Chronic B-Cell Dyscrasias Are an Important Clinical Feature of LGL Leukemia.

T-cell large granular lymphocyte leukemia (T-LGL) is a chronic clonal lymphoproliferation of CTL. The context of immune-mediated diseases led to the hypothesis that T-LGL represents an exaggerated clonal immune response to a persistent antigen such as an autoantigen or viral antigen or be associated with an immune surveillance reaction to occult malignancies. Based on the structural similarity of TCR CDR3 we have demonstrated that the transformation event in T-LGL may not be random and is driven by a related antigen. Similar to the clonal evolution in LGL, B cell expansion in low grade non-Hogkin lymphoma may also not be entirely stochastic. There have been coincidental case reports of T-LGL patients with concomitant B cell dyscrasia. It is therefore possible that similar pathogenic triggers may be operative in chronic proliferation of T and B cells, which subsequently predispose to clonal outgrowth. Consequently, we systematically examined a large series of T-LGL patients for evidence of B cell dyscrasias. When our patients (N=70) were studied we found a frequent association of low grade B cell lymphoproliferative disorders (28%). In general, all clinical comparisons with reported studies suggested that our LGL cohort had a composition equivalent to that of prior series and findings with regard to B cell dyscrasias are not due to selection bias. By comparison, a total of 51 patients with concomitant B and T cell dyscrasia were previously reported in small series or case reports. In our series, MGUS was the most common of the B cell disorders identified in T-LGL (21%), B-CLL also was present in 7%. Of note, 8 patients received rituximab and notably, evolution of clonal T cell expansion after therapy with rituximab has been identified in isolated case reports. In addition to clonal B cell expansion, polyclonal hyperglobulinemia was found in 26% of T-LGL, similar to previous report. Hypoglobulinemia was identified in 12% of patients. Evidence of involvement of both the T and B cell compartments in T-LGL fits into several models of disease pathogenesis. T-LGL may represent anti-tumor surveillance reflecting an exaggerated clonal expansion in the context of polyclonal anti-tumor response. An alternative theory is that both conditions may result from an initial polyclonal immune reaction directed against an unrelated common target; one could speculate that autoimmune/viral diseases associated with T-LGL or malignancies (e.g., MDS) provide antigenic triggers. It is also conceivable that impaired humoral immune response could result in an exuberant T cell reaction against an uncleared antigen. If B cell function is insufficient to fully clear the inciting pathogen, then chronic antigenic stimulation could polarize T cell-mediated response, resulting in LGL expansion. Finally, identification of decreased immunoglobulin levels in the context of LGL leukemia may also give merit to the theory that both B and T cell compartments are governed by regulatory/compensatory feedback mechanisms and T-LGL could evolve from unchecked T cell expansion in the context of B cell dysfunction. In sum, we describe here a high frequency of B cell dyscrasias in patients with T-LGL. The association is unlikely to be coincidental and provide important insight into dysregulated expression of T cell and B cell function.