associated with increased response rates to cyclophosphamide, methotrexate, cyclosporin A, and steroids. This study describes the clinical features and treatment outcomes of patients with T-LGLL, providing valuable information for clinical decision-making regarding T-LGLL treatment.

Prevalence of STAT3 mutations in patients with rheumatoid arthritis-associated T-cell large granular lymphocytic leukaemia and Felty syndrome.

OBJECTIVES: Neutropenia is a key presentation of Felty syndrome (FS) and rheumatoid arthritis (RA)-associated T-cell large granular lymphocytic (T-LGL) leukaemia. Clonal rearrangement of T-cell receptor (TCR) gene supports the diagnosis of T-LGL leukaemia but not FS. Mutations in the signal transducer and activator of transcription 3 (STAT3) gene are highly specific for T-LGL leukaemia, but their prevalence in FS remains poorly clarified. METHODS: The study included 100 patients with RA and unexplained neutropenia. TCR rearrangements were examined in blood (100 cases), bone marrow (47 cases), and spleen (12 cases) using the BIOMED-2 protocol. Patients were stratified into RA-associated T-LGL leukaemia cohort if a clonal TCR rearrangement was identified in any of the tested patient samples, and into FS cohort in other cases. Mutations in the STAT3 were examined using next-generation sequencing (NGS) technology in blood (100 cases), bone marrow (37 cases), and spleen (7 cases). RESULTS: STAT3 mutations were identified in 71% (49/69) patients with RA-associated T-LGL leukaemia and in 10% (3/31) patients with FS (p=4.7×10-8). Three samples from the RA-associated T-LGL leukaemia cohort and 5 samples from the FS cohort had STAT3 mutations in the absence of clonal TCR rearrangement. CONCLUSIONS: The results suggest that STAT3 mutations are significantly less common in FS than in RA-associated T-LGL leukaemia. Moreover, NGS can detect clones undetectable by fragment analysis. We speculate that in patients with RA and neutropenia, the detection of STAT3 mutations can point to T-LGL leukaemia even in the absence of clonal TCR rearrangement.

Clinical characteristics and outcomes of 100 adult patients with pure red cell aplasia.

Adult pure red cell aplasia (PRCA) is a rare syndrome characterized by a severe normocytic anemia, reticulocytopenia, and absence of erythroblasts from bone marrow. The standard treatment has not yet been established for PRCA, although cyclosporine (CsA), corticosteroids (CS) showed a response in PRCA. We retrospectively analyzed the clinical data of 60 primary and 40 secondary adult patients with acquired PRCA. The proportion of secondary PRCA is relatively high and commonly associated with large granular lymphocyte leukemia (LGLL) (28 cases, 70.0%). The remission-induced regimens included CS, CsA, or other agents, and the response rate was 66.7%, 71.4%, and 50%, respectively (P = 0.336). When treating with CsA, the response rate of LGLL-associated PRCA was lower than primary PRCA (42.1% vs 85.7%, P = 0.001). Logistic regression analysis showed that ORR was inversely related to LGLL-associated PRCA. LGLL-associated PRCA had poor therapeutic efficacy to CsA.

[Investigation of large granular lymphocytic leukemias: data from the laboratory of hematology at Nancy University Hospital, France]. / Investigation des leucémies à grands lymphocytes à grains : expérience d'un laboratoire d'hématologie.

Large granular lymphocytic leukemia (LGLL) is a rare clonal lymphoproliferative disorder from T or NK origin. PURPOSE: to report on the diagnostic and therapeutic management of LGLL investigated in the university hospital at Nancy, France. METHODS: retrospective (7 years) collection of clinical and biological data and patients' cohort analysis. RESULTS: Eight out of fifteen patients presented with neutropenia, including five profound neutropenia (neutrophils < 500 × 109/L). Four patients had an infection. Two patients have rheumatoid arthritis and an associated Felty's syndrome, one a Sweet syndrome. Two also suffered from chronic Lymphocytic Leukemia, and one from a diffuse large B-cell lymphoma. Twelve patients had LGLL-T and 3 had a chronic LGLL-NK. Eleven out of twelve patients had a clonal LGLL-T when polymerase chain reaction assessed. No KIR clonality was sought among the 3 LGL-NK patients. Five patients out of fifteen received immunosuppressive treatment. CONCLUSION: Although using simple and robust investigations, our series demonstrates a high heterogeneity in LGLL detection and assessment.

