Abstract
Large granular lymphocyte leukemia (LGLL) is a rare lymphoproliferative disorder characterized by the clonal expansion of cytotoxic T-LGL or NK cells. Chronic isolated neutropenia represents the clinical hallmark of the disease, being present in up to 80% of cases. New advances were made in the biological characterization of neutropenia in these patients, in particular STAT3 mutations and a discrete immunophenotype are now recognized as relevant features. Nevertheless, the etiology of LGLL-related neutropenia is not completely elucidated and several mechanisms, including humoral abnormalities, bone marrow infiltration/substitution and cell-mediated cytotoxicity might cooperate to its pathogenesis. As a consequence of the multifactorial nature of LGLL-related neutropenia, a targeted therapeutic approach for neutropenic patients has not been developed yet; moreover, specific guidelines based on prospective trials are still lacking, thus making the treatment of this disorder a complex and challenging task. Immunosuppressive therapy represents the current, although poorly effective, therapeutic strategy. The recent identification of a STAT3-mediated miR-146b down-regulation in neutropenic T-LGLL patients emphasized the pathogenetic role of STAT3 activation in neutropenia development. Accordingly, JAK/STAT3 axis inhibition and miR-146b restoration might represent tempting strategies and should be prospectively evaluated for the treatment of neutropenic LGLL patients.
Highlights
Large granular lymphocyte leukemia (LGLL) is a rare lymphoproliferative disorder characterized by the clonal expansion of cytotoxic T-large granular lymphocytes (T-LGL)or natural killer (NK) cells [1]
Since the diagnosis of LGLL is usually established by Peripheral blood (PB) analysis, bone marrow (BM) aspirate and/or biopsy are not routinely performed as part of the initial evaluation; BM investigation is rather recommended when the diagnosis is not straightforward, since it might help to elucidate the etiology of unexplained cytopenias [7] (Figure 4)
Chronic isolated neutropenia is the clinical hallmark of LGLL patients and the most common indication for treatment
Summary
Large granular lymphocyte leukemia (LGLL) is a rare lymphoproliferative disorder characterized by the clonal expansion of cytotoxic T-large granular lymphocytes (T-LGL). T-LGL leukemia (T-LGLL) and the chronic lymphoproliferative disorder of NK cells (CLPD-NK) represent the most common subsets of the disease, accounting for ~85% and. The clinical course of the disease is typically characterized by neutropenia, which turns out to be the main clinical feature, being present in up to 80%. Of patients along the disease course, with severe neutropenia characterizing 17–24% of cases [1,7]. Other relevant manifestations include anemia and thrombocytopenia, reported in 13–49% and 6–30% of cases, respectively [1,8,9,10,11]. We will focus on both current therapies and novel promising strategies for the treatment of neutropenic LGLL patients
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