Regulatory T cells predict the time to initial treatment in early stage chronic lymphocytic leukemia

Abstract

BACKGROUND: Early stage chronic lymphocytic leukemia is characterized by a highly variable course of disease. Because it is believed that regulatory T cells (T regs ) are potent suppressors of antitumor immunity, the authors hypothesized that increased T regs may favor disease progression. METHODS: T reg levels (cluster of differentiation 3 [CD3]-positive, [CD4]-positive, CD25-positive, and CD127-negative) in peripheral blood from 102 patients were analyzed by flow cytometry. Statistical analysis was used to evaluate correlations with clinical data. RESULTS: The relative T reg numbers in CD4-positive T cells were significantly greater in patients with chronic lymphocytic leukemia compared with the numbers in a control group of 170 healthy individuals (P ¼ .001). Patients were divided into 2 groups using a median T reg value of 9.7% (the percentage of CD4-positive T cells). Patients with higher T reg levels had a significantly shorter time to initial treatment (median, 5.9 years) compared with patients who had lower T reg levels (median, 11.7 years; log-rank P ¼ .019). Furthermore, T reg levels (the percentage of CD4-positive T cells) had significant prognostic power to predict the time to initial treatment in univariate analysis (P ¼ .023) and in multivariate Cox regression analysis that included the variables Rai stage, immunoglobulin heavy-chain variable region gene mutational status, chromosomal aberrations, and CD38 expression (P ¼ .028). CONCLUSIONS: Higher T reg levels had significant and independent prognostic power for predicting the time to initial treatment in patients with low to intermediate stage chronic lymphocytic leukemia.

Idelalisib given front-line for treatment of chronic lymphocytic leukemia causes frequent immune-mediated hepatotoxicity

“…32 For example, 2 studies have previously reported that patients with mutated IGHV CLL have reduced numbers of Tregs. 33,34 We did find a lower baseline median percentage of Tregs in our patients with IGHV mutated disease (data not shown), although the difference was not statistically significant.…”

The Skewed Balance Between Tregs and Th17 in Chronic Lymphocytic Leukemia

“…Moreover, Jack et al showed that the increased frequency of Tregs in CLL patients is due to increased formation through CD27-CD70 interaction and increased resistance to apoptosis via increased levels of Bcl-2 antiapoptotic protein [71]. Following these findings, the increased frequency and absolute number of Tregs in CLL patients and its association with disease progression were demonstrated, repeatedly [72][73][74][75][76] (as shown in Table 2). …”

“…The increased frequency of Tregs not only was correlated with disease progression but also associated with different prognostic markers of CLL patients such as IGHV mutation status [72], CD38 expression [72] and the stage of disease [23][24]70,73].…”

Increased CD39 expression on CD4+ T lymphocytes has clinical and prognostic significance in chronic lymphocytic leukemia

“…Tregs are elevated in patients with CLL and correlate with a progressive disease [17]. It was recently reported that elevated Treg levels have a significant and independent prognostic power to predict the time to initial treatment in patients with low to intermediate stage CLL [18]. These observations parallel a recent report from Christopoulos et al [19] who describe a genetic signature presented by in vitro-stimulated CD4 + cells from patients with CLL that is compatible with the downregulation of proximal and intermediate T cell receptor signaling cascades and globally reduced cytokine secretion.…”