Large granular lymphocytic leukemia

Large granular lymphocytic leukemia is a disease that exhibits an unexplained, chronic (> 6 months) elevation in large granular lymphocytes (LGLs) in the peripheral blood.

It is sometimes known as T-cell large granular lymphocyte leukemia (specifying involvement of the T cells). However, NK large granular lymphocyte leukemia (involving natural killer cells) is also possible.

It is also known by the following terms: proliferation of large granular lymphocytes (LGLs), LGL leukemia, Tγ-lymphoproliferative disorder, and, in common with other T cell leukemias such as T-cell prolymphocytic leukemia, T-cell chronic lymphocytic leukemia.

Epidemiology
T-LGL is a rare form of leukemia, comprising 2-3% of all cases of small lymphocytic leukemias.

Etiology
The postulated cells of origin are a 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.

Clinical presentation
This disease is known for an indolent clinical course and incidental discovery. The most common physical finding is moderate splenomegaly. B symptoms are seen in a third of cases, and recurrent infections due to the associated neutropenia are seen in almost half of cases.

Rheumatoid arthritis is commonly observed in patients with T-LGL, leading to a clinical presentation similar to Felty's syndrome. Signs and symptoms of anemia are commonly found, due to the association between T-LGL and erythroid hypoplasia.

Laboratory findings
The requisite lymphocytosis of this disease is typically 2-20x109/L.

Immunoglobulin derangements including hypergammaglobulinemia, autoantibodies, and circulating immune complexes are commonly seen.

Sites of involvement
The leukemic cells of T-LGL can be found in peripheral blood, bone marrow, spleen, and liver. Nodal involvement is rare.

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

Peripheral blood
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.

Bone marrow
Bone marrow involvement in this disease is often present, but to a variable extent. The lymphocytic infiltrate is usually interstitial, but a nodular pattern rarely occurs.

Immunophenotype
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. Variable expression of CD11b, CD56, and CD57 are observed. Immunohistochemistry for perforin, TIA-1, and granzyme B are usually positive.

Genetic findings
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.

Treatment
Alemtuzumab has been investigated for use in treatment of refractory T-cell large granular lymphocytic leukemia.