T Cell Large Granular Lymphocytic Leukemia
Large granular lymphocyte (LGL) leukemia is a rare chronic lymphoproliferative disorder that is further classified into two subcategories: T cell LGL (T-LGL) leukemia and natural killer cell LGL leukemia. T-LGL leukemia is the most common form and, as its name suggests, it is characterized by the clonal proliferation of LGLs, specifically cytotoxic T cells. This malignancy typically affects older adults – with a median age of 60 at diagnosis – and the clinical course is usually indolent and chronic, even asymptomatic in some patients. One of the unique features of this disease is its frequent coexistence with several types of autoimmune disorders – most commonly rheumatoid arthritis (RA) – or other blood disorders and malignancies.
Formation
An unknown antigen is thought to initiates the pathway leading to T-LGL leukemia. Chronic and persistent antigen exposure results in the development and expansion of a monoclonal cytotoxic lymphocyte population.1 This results in the production of inflammatory cytokines, the release of cytotoxic granules from functional killer cells, and STAT3 activation, which plays a role in LGL resistance to apoptosis.1, 2
Diagnosis and treatment assessment
T-LGL leukemia diagnosis is reliant on multiple clinical observations, neutropenia being the most common along with a sustained increase in LGLs. These cells usually represent between 10% and 15% of total lymphocytes in the peripheral blood of a healthy individual, however, this number greatly increases in most – but not all – patients with T-LGL leukemia. A clear diagnosis relies on confirming that the lymphoproliferation is caused by clonality rather than an autoimmune disorder or infectious disease.3
Clonality can be established by PCR and molecular analysis with probes for T cell receptor (TCR)γ, or through flow cytometry assessing the TCR Vβ repertoire.3 Flow cytometry can recognize 22 Vβ protein families, though no recurrent family has been found to exist between all LGL leukemia patients.4 Vβ flow cytometry can also be used to monitor treatment success in T-LGL leukemia patients, identify recurrent TCR rearrangements by characterizing Vβ skewing, and potentially discover LGL clones silently underlying other hematological conditions.4
Cell markers
Leukemic cells typically display TCR αβ, CD3, CD5dim, CD8, CD16, CD45RA, and CD57,2 and are negative for CD4, CD27, CD28, and CD45RO.4
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References
- Lamy T, Moignet A et al. (2017) LGL leukemia: from pathogenesis to treatment. Blood. 129 (9): 1082–1094. doi:10.1182/blood-2016-08-692590
- Steinway SN, LeBlanc F et al. (2014) The pathogenesis and treatment of large granular lymphocyte leukemia. Blood Rev. 28(3):87-94. doi:10.1016/j.blre.2014.02.001
- Cheon H, Dziewulska KH et al. (2020) Advances in the Diagnosis and Treatment of Large Granular Lymphocytic Leukemia. Curr Hematol Malig Rep. 15(2):103-112. doi:10.1007/s11899-020-00565-6
- Giudice V, D'Addona M et al. (2021) The Value of Flow Cytometry Clonality in Large Granular Lymphocyte Leukemia. Cancers (Basel). 13(18):4513. doi:10.3390/cancers13184513
