How I treat LGL leukemia

Abstract

Large granular lymphocyte (LGL) leukemia is characterized by a clonal expansion of either CD3(+) cytotoxic T or CD3(-) NK cells. Prominent clinical features of T-LGL leukemia include neutropenia, anemia and rheumatoid arthritis (RA). The terminal effector memory phenotype (CD3(+)/CD45RA(+)/CD62L(-)CD57(+)) of T-LGL suggests a pivotal chronic antigen-driven immune response. LGL survival is then promoted by platelet-derived growth factor and interleukin-15, resulting in global dysregulation of apoptosis and resistance to normal pathways of activation-induced cell death. These pathogenic features explain why treatment of T-LGL leukemia is based on immunosuppressive therapy. The majority of these patients eventually need treatment because of severe or symptomatic neutropenia, anemia, or RA. No standard therapy has been established because of the absence of large prospective trials. The authors use low-dose methotrexate initially for T-LGL leukemia patients with neutropenia and/or RA. We recommend either methotrexate or oral cyclophosphamide as initial therapy for anemia. If treatment is not successful, patients are switched to either the other agent or cyclosporine. The majority of patients experience an indolent clinical course. Deaths infrequently occur because of infections related to severe neutropenia. As there are no curative therapeutic modalities for T-LGL leukemia, new treatment options are needed.

Figure 1

How to establish the diagnosis of LGL leukemia. The diagnosis of LGL leukemia is made on the following criteria: common criteria of LGL leukemia. The diagnosis is based on a LGL peripheral expansion (> 0.5 × 10⁹/L). Specific criteria for T-LGL leukemia include: expression of LGL surface markers compatible with an activated T-cell (commonly CD3⁺/CD8⁺/CD57⁺ and/or CD16⁺) phenotype; and clonal rearrangement of TCR-γ gene using PCR or specific and clonal Vβ expression using FCM. Specific criteria for NK-LGL leukemia and NK-LGL lymphocytosis include: expression of LGL surface markers compatible with an NK cell (commonly CD3⁻/CD8⁺/CD16⁺ and/or CD16⁺/CD56⁺) phenotype. The term chronic NK-LGL lymphocytosis is used for patients with relatively few symptoms and chronic illness, whereas patients with massive tissue LGL infiltration of the spleen, liver, and bone marrow and presenting aggressive clinical behavior are considered as having NK-LGL leukemia.

Figure 2

Small and large granular lymphocytes. Distinction between small lymphocytes (A) and large granular lymphocytes (B) on blood smears. Micrographs were viewed with a Leica Leitz DMRB microscope using a 100×/1.30 oil immersion objective. Images were captured with a Sony Exwave HAD camera and manipulated using Tribyn Version 1.3 software.

Figure 3

Bone marrow features of T-LGL leukemia. Hematoxylin and eosin staining of marrow biopsy reveals a slightly hypercellular marrow with subtle increase in interstitial lymphocytes, as shown by arrow (left). Immunohistochemistry analyses (right) highlight the presence of intrasinusoidal cytotoxic T-cell infiltrates, staining positive for CD8 (arrow) and granzyme B (inset). Micrographs were viewed with a Leica Leitz DMRB microscope using a 100×/1.30 oil immersion objective. Images were captured with a Sony Exwave HAD camera and manipulated using Tribyn Version 1.3 software.

Figure 4

Flow cytometry analysis in LGL leukemia. (A) Blue: Normal nonclonal CD3⁺ T cells showing a polyclonal Vβ repertoire pattern. Red: LGL population showing a CD3⁺/CD8⁺/CD5^dim phenotype with a unique clonal Vβ7.1 expression (> 92%). (B) The NK CD3⁻ LGL population strongly expresses the CD94/KIR ag.

Figure 5

Treatment algorithm