Spectrum of lymphoma subtypes based on the latest World Health Organization classification in southern Iran from 2000 to 2011.

Background: Lymphoma, both Hodgkin and non-Hodgkin, is one of the most common malignancies, with a distinct subtype distribution throughout the world. Methods: A total of 453 lymphoma cases, identified retrospectively from January 2000 to October 2011, were studied to identify the subtype distribution of lymphoma in our center, located in southern Iran, according to the latest WHO classification. Results: The most common sites of involvement of all lymphomas were extranodal (59.16%). The highest frequency of extranodal sites in all lymphoid neoplasms were associated with diffuse large B-cell lymphoma (22.95%) and classical Hodgkin lymphoma (10.15%). Of 453 cases, 23 (5.32%) were T and natural killer cell neoplasms, of which the most common subtypes were T-cell large granular lymphocytic leukemia and anaplastic large cell lymphoma. Conclusion: This study indicated that the subtype distribution of lymphoma (except for the higher prevalence of diffuse large B-cell lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma and lower rate of follicular lymphoma) in this part of Iran is similar to that in the Middle Eastern countries. Mature B-cell neoplasms are less frequent compared with both western and far east Asian countries.

Large granular lymphocytic leukemia - A retrospective study of 319 cases.

Large granular lymphocytic leukemia (LGLL) is a rare hematological malignancy that arises from cytotoxic T lymphocytes (T-LGLL) in 85% of cases and natural killer (NK) cells in the rest. A significant knowledge gap exists regarding the pathogenesis, treatment choices, and prognostic factors of LGLL. We report a cohort of 319 consecutive LGLL patients who presented to our cancer center between 2001 and 2020. A total of 295 patients with T-LGLL and 24 with chronic NK-cell lymphoproliferative disorder (CLPD-NK) were identified. The median age was 65 years (range, 17-90 years). Eighty-three patients (26.0%) had autoimmune diseases. A total of 119 patients (37.3%) had coexisting malignancies, 66 (20.7%) had solid tumors, and 59 (18.5%) had hematological malignancies. Most coexisting malignancies were diagnosed before the diagnosis of LGLL. Treatment was needed for 57% of patients. Methotrexate (MTX), cyclophosphamide (Cy), and cyclosporine A (CSA) were most used and had similar response rates between 61.5%-74.4%. Cy produced more complete responses (32.3%) compared to MTX and CSA (15.7% and 23.1%, respectively). Thrombocytopenia, splenomegaly, and female gender (after controlling for autoimmune diseases) were associated with decreased response rates to MTX, CSA, or Cy. Autoimmune diseases were associated with increased response rates. Thrombocytopenia was an independent risk factor for worse survival.

Prevalence and Characteristics of Persistent Clonal T Cell Large Granular Lymphocyte Expansions in Rheumatoid Arthritis: A Comprehensive Analysis of 529 Patients.

OBJECTIVE: Up to one-third of patients with T cell large granular lymphocyte (T-LGL) leukemia display symptoms of rheumatoid arthritis (RA). In Crohn's disease and psoriasis, treatment with tumor necrosis factor (TNF) inhibitors is associated with hepatosplenic γδ T cell lymphoma and with clonal expansion of γδ T cells, respectively. This study was undertaken to determine the prevalence of clonal T-LGL cells in patients with RA and define risk factors for this rare hematologic malignancy. METHODS: A total of 529 RA patients were recruited between November 2013 and August 2015. Eight-color flow cytometry (fluorescence-activated cell sorting [FACS]) was performed to screen for aberrant T cell populations of LGLs. Molecular analysis of the T cell receptor was used to confirm the diagnosis in patients with suggestive FACS findings. Electronic patient files were used to determine risk factors. Patients with clonal populations were monitored prospectively for up to 4 years. RESULTS: The median patient age was 61 years, and 74% were female. The median duration of RA was 12 years. The median Disease Activity Score in 28 joints was 2.8, and 69.9% of patients had ever been treated with biologic disease-modifying antirheumatic drugs. We identified clonal T-LGL expansions in 19 patients, equaling a prevalence of 3.6%. The T-LGL cell clone was constant over time in most patients and was significantly associated with the duration of the exposure to TNF-blocking agents (P = 0.01). No other risk factors could be detected. CONCLUSION: RA patients with long-term exposure to TNF-blocking agents were at a greater risk of developing clonal expansions of LGLs. This finding may prompt clinicians to refrain from using these substances in RA patients with known T cell aberrations.

