Large granular lymphocyte (LGL) leukemia

A clonal proliferation disorder of cytotoxic T cells associated with pancytopenia and modest lymphocytosis.

Large granular lymphocyte (LGL) leukemia is caused by a clonal population of cytotoxic T cells or NK cells and involves an increased number of LGLs. usually > 2 × 109/L.

LGL leukemia is divided into 3 categories according to the most recent World Health Organization classification.

It is a lymphoproliferation of mature cytotoxic T cells or natural (NK) cells.

Characterized by pancytopenia, which contributes the majority of its morbidity.

T-cell LGL leukemia, which is about 85% of cases, is considered indolent but can cause significant cytopenias and is often associated with autoimmune disease.

Cells usually express a CD3+, CD8+, CD16+ and CD57+ phenotype. 

Survival is about 70% at 10 years.

Generally affects elderly patients.

The average age at diagnosis is 60 for LGL leukemia

One third of patients have associated rheumatoid arthritis.

There is a strong association of LGL leukemia with autoimmune disease

Aggressive NK-cell LGL leukemia (about 5%) is associated with Epstein-Barr virus infection and occurs in younger patients.

It is characterized by severe cytopenias, “B symptoms” (i.e., fever, night sweats, weight loss), and has a very poor prognosis.

Like chronic NK-cell lymphocytosis, cells express a CD3–, CD16+ and CD56+ phenotype. Fas (CD95) and Fas-ligand (CD178) are strongly expressed.

Chronic NK-cell lymphocytosis (about 10%) also tends to have an indolent course with cytopenia and an autoimmune association, and with a similar prognosis to T-cell LGL leukemia.

Cells express a CD3–, CD16+ and CD56+ phenotype.

Often associated with an underlying or autoimmune disease, or malignancy, including hematologic disorders and solid tumors.

Approximately 1/3 patients are asymptomatic at presentation.

Symptoms associated include: neutropenia with recurrent infections, splenomegaly, and B symptoms such as fatigue, weight loss, and night sweats.

Invasion of large granular lymphocytes in the bone marrow, spleen and liver.

May be derived from either CD3- or CD+ large granular lymphocytes, designated NK and CD3+ large granular lymphocyte leukemia.

Most cases of LGL leukemia can be diagnosed on the basis of classic morphology on peripheral blood smear and evidence of clonality on flow cytometry or gene rearrangement studies.

T-cell receptor gene studies cannot be used to establish clonality in the NK subtypes, as NK cells do not express T-cell receptors.

90% of patients with LGL/rheumatoid arthritis have DR4 haplotype, as do almost all patients with Felty’s syndrome.

T cell form typified by neutropenia and anemia.

Patients with LGL leukemia commonly have or develop autoimmune conditions.

Immune-mediated cytopenias including pure red cell aplasia, aplastic anemia, and autoimmune hemolytic anemias can occur.

Neutropenia, the most common cytopenia in LGL leukemia, is thought to be at least partly autoimmune, as the degree of neutropenia is often worse than would be expected solely from bone-marrow infiltration of LGL cells.

Rheumatoid arthritis is the most common autoimmune condition associated with LGL leukemia, with a reported incidence between 11% and 36%.13–15

Felty syndrome (rheumatoid arthritis, splenomegaly and neutropenia) is often associated with LGL leukemia and is thought by some to be part of the same disease process.

In addition to having a high incidence of rheumatoid arthritis patients may have an autoimmune syndrome of hypergammaglobulinemia, circulating immune complexes and multiple autoantibodies.

The clinical presentation, immunologic, pathologic, molecular and genetic features of this disease with rheumatoid arthritis and Felty’s syndrome are indistinguishable.

No standard of care exists.

Responds to low dose oral methotrexate

Relative indolent disease as indicated with a median survival of 14.5 years.

Treat with immunosuppressives if needed

Indications for treating LGL leukemia include the development of cytopenias and associated autoimmune diseases. 

Immunosuppressive agents such as methotrexate, cyclophosphamide and cyclosporine, are commonly used.

 Most evidence of treatment efficacy is from retrospective studies and case reports, with widely variable response rates that overall are around 50%.

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