Serum Interleukin-18 Levels Are Associated with Response to Treatment and Survival in Patients with Aggressive Non-Hodgkin’s Lymphoma.

Interleukin-18 (IL-18), originally designated as an interferon (IFN)-gamma inducing factor, is a cytokine which induces cytotoxic NK cell activity and stimulates T cells to produce IFN-gamma, IL-2, and GM-CSF. Increased serum IL-18 levels have been found in patients with acute lymphoblastic leukemia, chronic myelocytic leukemia, multiple myeloma and non-Hodgkin’s lymphoma (NHL). The aim of the present study was to assess the prognostic significance of serum IL-18 in aggressive NHL. Consecutive 99 previously untreated patients with aggressive NHL (diffuse large B-cell lymphoma; 84 patients, peripheral T-cell lymphoma; 15 patients) prospectively participated in this study between 1997 and 2003. The patients were treated with 6–8 cycles of CHOP or THP (pirarubicin) -COP regimens. To evaluate serum levels of IL-18, venous blood samples were drawn from patients immediately before the initiation of treatment. In all patients with aggressive NHL, the mean ± SD of serum IL-18 level was 1200.8±151.5 pg/ml (range 96–6603.5) with a median of 556.75 pg/ml. Several poor prognostic features such as poor PS, multiple extranodal sites, advanced disease (clinical stage III/IV), existence of B-symptom, and high soluble interleukin-2 receptor (sIL-2R) were strongly associated with a high serum IL-18 levels. An increased LDH and gender were weakly associated with a high serum IL-18. Histology and age were not associated with serum IL-18 levels. The median serum IL-18 levels of the different IPI risk groups were; 321 pg/ml for the L risk; 442 pg/ml for the LI risk; 557 pg/ml for the HI risk; 1532 pg/ml for the H risk, respectively (P<0.005). The CR rate of patients with an IL-18 level of less than 700 pg/ml was better than that of 700 pg/ml or higher (77% and 50%, P<0.01). Patients with high IL-18 (700 pg/ml and over) at onset had a significantly lower survival rate (5-year: 25%) than those with low IL-18 (below 700 pg/ml) (68 %) ( p<0.0001). Multivariate analysis employing IL-18 and some conventional prognostic factors demonstrated that IL-18, performance status and the number of extranodal sites were significantly poor prognostic factors for both overall survival (OS) and event free survival (EFS). The results suggest that a high serum IL-18 level predicts a poor prognosis in aggressive NHL and may be a useful biomarker for selecting appropriate treatment.