Ask the Hematologist: LGL Leukemia

A 56-year-old man has a one- to two-year history of recurrent infections including sinusitis and peri-rectal abscess. He has been diagnosed for several years with seropositive rheumatoid arthritis, with involvement of bilateral metacarpophalangeal and proximal interphalangeal joints. Physical examination is also notable for splenomegaly. He has had documented neutropenia for one year and has been considered as having Felty's syndrome. Current CBC shows WBC of 10,000/µl, with an absolute neutrophil count of 100/µl and a total lymphocyte count of 9,500/µl.

Review of the peripheral blood smear shows that most of the lymphocytes had morphology typical of large granular lymphocytes (LGLs). This case illustrates the importance of careful review of the blood smear in patients with neutropenia and/or rheumatoid arthritis. The recognition of LGL leukemia as a distinct entity was based on demonstrating increased numbers of circulating LGL, by examining the blood smear. In this era of translational medicine, typically defined as bench-to-bedside research, it is important to emphasize that clinical observations can also lead to new knowledge and trigger laboratory investigations.

LGL leukemia results most often from a clonal expansion of T cells with a typical CD3+ CD8+ CD57+ phenotype. Clonality is proven by T-cell receptor gene rearrangement studies. The typical workup then, in addition to review of the smear, includes flow cytometry and T-cell receptor gene rearrangement studies. Less commonly, the expanded LGLs are of natural killer (NK) lineage.

Current evidence indicates that leukemic LGLs are most likely antigen-driven cytotoxic T lymphocytes (CTLs). Leukemic LGLs are characterized as terminal-effector memory cells as defined by a CD45RA positive and CD62 ligand negative phenotype. Gene expression data showing extensive upregulation of perforin and cytotoxic proteases resembles patterns of gene expression observed in activated CTLs. Molecular analyses of the antigen-specific portion of the T-cell receptor show a non-random clonal selection consistent with an antigen-driven process. Normally activated CTLs are downregulated by Fas-mediated apoptosis. In contrast, leukemic LGLs are Fas-resistant. Constitutive activation of multiple survival pathways, including STAT3/Mcl-1, MAPK/ERK, and PI3Kinase, appears central to the pathogenesis of LGL leukemia.

There is growing appreciation of a considerable overlap of LGL leukemia and other disorders characterized by a CTL attack on the marrow, including aplastic anemia, pure red cell aplasia, and some cases of MDS. The most commonly identified association with pure red cell aplasia is not thymoma, but LGL leukemia. A recent study identified clonal LGL in 50 percent of patients with MDS. Autoimmune hematologic presentations, such as hemolytic anemia or ITP, can also occur with LGL leukemia. Rheumatoid arthritis is a common feature of LGL leukemia. As with the case presented here, the diagnosis of Felty's syndrome is often considered. It is my opinion that Felty's syndrome and LGL leukemia/RA are part of the same disease process. Clinical, immunologic, pathologic, molecular, and genetic data support this contention.

Immunosuppressive regimens are the treatment of choice. However, there are no large prospective studies available to establish standard of care. Methotrexate, cyclosporine, and oral cytoxan all appear effective as single agents in about 50 percent of patients. Treatment should be continued for at least four months before considering alternative therapies because of lack of response. Participation in clinical trials should be encouraged. ECOG 5998 is investigating use of methotrexate/prednisone as initial therapy. A phase II trial sponsored by NHLBI is examining alemtuzumab treatment. Humanized MiK-beta1 monoclonal antibody directed at CD122, the IL-2 receptor gamma chain, is undergoing testing in a phase I trial. A phase II trial of tipifarnib, a farnesyltransferase inhibitor, is underway. This trial is sponsored by CTEP and the Rare Diseases Clinical Research Network. Patients with LGL leukemia are also encouraged to participate in the LGL Leukemia Registry.