Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027947 (neutropenia)
 17,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A 54-year-old woman presented with a severe autoimmune anemia, thrombocytopenia, neutropenia (Evans' syndrome), and CD8+ lymphocytosis, without signs of lymphadenopathy or splenomegaly. A diagnosis of T cell large granular lymphocyte (T-LGL) leukemia was made, based on cytomorphology, the typical CD3+/CD4-/CD8+/CD16+/CD56-/CD57-/HLA-DR(+/-) immunophenotype of the lymphocytosis (9 x 10(9)/l), and biallelic clonally rearranged T cell receptor beta (TCR beta) genes. Clonality of the TCR alphabeta+ T-LGL was also demonstrated with a panel of antibodies against variable domains of TCR beta chains, which showed single Vbeta7.1 expression on the CD3+ T-lymphocytes. After treatment failure with corticosteroids, splenectomy, and cyclophosphamide, respectively, a complete clinical remission was induced and sustained with cyclosporin A. Vbeta7.1/CD8/CD3 triple immunofluorescence stainings appeared to be valuable for titrating the cyclosporin A dosage by monitoring the T-LGL cells during treatment.
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PMID:Induction of clinical remission in T-large granular lymphocyte leukemia with cyclosporin A, monitored by use of immunophenotyping with Vbeta antibodies. 951 76

Large granular lymphocyte leukaemia (LGL leukaemia) is a rare, chronic lymphoproliferative bone marrow disease which can be considered a subtype of chronic T-cell lymphocytic leukaemia (T-CLL). We describe three patients with large granular lymphocyte leukaemia. They all suffered from chronic disease with neutropenia and relative lymphocytosis. An expansion of mature lymphocytes with the CD3+, CD8+, CD57+ immunophenotype was demonstrated in all three patients. Two patients had a history of recurring infections. Serological findings compatible with rheumatic disease were present in all three patients, and two suffered from rheumatoid arthritis. We have made a brief survey of this disease, which is characterized by relative or absolute lymphocytosis, neutropenia, and an increased risk of infection. Rheumatoid arthritis and other associated autoimmune manifestations occur frequently. Large granular lymphocyte leukaemia should be considered a possible diagnosis in patients with chronic neutropenia and relative lymphocytosis, in particular if rheumatic manifestations are also present. Flow cytometric immunophenotyping is a sensitive method in diagnosing this disease.
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PMID:[Large granular lymphocytic leukemia]. 953 26

T-cell large granular lymphocyte (T-LGL) leukemia is clinically indolent, but is associated with severe neutropenia in approximately 50% of cases. The pathogenesis of the neutropenia is unclear. We report reversal of severe neutropenia associated with T-LGL leukemia in five patients treated with cyclosporine (CSA). All five had persistent neutrophil counts below 0.5 x 10(9)/L, two had agranulocytosis, and four had recurrent infections. Increased populations of LGL were present in blood and marrow, with a T-LGL immunophenotype (CD3(+)CD8(+)CD16(+/-)CD56(+/-)CD57(+)) shown by multiparameter flow cytometry, and clonal T-cell receptor (TCR) gene rearrangements in two of two pretreatment blood samples studied. CSA was initiated at doses of 1 to 1.5 mg/kg orally every 12 hours, with subsequent dose adjustments based on trough serum levels. Four patients attained normal neutrophil counts with CSA alone; one required addition of low-dose granulocyte-macrophage colony-stimulating factor. Time to attainment of 1.5 x 10(9)/L neutrophils ranged from 21 to 75 days. Attempts to taper and withdraw CSA resulted in recurrent neutropenia. Three patients have maintained normal neutrophil counts on continued CSA therapy for 2, 8, and 8.5 years. Two patients died 1.7 and 4.6 years after initiation of CSA despite normal neutrophil counts-one of metastatic melanoma and one of complications after aortofemoral bypass surgery. Despite resolution of neutropenia, increased populations of T-LGL cells have persisted in all patients during CSA therapy, as shown by morphology and flow cytometry and by the presence of clonal TCR gene rearrangements in four patients' posttreatment blood samples. We conclude that CSA is an effective therapy for neutropenia associated with T-LGL leukemia, and that resolution of neutropenia despite persistence of abnormal cells implies that CSA may inhibit T-LGL secretion of yet unidentified mediators of neutropenia.
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PMID:Neutropenia associated with T-cell large granular lymphocyte leukemia: long-term response to cyclosporine therapy despite persistence of abnormal cells. 955 95

