Serum Evaluation of a Panel of 10 Cytokines in Patients with Follicular Lymphoma: High Serum Level of TGF-β Correlates with Good Prognosis, Independently of the FLIPI Score.

The course of follicular lymphoma (FL) can be predicted using the FLIPI score but additional prognostic biomarkers are required. The immune microenvironment plays an important role in the physiopathology of FL. As cytokines are involved in the interaction between tumor cells and immune bystander cells, it is relevant to evaluate their prognostic value in FL. Nine cytokines (IL-1ra, IL-6, IL-7, IL-10, IL-13, TNFα, VEGF, PDGF, β-FGF) were measured by multiplex ELISA whereas TGF-β was measured by ELISA sandwich technique in the sera of 60 patients treated for FL (31 at diagnosis, 12 in complete remission (CR) and 21 at first relapse) and 20 healthy persons used as controls. All cytokines but β-FGF were detectable. High IL-6 levels were correlated with increased LDH levels. Increased levels of IL-10 at diagnosis were correlated with advanced stage (p=0.05), bone marrow involvement (p=0.05) and high FLIPI (trend, p=0.07). Levels of IL-10 were higher in FL patients at any time of the disease (diagnosis, relapse or CR) than in controls (respectively p<0.001, p=0.0001 and p=0.04). Levels of TGF-β were significantly lower in FL patients in relapse than in patients in CR (p=0.01) or controls (p=0.001). With a median follow-up of 9 years, overall survival (OS) rates in all patients were 69.9% and 57.5% at 6 and 10 years, respectively. Univariate analysis using clinical prognostic factors (β-2 microglobulin rate, stage, FLIPI score) showed that patients at diagnosis with elevated levels of IL-10 (HR=1.005, p=0.026) and decreased levels of TGF-β (HR=0.929, p=0.01) had shorter survival. In multivariate analysis, Ann Arbor stage I-II and high levels of TGF-β were independent prognostic factors associated with better survival. An elevation by 1ng/ml of TGF-β levels reduced the risk of death by 7%. In follicular lymphoma, a high level of TGF-β is an independent prognostic factor correlated with better survival. As immune microenvironment cells are correlated with survival, we propose to analyse the relationship between immunohistochemical staining of these cells and serum cytokine levels in patients. This is currently being investigated.