Large granular lymphocytic leukemia

Large granular lymphocytic (LGL) leukemia is a chronic lymphoproliferative disorder that exhibits an unexplained, chronic (> 6 months) elevation in large granular lymphocytes (LGLs) in the peripheral blood.^[1]

It is divided in two main categories: T-cell LGL leukemia (T-LGLL) and natural-killer (NK)-cell LGL leukemia (NK-LGLL). As the name suggests, T-cell large granular lymphocyte leukemia is characterized by involvement of cytotoxic-T cells).^[2]

In a study based in the US, the average age of diagnosis was 66.5 years^[3] whereas in a French study the median age at diagnosis was 59 years (with an age range of 12–87 years old).^[4] In the French study, only 26% of patients were younger than 50 years which suggests that this disorder is associated with older age at diagnosis.^[4] Due to lack of presenting symptoms, the disorder is likely to be underdiagnosed in the general population.^[5]

This disease is known for an indolent clinical course and incidental discovery.^[1] The most common physical finding is moderate splenomegaly. B symptoms are seen in a third of cases, and recurrent infections due to anaemia and/or neutropenia^[6] are seen in almost half of cases.^{[7][8][9][10]}

Rheumatoid arthritis is commonly observed in people with T-LGLL, leading to a clinical presentation similar to Felty's syndrome.^[11] Signs and symptoms of anemia are commonly found, due to the association between T-LGLL and erythroid hypoplasia.^[12]

The leukemic cells of T-LGLL can be found in peripheral blood, bone marrow, spleen, and liver. Nodal involvement is rare.^[1][7]

The postulated cells of origin of T-LGLL leukemia are transformed CD8+ T-cell with clonal rearrangements of β chain T-cell receptor genes for the majority of cases and a CD8- T-cell with clonal rearrangements of γ chain T-cell receptor genes for a minority of cases.^[1]

The requisite lymphocytosis of this disease is typically 2-20x10⁹/L.^[12]

Immunoglobulin derangements including hypergammaglobulinemia, autoantibodies, and circulating immune complexes are commonly seen.^{[10][13][14][15]}

The neoplastic lymphocytes seen in this disease are large in size with azurophilic granules that contains proteins involved in cell lysis such as perforin and granzyme B.^[16] Flow cytometry is also commonly used.^[17]

Bone marrow involvement in this disease is often present, but to a variable extent. Bone marrow biopsy is commonly used for diagnosis. The lymphocytic infiltrate is usually interstitial, but a nodular pattern rarely occurs.^[1]

The neoplastic cells of this disease display a mature T-cell immunophenotype, with the majority of cases showing a CD4-/CD8+ T-cell subset immunophenotype versus other permutations of those markers.^[8][9] Variable expression of CD11b, CD56, and CD57^[10] are observed. Immunohistochemistry for perforin, TIA-1, and granzyme B are usually positive.^[1]

Clonal rearrangements of the T-cell receptor (TCR) genes are a necessary condition for the diagnosis of this disease. The gene for the β chain of the TCR is found to be rearranged more often than the γ chain. of the TCR.^[14][18]

Current evidence suggests that patients with STAT3 mutations are more likely to respond to methotrexate therapy.^[19]

First line treatment is immunosuppressive therapy. A weekly dosage of Methotrexate (with or without daily Prednisone) may induce partial or complete response in some patients while others may require Cyclosporine or Cyclophosphamide.^[6]

Alemtuzumab has been investigated for use in treatment of refractory T-cell large granular lymphocytic leukemia.^[20]

Experimental data suggests that treatment with calcitrol (the active form of vitamin D) may be useful in treating T-cell LGL due to its ability to decrease pro-inflammatory cytokines.^[21]

The 5 year survival has been noted as 89% in at least one study from France of 201 patients with T-LGL leukemia.^[4]

T-LGLL is a rare form of leukemia, comprising 2-3% of all cases of chronic lymphoproliferative disorders.^{[citation needed]}

LGLL was discovered in 1985 by Thomas P. Loughran Jr. while working at Fred Hutchinson Cancer Research Center.^[22] Specimens from patients with LGLL are banked at the University of Virginia for research purposes, the only bank for such purposes.^[23]