T-cell large granular lymphocyte leukaemia (T-LGL) is a clonal disorder of T cells associated with neutropenia and anaemia. The clinical consequences are recurrent infections and transfusion dependence. The optimum treatment for severely affected patients remains to be defined. Current therapies require long-term administration to maintain an effect. We report the reversal of severe neutropenia and/or anaemia in four patients treated with fludarabine which has been maintained since stopping treatment. The therapeutic side-effects were restricted to one episode of fever not associated with neutropenia. We conclude that fludarabine is effective in T-LGL, may be given safely despite severe neutropenia and induces durable treatment-free remissions.
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PMID:Neutropenia and anaemia associated with T-cell large granular lymphocyte leukaemia responds to fludarabine with minimal toxicity. 1258 60

T-large granular lymphocyte lymphoproliferative disorder (T-LGL LPD) is an indolent disease characterized by prolonged cytopenia and the presence of circulating large granular lymphocytes in the patient's peripheral blood. Although the disease is commonly thought of as indolent, most patients eventually require therapy because of recurrent infections secondary to neutropenia as well as a need for frequent blood product transfusions. CD26 is a 110-kDa surface glycoprotein with an essential role in T-cell function, including being a marker of T-cell activation and a mediator of T-cell activating signals. In this study, we evaluated CD26 expression in T-LGL patients and correlate CD26 expression with clinical behaviour. In addition, we examined the potential mechanism of cytopenia that is associated with this disorder. Our findings suggest that CD26 is a marker of aggressive T-LGL LPD and that CD26-related signalling may be aberrant in T-LGL LPD. Furthermore, inhibition of granulocyte-macrophage colony-forming units may be mediated by CD8+ cells of T-LGL LPD patients and is major histocompatibility complex class I-restricted.
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PMID:T-large granular lymphocyte lymphoproliferative disorder: expression of CD26 as a marker of clinically aggressive disease and characterization of marrow inhibition. 1278 96

T-cell large granular lymphocytic lymphoproliferative disease (T-LGL) is often associated with life-threatening cytopenias. Twenty-five subjects with anaemia and/or neutropenia caused by T-LGL were treated with cyclosporin A (CSA) 5-10 mg/kg/d for at least 3 months. Eighteen patients survived between 35 and 77 months after starting treatment. Fourteen patients [56%; 95% confidence interval (CI) 35-76%] responded to CSA with sustained improvement in the neutrophil count or transfusion independence. Seven had complete normalization of blood counts, and four achieved a durable response only after the addition of erythropoietin. Sustained response required continued low-dose CSA. In a multivariate analysis, HLA-DR4 was highly predictive of CSA responsiveness (odds ratio 18; 95% CI 1.8-184). T-LGL subtype, LGL counts after therapy, lymphocytic marrow infiltration and bone marrow cellularity did not significantly affect the probability of response. We conclude that CSA is effective in inducing haematological responses in HLA-DR4-positive patients and that T-LGL is likely to have an immune pathogenesis.
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PMID:HLA-DR4 predicts haematological response to cyclosporine in T-large granular lymphocyte lymphoproliferative disorders. 1461 4

T-cell large granular lymphocyte (T-LGL) leukemia is a clonal lymphoproliferation of cytotoxic T cells (CTLs) associated with cytopenias. T-LGL proliferation seems to be triggered/sustained by antigenic drive; it is likely that hematopoietic progenitors are the targets in this process. The antigen-specific portion of the T-cell receptor (TCR), the variable beta (VB)-chain complementarity-determining region 3 (CDR3), can serve as a molecular signature (clonotype) of a T-cell clone. We hypothesized that clonal CTL proliferation develops not randomly but in the context of an autoimmune response. We identified the clonotypic sequence of T-LGL clones in 60 patients, including 56 with known T-LGL and 4 with unspecified neutropenia. Our method also allowed for the measurement of clonal frequencies; a decrease in or loss of the pathogenic clonotype and restoration of the TCR repertoire was found after hematologic remission. We identified 2 patients with identical immunodominant CDR3 sequence. Moreover, we found similarity between multiple immunodominant clonotypes and codominant as well as a nonexpanded, "supporting" clonotypes. The data suggest a nonrandom clonal selection in T-LGL, possibly driven by a common antigen. In contrast, the physiologic clonal CTL repertoire is highly diverse and we were not able to detect any significant clonal sharing in 26 healthy controls.
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PMID:Pathologic clonal cytotoxic T-cell responses: nonrandom nature of the T-cell-receptor restriction in large granular lymphocyte leukemia. 1591 62