T-Cell Large Granular Lymphocytic Leukemia and Coexisting B-Cell Lymphomas: A Study From the Bone Marrow Pathology Group.

OBJECTIVE: T-cell large granular lymphocytic (T-LGL) leukemia is associated with B-cell lymphomas (BCLs), especially small BCLs. We aimed to explore and expand upon its association with BCLs. METHODS: We retrospectively studied clinicopathologic features of T-LGL leukemia patients with coexisting BCL from January 2001 to December 2016. RESULTS: Among 432 patients with T-LGL leukemia, 22 (5.1%) had an associated B-cell non-Hodgkin lymphoma. Thirteen (59%) patients had large and nine (41%) had small BCL. T-LGL leukemia occurred synchronously with BCL in five, preceded BCL in three, and followed BCL in 14 patients. Anemia was the most common cytopenia (68%). Only one patient had a history of rheumatoid arthritis. CONCLUSION: To our knowledge, this is the first multicenter study looking at the spectrum and incidence of BCLs in patients with T-LGL leukemia and highlights its association with large BCLs (3% of T-LGL leukemias).

Distinctive clinical characteristics and favorable outcomes in patients with large granular lymphocytosis after allo-HCT: 12-year follow-up data.

An increase in large granular lymphocytes (LGL) is frequently seen in patients following allogeneic hematopoietic cell transplantation (allo-HCT) and it has been associated with better outcomes in some reports. We assessed 826 consecutive patients at our institution with over 12 years of follow-up for the occurrence of LGL lymphocytosis after allo-HCT. The 3-year cumulative incidence of LGL lymphocytosis was 14.5% with a median duration of over 3.5 years. The development of LGL lymphocytosis was strongly correlated with CMV viremia and GVHD. The clinical course of patients with LGL lymphocytosis after allo-HCT was indolent, with the majority of these patients not displaying any clinical signs or symptoms related to the LGL proliferation. LGL lymphocytosis was associated with better outcomes, including higher overall survival (OS 86.6% vs 44.7% at 3 years), lower non-relapse mortality (NRM 5.5% vs 30.4% at 3 years), and lower risk of relapse (8.9% vs 22.9% at 3 years). A time-dependent multivariable analysis confirmed the favorable impact of LGL lymphocytosis on OS and NRM, but not on the risk of relapse. In multivariable analysis, a longer duration of LGL lymphocytosis was associated with better OS and NRM. Improved immunomodulatory properties of these cells, regulating GVHD and infections, may explain the observed favorable outcomes of patients who developed LGL lymphocytosis following allo-HCT.

A population-based study of large granular lymphocyte leukemia.

Large granular lymphocyte (LGL) leukemia is a lymphoproliferative disorder of cytotoxic cells. T-cell LGL (T-LGL) leukemia is characterized by accumulation of cytotoxic T cells in blood and infiltration of the bone marrow, liver or spleen. Population-based studies have not been reported in LGL leukemia. We present clinical characteristics, natural history and risk factors for poor survival in patients with LGL leukemia using the Surveillance, Epidemiology, and End Results Program (SEER) and the United States National Cancer Data Base (NCDB). LGL leukemia is an extremely rare disease with the incidence of 0.2 cases per 1 000 000 individuals. The median age at diagnosis was 66.5 years with females likely to be diagnosed at 3 years earlier compared with males. Analysis of patient-level data using NCDB (n=978) showed that 45% patients with T-LGL leukemia required some form of systemic treatment at the time of diagnosis. T-LGL leukemia patients have reduced survival compared with general population, with a median overall survival of 9 years. Multivariate analysis showed that age >60 years at the time of diagnosis and the presence of significant comorbidities were independent predictors of poor survival.

[Large granular lymphocyte leukemia: clinical and pathogenic aspects]. / Les leucémies à grands lymphocytes granuleux : de la clinique à la physiopathologie.

