Pathophysiologic mechanisms and management of neutropenia associated with large granular lymphocytic leukemia

Abstract

Large granular lymphocyte (LGL) syndrome includes a spectrum of clonal T cell and natural killer cell chronic lymphoproliferative disorders. These conditions are thought to arise from chronic antigenic stimulation, while the long-term survival of the abnormal LGLs appears to be sustained by resistance to apoptosis and/or impaired survival signaling. T-cell LGL (T-LGL) leukemia is the most common LGL disorder in the Western world. Despite its indolent course, the disease is often associated with neutropenia, the pathogenesis of which is multifactorial, comprising both humoral and cytotoxic mechanisms. This article addresses the pathogenesis of T-LGL leukemia and natural killer cell chronic lymphoproliferative disorder, as well as that of T-LGL leukemia-associated neutropenia. Furthermore, as symptomatic neutropenia represents an indication for initiating treatment, available therapeutic options are also discussed.

Indolent, T-cell, large granular lymphocytic leukaemia in a dog presenting with severe neutropenia and an absence of lymphocytosis

“…Many patients have positive anti-nuclear antibody and rheumatoid factor (Lamy et al, 2017). The pathogenesis of LGLL-assciated neutropenia is not fully understood and is likely to be multifactorial, comprising both humoral and cytotoxic mechanisms (Pontikoglou et al, 2011). Since normal neutrophil survival is, at least in part, regulated by the Fas-Fas ligand apoptotic system, it has been suggested that LGLL neutropenia might be partly mediated by dysregulated Fas ligand expression.…”

Neutropenia in a Patient With Rheumatoid Arthritis Associated With alpha-beta/gamma-delta T-Cell Large Granular Lymphocyte Lymphoproliferative Disorder Manifesting as Felty’s Syndrome: From Diagnosis to Therapy

“…Treatment with G-CSF often improves neutropenia in patients with T-LGL-LPD (including T-LGLL) and Felty's syndrome, being especially useful when used for short periods of time, during intercurrent infections [9,10,18]. Unfortunately, this patient did not show a satisfactory response to G-CSF and suffered from a rare side effect, which is thrombocytopenia.…”

“…Neutropenia is usually the most significant problem both in Felty's syndrome and T-LGLL patients and in generally it cannot be explained by tissue infiltration by the LGL [1,6,9]. Possible pathogenic mechanisms include autoantibody or immune complex mediated peripheral destruction of mature neutrophils, induction of Fas/FasL mediated neutrophil apoptosis, autoimmune destruction of the myeloid precursor cells and deregulation of the granulocytic cell maturation [10], probably related to the production of proinflammatory cytokines [16,17]. In the case reported herein, positive antineutrophil autoantibodies and a normal bone marrow, argue for an autoimmune mechanism.…”

“…In spite of the indolent behaviour, the majority of pa-tients with T-LGLL require treatment at some point during the disease course and the most common indications are symptomatic cytopenias, especially chronic neutropenia associated with recurrent infections [1,9]. Improvement of cytopenias is usually achieved with immunosuppressive agents, including methotrexate (MTX), cyclophosphamide and cyclosporine A (CsA); corticoids alone normally do not produce sustained neutrophil increase, and secondary long- term effects are not negligible; treatment with G-CSF may also improve neutropenia, being particularly beneficial for short periods of time during infectious complications [9][10][11][12]. Herein, we report a case of a patient with RA with 15 years of evolution and a proliferation of TCRαβ+ and TCRγδ T-LGL who suffered from severe chronic neutropenia, refractory to MTX, leflunamide and corticoids.…”

Moderate-dose cyclophosphamide in the treatment of relapsed/refractory T-cell large granular lymphocytic leukemia-associated pure red cell aplasia

“…[1][2][3][4] However, one-third of all patients are asymptomatic and require no treatment. In western countries, the major clinical manifestations have been reported to be neutropenia, recurrent infection and mouth ulcers, and autoimmune disorders such as rheumatoid arthritis, 5,6 whereas in Asian countries, T-LGLL usually presents as anemia-associated symptoms. [7][8][9] Some, but not all, of these patients are diagnosed as having T-cell large granular lymphocytic leukemia-associated pure red cell aplasia (PRCA) and consequently require treatment.…”