Abstract
Simple SummaryLarge Granular Lymphocytic Leukemia (LGLL) is a clonal disorder of cytotoxic T-cells. Because of the variety of clinical presentations ranging from the mere presence of lymphocytosis to cytopenias and autoimmune conditions, this rare lymphoma may require treatment to control such manifestations. Although first-line treatments are more established, refractory cases are often managed based on the experience of the attending physician. Herein, we review the pathways involved in the pathogenesis of LGLL, including refractory cases, inferring clues as to the potentially actionable targets.Large Granular Lymphocyte Leukemia (LGLL) is a rare, chronic lymphoproliferative disorder of effector cytotoxic T-cells, and less frequently, natural killer (NK) cells. The disease is characterized by an indolent and often asymptomatic course. However, in roughly 50% of cases, treatment is required due to severe transfusion-dependent anemia, severe neutropenia, or moderate neutropenia with associated recurrent infections. LGLL represents an interesting disease process at the intersection of a physiological immune response, autoimmune disorder, and malignant (clonal) proliferation, resulting from the aberrant activation of cellular pathways promoting survival, proliferation, and evasion of apoptotic signaling. LGLL treatment primarily consists of immunosuppressive agents (methotrexate, cyclosporine, and cyclophosphamide), with a cumulative response rate of about 60% based on longitudinal expertise and retrospective studies. However, refractory cases can result in clinical scenarios characterized by transfusion-dependent anemia and severe neutropenia, which warrant further exploration of other potential targeted treatment modalities. Here, we summarize the current understanding of the immune-genomic profiles of LGLL, its pathogenesis, and current treatment options, and discuss potential novel therapeutic agents, particularly for refractory disease.
Highlights
Introduction to Large Granular Lymphocytic LeukemiaIn addition to genetic mutations (see below), some reports suggested possible viral infections acting as triggers for exuberant CTL responses
Effective in rheumatoid arthritis (RA) [60], we previously reported the successful treatment of patients with refractory Large Granular Lymphocytic Leukemia (LGLL) in association with RA and neutropenia with a response seen in 4/8 patients [43,57]
The efficacy of this agent has been evaluated in ex vivo and in vitro studies, which showed that BNZ-1 led to apoptosis in LGLL cells with IL-2 and IL-15 proliferative responses [66]
Summary
In addition to genetic mutations (see below), some reports suggested possible viral infections acting as triggers for exuberant CTL responses. The majority of cases represent an activated post-thymic cell proliferation expressing CD3+ , CD4− , CD5dim , CD8+ , CD16+ , and CD57+ , mostly with TCR αβ+ restriction. Recurrent gain-offunction STAT3 mutations can be found in up to 40% of patients, whereas STAT5 lesions are identified much less commonly and with preferential presence in specific disease subtypes (see Section 2.1) [8,9,10]. The evidence of T-LGLL clonal expansion may be assessed by using TCR γ-polymerase chain reaction analysis and Vβ gene rearrangement testing, which help to distinguish between reactive and leukemic LGLL cells. Figures were generated with BioRender.com (accessed on 20 August 2021)
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