Large granular lymphocyte leukemia (LGL) is a hematologic disorder characterized by a monoclonal expansion of large lymphocytes containing azurophilic granules with a T CD3(+)CD57(+) or Natural Killer (NK) CD3(-)CD56(+) phenotype. The World Health Organization (WHO) classification identifies three entities: the T LGL, the chronic lymphoproliferative disorder of NK-cells, and the aggressive NK-cell leukemia. T LGL and chronic lymphoproliferative disorder of NK-cells are indolent diseases frequently associated with cytopenias and a wide spectrum of auto-immune manifestations. Neutropenia can lead to recurrent bacterial infections, which represent an indication of initiating a treatment in most of the cases. Immunosuppressive therapies are usually used in this context. In contrast, aggressive NK-cell leukemia follows a fulminant course with a poor prognosis because patients are refractory to most of the treatments. There is now a considerable interest in the pathophysiology of the disease with the perspective of new therapeutic options.

Bendamustine salvage therapy for T cell neoplasms.

Treatment of relapsed/refractory T cell neoplasms represents an unmet medical need. We recorded, retrospectively, data on 20 consecutive adult patients with T cell neoplasms (8 T cell lymphoma not otherwise specified (T-NOS), 4 angioimmunoblastic (AILT), 3 prolymphocytic leukemia (T-PLL), 3 advance-stage mycosis fungoides (MF) or Sézary syndrome (SS), and 2 T cell large granular lymphocytic leukemia (T-LGL)), treated with bendamustine. Partial (PR) and complete response (CR) rates were reached in nine (45 %) and two (10 %) patients, respectively, including three PR in T-NOS, one CR in AILT, three PR in T-PLL, two PR in MF/SS, and one CR and one PR in T-LGL lymphoma. The 6 months estimated progression free and overall survival was 44 and 67 %, respectively. Grade 3-4 neutropenia and thrombocytopenia were registered in 44 and 25 % of cases. Four patients developed major infectious complications. At a median follow-up of 6 months (range 1-18), 13 patients are alive and 7 patients died all because of lymphoma progression. Bendamustine deserves further investigation in patients with T cell neoplasms.

Analysis of a French cohort of patients with large granular lymphocyte leukemia: a report on 229 cases.

BACKGROUND: Large granular lymphocyte leukemia is a rare lymphoproliferative disorder associated with autoimmune diseases and impaired hematopoiesis. This study describes the clinical and biological characteristics of 229 patients with T-cell or NK-cell large granular lymphocyte leukemia. DESIGN AND METHODS: The diagnosis was based on a large granular lymphocyte expansion (> 0.5x10(9)/L) lasting more than 6 months. Monoclonal T-cell receptor gamma gene rearrangement was detected in all the cases of T-cell large granular lymphocyte leukemia. Patients with chronic NK-cell lymphocytosis had an indolent disease, while those with multiorgan large granular lymphocyte infiltration and an aggressive clinical disease were considered to have NK-cell large granular lymphocyte leukemia. RESULTS: The diagnosis of T-cell large granular lymphocyte leukemia was confirmed in 201 cases, chronic NK-cell lymphocytosis in 27 cases and NK-cell large granular lymphocyte leukemia in one case. Associated autoimmune diseases or other neoplasms were present in 74 and 32 cases, respectively. One hundred patients (44%) required treatment, mainly for neutropenia-associated infections (n=45), symptomatic autoimmune diseases (n =24), transfusion-dependant anemia (n=18), and other causes (n=13). Patients were treated with steroids (n= 33), methotrexate (n=62), cytoxan (n=32), or cyclosporine (n=24) either as first-, second-, third- or fourth-line therapy. The overall response rate at 3 months and complete response rate for the various treatments were as follows: steroids (12% and 3%), methotrexate (55% and 21%), cytoxan (66% and 47%), cyclosporine (21% and 4%), respectively. Four out of 13 patients responded to splenectomy. Eleven out of 15 patients responded to cytoxan after methotrexate treatment had failed. The mean number of treatments was 3.4 (range, 1-7). There were 15 large granular lymphocyte leukemia-related deaths. CONCLUSIONS: Patients with T-cell large granular lymphocyte leukemia and chronic NK-cell lymphocytosis have similar clinical and biological features and responses to treatment. First-line therapy with cytoxan should be tested in a prospective trial.

T-cell large granular lymphocyte leukemia: an Asian perspective.

