Chapter 58: Large Granular Lymphocytic Leukemia

• T-cell large-granular lymphocytic (T-LGL) leukemia results from the clonal expansion of large granular lymphocytes (LGL) with a T-cell (CD3+) phenotype and a clonal T-cell receptor gene rearrangement(s).

• Natural killer (NK)-LGL leukemia is a clonal expansion of LGL with a NK cell (CD3-) phenotype. It lacks convenient markers to determine clonality such as antigen receptor rearrangements.

Etiology and Pathogenesis

• Suggestive evidence of a role for human T lymphotropic virus (HTLV) retroviral infection in some patients.

• Most patients are not infected with either HTLV-I or HTLV-II.

• Cytomegalovirus implicated in rare cases of CD4+ T-LGL.

• Epstein-Barr virus implicated in some cases of NK-LGL.

• Leukemic cells have features of antigen-activated cytotoxic T lymphocytes (CTL), suggesting role for antigen in initial LGL expansion.

• Constitutive overexpression of the Fas ligand (CD178), which also is found at high levels in patients' sera, may be a factor in many disease manifestations (e.g., neutropenia, rheumatoid arthritis).

Clinical Features

• About half of patients have palpable splenomegaly.

• About one-third of patients have recurrent bacterial infections and/or "B symptoms" (e.g., low-grade fevers, night sweats, and/or weight loss) (aggressive variant) (see Table 58–1).

• About one-quarter of patients have rheumatoid arthritis, often with features of "Felty syndrome."

• Less than 10 percent of patients have lymphadenopathy.

Laboratory Features

• Immunophenotype of LGL cells in blood and marrow: CD3+CD8+CD16+ CD57+ CD4-CD56-, and, often, HLA-DR+.

• Patients have clonal T-cell–receptor gene rearrangement(s), usually involving α and β chains.

• Nearly 85 percent of patients have neutropenia, often less than 0.5 × 10⁹/L.

• Approximately half of the patients have anemia, often caused by pure red cell aplasia and/or autoimmune hemolytic anemia.

• Approximately one-fifth of patients have thrombocytopenia.

• About one-quarter of patients do not have increased blood total lymphocyte counts.

• The median LGL count in patients is 4.0 × 10⁹/L (normal mean 0.3 ×10⁹ /L) (Fig. 58–1).

• More than 90 percent of patients have LGL infiltration of the marrow and splenic red pulp.

• Marrow infiltration may be nodular or interstitial. If interstitial, it may be difficult to appreciate involvement without staining for neoplastic cells using immunocytochemistry.

• Patients commonly have elevated levels of certain autoantibodies and other serologic abnormalities (Table 58–2).

Differential Diagnosis

• T-LGL leukemia should be considered in patients with increased blood LGL counts and

  — Chronic or cyclic neutropenia.

  — Pure red cell aplasia.

  — Rheumatoid arthritis.

• T-LGL leukemia can be distinguished from NK-LGL leukemia by immunophenotype and clonal T-cell–receptor gene rearrangement (Table 58–1).

Therapy, Course, and Prognosis

• Chronic.

• Unusual cases that coexpress CD3 and CD56 may have a more aggressive clinical course.

• Significant morbidity/mortality from infections.

• Low-dose methotrexate 10 mg/m² orally once weekly or cyclophosphamide 100 mg PO daily, or cyclosporine may be effective in alleviating neutropenia/anemia.

• Coexisting B-cell neoplasms (e.g., essential monoclonal gammopathy or chronic lymphocytic leukemia) occur in 25 percent of patients.

Etiology and Pathogenesis

• Epstein-Barr virus infection implicated in the pathogenesis.

Clinical Features

• Fever, night sweats, weight loss are common (see Table 58–1).

• Massive hepatosplenomegaly typical.

• Lymphadenopathy and gastrointestinal tract involvement are common.

• Patients tend to be of younger age than those with CD3+ LGL leukemia.

Laboratory Features

• LGL lack expression of CD3 and clonal T-cell receptor rearrangements.

• NK-leukemic LGL is usually CD4+CD16+CD56+CD8–CD57-.

• LGL counts are generally high and may exceed 50 × 10⁹/L.

• Severe neutropenia (e.g., < 0.5 × 10⁹/L) is observed in less than one-fifth of patients.

• Anemia and thrombocytopenia very common.

• Coagulopathy frequently occurs.

• Clonal cytogenetics may be present.

• Serologic abnormalities listed in Table 58–2 are uncommon in NK-LGL leukemia.

Therapy, Course, and Prognosis

• Acute presentation and aggressive course is common.

• Patients with chronic NK lymphocytosis may not require treatment.

• Effective combination chemotherapy has not been reported.

• Patients with NK-LGL usually die a few months after diagnosis despite aggressive multidrug chemotherapy.