T/B and not T/B: High frequency of B-cell dyscrasias in T-LGL leukemia

In this issue of the journal, Viny et al. [1] report the presence of B-cell dyscrasias in 27, or 43 percent, of a cohort of 63 patients with T-cell large granular lymphocyte (T-LGL) leukemia. These B cell abnormalities included monoclonal gammopathy of unknown significance, chronic lymphocytic leukemia (CLL), follicular lymphoma, lymphoplasmacytic lymphoma, polyclonal hypergammaglobulinemia and hypogammaglobulinemia. The coexistence of T-LGL leukemia and not only B cell abnormalities, reported by Viny et al., but also hairy cell leukemia, Hodgkin disease, mantle-cell lymphoma and multiple myeloma, had been previously identified in case reports, but the report of Viny et al. is the first systematic study of the frequency of this association, and this frequency was surprisingly high. T-LGL leukemia is a rare indolent chronic lymphoproliferative disorder for which consistent diagnostic criteria have been proposed [2,3]. In Viny et al.’s report, the diagnosis was established by fulfillment of at least three of the following criteria: presence of 41000/mL LGLs in the peripheral blood for more than 6 months, a CD3þCD57þCD28-phenotype, T-cell receptor (TCR)-g clonal rearrangement, and restricted TCR Vb expansion in the CD8þ T cell population. Clonal TCR-g rearrangement and restricted TCR Vb expansion were both present in almost all cases in the series. Of note, peripheral blood LGL counts were relatively low in the patients with Bcell abnormalities (median 1030/mL; range, 980– 1960). The reason for the low peripheral blood LGL counts in these patients is unclear, as is their significance. T-LGL leukemia is asymptomatic in 30% of patients, and, in the other 70%, presents with neutropenia or other cytopenias and/or autoimmune phenomena, rather than progressive lymphoproliferation. Cytopenias associated with T-LGL leukemia respond to treatment with cyclosporin A [4] and with methotrexate [5] at immunosuppressive doses. Severe neutropenia is the most frequent indication for therapy, but, interestingly, was relatively infrequent in patients with B-cell dyscrasias (3 of 17 patients, or 18%). The reason for the low frequency of severe neutropenia in these patients is unclear, as is its significance. T-LGL leukemia occurs in the setting of autoimmune disorders, most notably including rheumatoid arthritis, and both solid tumors and hematologic malignancies, including the B-cell dyscrasias in the report of Viny et al. In addition, transient clonal and non-clonal T-LGL proliferation has been reported during viral infections and the immune reconstitution process after hematopoietic stem cell transplantation. These associations led to the hypothesis that T-LGL leukemia arises as a non-random clonal response to an autoor alloantigen or a viral antigen [6]. T-LGL leukemia cells have been shown to be resistant to Fas-mediated apoptosis by virtue of phosphatidylinositol-3-phosphate kinase pathway activation [7] and impaired Fas-induced deathinducing signalling complex formation [8]. In the case of T-LGL leukemia in association with B-cell dyscrasias, the hypothesis would be that clonal T cell expansion is stimulated by aberrant B cells, and that apoptosis of the expanded T cell clone is impaired, ultimately resulting in T-LGL leukemia. Interesting in this regard is the finding that 25% of CLL patients