T-Large Granular Lymphocyte (T-LGL) leukaemia is a rare clonal disease characterized by neutropenia and/or anaemia. Because of its strong association with rheumatoid arthritis (RA), T-LGL leukaemia is an important differential diagnosis to Felty's syndrome. This differentiation might be especially difficult since, in severe RA with extraarticular manifestations, there is often an expanded memory effector T-cell population which can hardly be separated from T-LGL leukaemia cells by means of immunophenotyping. The main criterion for T-LGL leukaemia is the detection of a clonal T-cell-receptor rearrangement by PCR. First-line therapy consists of weekly low-dose methotrexate. Alternatively, other immunosuppressives or cytotoxic agents can be useful. There are very limited data from therapy studies. The German CLL study group has initiated a protocol using parenteral low-dose methotrexate as first-line therapy and fludarabine as second-line medication.
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PMID:[T-large granular lymphocyte leukaemia. An important differential diagnosis to Felty's syndrome]. 1645 Jan 50

Abnormalities diagnosed on routine blood work, such as mild neutropenia, anaemia, thrombocytopenia and relative lymphocytosis, often have obscure aetiologies. A series of 30 patients were evaluated for various unexplained haematological abnormalities between 1997 and 2005, and found to have circulating monoclonal T-cell large granular lymphocytes (T-LGL). These patients fit the diagnosis of T-cell clonopathy of unknown significance (TCUS), which may represent a clinical spectrum of clonal T-LGL proliferation. Our patients were characterised by a complete absence of severe neutropenia (<0.5 x 10(9)/l), absence of recurrent neutropenic infection (0%), negative rheumatoid serology (0%) and a low incidence of constitutional symptoms (20%). This overall asymptomatic clinical presentation appeared to be different from other previously reported series of TCUS or T-LGL leukaemia who typically had symptomatology and required treatment. Our series of 30 patients represented the benign end of the spectrum of clonal T-LGL proliferation, and might reflect diagnosis at earlier stages of the condition relative to other reported series. TCUS may be a heterogeneous and under-diagnosed condition. This study further broadens our understanding of the clinical and laboratory manifestations of indolent clonal T-cell proliferation, and raises our awareness of this condition. We suggest that TCUS should be considered in the diagnostic evaluation of unexplained haematological problems.
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PMID:Are clonal T-cell large granular lymphocytes to blame for unexplained haematological abnormalities? 1709 7

Signal transduction pathways integrate a variety of microenvironmental cues to guide cell function by regulating gene transcription, cell cycle status, growth, and differentiation. It is well established that perturbation of these processes plays a key role in hematologic malignancies including lymphomas and chronic and acute lymphocytic leukemias. Altered intracellular signaling pathways have been proposed to mediate many biological properties of T cell large granular lymphocytic leukemia (T-LGL), a disorder characterized by a clonal proliferation of CD8 T cells resulting in immune-mediated cytopenias, most commonly neutropenia. Since T-LGL offers a unique opportunity to study signal transduction in the pathologic clonal cytotoxic T cell (CTL) compared to normal CTL, we have investigated a potential imbalance in T-LGL pro-survival signaling to define the mechanisms underlying the semi-autonomous proliferation leading to leukemia. Increased activity of the PI3K-AKT signaling axis in T-LGL cells appears to operate in conjunction with or parallel to increased STAT3 activation in these cells to inhibit the apoptotic program. Thus, the ability to define pathophysiology at the molecular level opens new avenues for targeted therapeutics.
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PMID:Pathophysiology defined by altered signal transduction pathways: the role of JAK-STAT and PI3K signaling in leukemic large granular lymphocytes. 1717 39


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