Large granular lymphocytic leukemia: a brief review

Abstract

LGL leukemia is a rare chronic lymphoproliferative disorder of cytotoxic lymphocytes which can be immunophenotypically either T cell or NK cell-derived. According to the World Health Organization classification, it can be divided into three subtypes: chronic T-cell leukemia and chronic natural killer cell lymphocytosis, and aggressive natural killer cell LGL leukemia. Clonal proliferation of large granular lymphocytes can be because of stimulation of various molecular pathways namely JAK-STAT3 pathway, FAS/FAS-L pathway, RAS-RAF-1-MEK1-ERK pathway, PI3K/AKT pathway, NF-KB pathway, and Sphingolipid Rheostat pathways. The most common clinical features presenting with this leukemia are neutropenia, anemia, thrombocytopenia. This leukemia is also associated with various autoimmune conditions. It usually has an indolent course except for the aggressive NK cell LGL leukemia. The cause of death in the indolent cases was mostly due to infectious complications related to the neutropenia associated with the disease. The rarity of the disease coupled with the availability of only a handful of clinical trials has been a hindrance to the development of a specific treatment. Most of the cases are managed with immunomodulators. The advances in the knowledge of molecular pathways associated with the disease have brought few targeted therapies into the limelight. We discuss here the evolution, epidemiology, demographic profile, pathophysiology, differential diagnosis, the available treatment options along with the survival and prognostic variables which may help us in better understanding and better management of the disease and hopefully, paving the way for a targeted clinical approach.

Keywords: LGL leukemia; NK cell; T cell.

Figure 1

Antigen, Cytokines and Molecular pathways involved in the pathogenesis of LGLs. Mainly HTLV1 virus and cytokines like IL15 and PDGF acts as an antigen stimulus for polyclonal proliferation of LGLs this is followed by acquisition of mutations at various molecular pathways leading to clonal proliferation and increased survival of these cells. The major pathways involved are described here. JAK-STAT3 Signalling Pathway: STAT3 is continuously activated in LGL leukemia, it inhibits apoptosis by increasing the transcription of Mcl-1 which is an anti-apoptotic protein; FAS/FAS-L-mediated Pathway: LGL leukemia cells are resistant to FAS mediated apoptosis, soluble cleaved product of FAS (sFAS) is interferes with the anti-apoptotic action of FAS; RAS-RAF-1-MEK1-ERK Pathway: This pathway acts by modulating the transcription of Mcl-1, this pathway is upregulated in LGL leukemia and is associated with inhibition of apoptosis; PI3K/AKT Pathway: Increased activity of this is seen in LGL leukemia, it also controls apoptosis through Mcl-1 and is responsible for inhibition of apoptosis; NF-KB Pathway: activity is increased in LGL leukemia and it acts through downstream of the PI3K-AKT pathway to prevent apoptosis; Sphingolipid Rheostat Pathway: SP1 level is increased in LGL leukemia and is responsible for increased survival of the cells and when its metabolite ceramide levels are increased, it puts in the signal for apoptosis. It acts through downstream of ERK pathways and prevents apoptosis.

Figure 2

A-C. Shows LGL in peripheral blood smear, stained with May Grunwald Giemsa stain and viewed under 100 × magnification.

Figure 3

Flow cytometric analysis of a typical case of T CD3+ LGL leukemia. A. Lymphocytes are gated on CD45 versus side scatter. B. CD3+ T cells are gated. C. Majority (~84%) CD3+ cells are CD8+. D. CD3+CD8+ are showing dim to negative expression of CD5. E. CD3+CD8+ are showing negative expression of CD94 and CD57. F. CD3+CD8+ are showing negative expression of CD16.

Figure 4

Therapeutic algorithm of LGL leukemia.