To characterize T-cell large granular leukemia in Asia, 22 Chinese patients from a single institute were reported, together with an analysis of 88 Asian and 272 Western patients identified from the literature. In our cohort, anemia due to pure red cell aplasia (PRCA) occurred in 15/22 (68%) of cases, being the most common indication for treatment. Neutropenia was only found in 8/22 (36%) cases, and recurrent infections, the most important clinical problem in Western patients, were not observed. None of our cases presented with rheumatoid arthritis. These clinical features were consistently observed when compared with the 88 other Asian patients. Combined data from our cohort and other Asian cases showed that Asian patients, compared with Western patients, had more frequent anemia (66/110, 60% versus 113/240, 47%; p=0.044), attributable to a much higher incidence of PRCA (52/110, 47% versus 6/143, 4%; p<0.001). However, Western patients presented more frequently than Asian patients with neutropenia (146/235, 62% versus 33/110, 30%; p<0.001) and splenomegaly (99/246, 40% versus 16/110, 15%; p< 0.001). Notably, Western patients were about eight to ten times more likely than Asian patients to have rheumatoid arthritis (73/272, 27% versus 4/106, 4%; p<0.001) and recurrent infections (81/272, 30% versus 3/107, 3%; p<0.001). These clinicopathologic differences have important implications on disease pathogenesis and treatment.

Long-term responses and outcomes following immunosuppressive therapy in large granular lymphocyte leukemia-associated pure red cell aplasia: a Nationwide Cohort Study in Japan for the PRCA Collaborative Study Group.

Large granular lymphocyte leukemia-associated pure red cell aplasia accounts for a significant portion of secondary pure red cell aplasia cases. However, because of its rarity, long-term responses and relapse rates after immunosuppressive therapy are largely unknown. We conducted a nationwide survey in Japan and collected 185 evaluable patients. Fourteen patients with large granular lymphocyte leukemia-associated pure red cell aplasia were evaluated. Cyclophosphamide, cyclosporine A and prednisolone produced remissions in 6/8, 1/4 and 0/2 patients respectively. Seven and 5 patients were maintained on cyclophosphamide or cyclosporine A respectively. Two patients relapsed after stopping cyclophosphamide, and 2 patients relapsed during maintenance therapy with cyclosporine A. The median relapse-free survival in the cyclophosphamide - and the cyclosporine A groups was 53 and 123 months respectively. Large granular lymphocyte leukemia-associated pure red cell aplasia showed a good response to either cyclophosphamide or cyclosporine A. Most patients continued to receive maintenance therapy and it remains uncertain whether cyclophosphamide or cyclosporine A can induce a maintenance-free hematologic response in large granular lymphocyte leukemia-associated pure red cell aplasia.

Allogeneic hematopoietic stem cell transplantation for Epstein-Barr virus-associated T/natural killer-cell lymphoproliferative disease in Japan.

Epstein-Barr virus (EBV)-associated T/NK-cell lymphoproliferative disease (LPD) has been linked to several different disorders. Its prognosis is generally poor and a treatment strategy has yet to be established. There are reports, however, that hematopoietic stem cell transplantation (HSCT) can cure this disease. To clarify the current situation regarding allogeneic hematopoietic stem cell transplantation (allo-HSCT) for EBV-associated T/NK-LPD, a nationwide survey was performed in Japan. Data for 74 patients were collected. There were 42 cases of chronic active EBV infection (CAEBV), 10 cases of EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH), and 22 cases of EBV-associated lymphoma/leukemia (EBV-lymphoma/leukemia). Of those with CAEBV, 54% had the EBV-infected T-cell type and 59% with EBV-lymphoma/leukemia had the EBV-infected NK-cell type. Most patients with EBV-HLH and EBV-lymphoma/leukemia received allo-HSCT within 1 year after onset compared to only 14% of patients with CAEBV. The event-free survival (EFS) rate following allo-HSCT was 0.561 +/- 0.086 for CAEBV, 0.614 +/- 0.186 for EBV-HLH, and 0.309 +/- 0.107 for EBV-lymphoma/leukemia. The EFS of allo-HSCT with conventional conditioning was 0.488 +/- 0.074 and with reduced-intensity conditioning was 0.563 +/- 0.124. Thus, in a substantial number of cases, EBV-associated T/NK-LPD can be cured by either allogeneic conventional stem cell transplantation or reduced-intensity stem cell transplantation.