Serum Interleukin-18 Level Determines Clinical Outcome in Patients with Diffuse Large B-Cell Lymphoma in Rituximab Era.

Diffuse large B cell lymphoma (DLBCL) is a heterogeneous entity, with patients exhibiting a wide range of outcomes. The introduction of rituximab to CHOP (R-CHOP) has significantly altered improvement in survival. This raises concern regarding the utility of previously identified prognostic factors. Before rituximub era, some investigators have suggested that serum levels of some cytokines and their soluble receptors might reflect tumor growth and host tumor responses. Interleukin-18 (IL-18), originally designated as an interferon (IFN)-gamma inducing factor, is a cytokein which stimulates cytotoxic NK cell activity and T cells to produce IFN-gamma, IL-2, and GM-CSF. Increased IL-18 serum levels have been found in patients with some hematopoietic neoplasms. IL-18 is also immunostimulatory cytokine with antitumor activity in preclinical models, and a phase I study of recombinant human IL-18 was done to patients with advanced cancer. We have previously reported that IL-18 was strong prognostic factor in aggressive lymphoma patients who received CHOP without rituximab (ASH 2004, abstract #4543). The aim of the present study is to re-assess the prognostic significance of serum IL-18 in DLBCL treated with rituximab, and we also assessed IL-18 with subtype of DLBCL, GCB type and non GCB type.

Consecutive 154 previously untreated patients with DLBCL prospectively participated in this study between 2002 and 2008. The patients were treated with 6-8 cycles of R-CHOP or R-THP (pirarubicin) -COP regimens. There was no difference with CHOP and THP-COP in our recent prospective randomized study (Tsurumi H et. al. JCRCO 2004). Serum IL-18 was determined by ELISA, and we classified subgroups of DLBCL according to Hans et al.

In all patients with DLBCL, the mean ± SD of serum IL-18 level was 829.5±1280.8 pg/ml (range 56 - 8697.5) with a median of 415.8 pg/ml. Various poor prognostic features, such as poor PS, many extranodal sites, advanced disease (CS III/IV) increased LDH and elderly people were strongly associated with a high serum IL-18 levels. The median serum IL-18 levels of the different IPI risk groups were as follows: 201pg/ml for the L risk; 361pg/ml for the LI risk; 440pg/ml for the HI risk; 691pg/ml for the H risk, respectively (P<0.0001). A similar result was provided in rivised IPI (219pg/ml for the very good risk; 271 pg/ml for the good risk; 658 pg/ml for the poor risk, respectively P<0.0001). In addition, the serum IL-18 levels were higher in the non-GCB subgroup than in the GCB subgroup (P<0.005). Patients with high IL-18 (500 pg/ml and over) at onset had significantly lower progression free survival (PFS) rates (5-year: 52%), than those with low IL-18 (5-year: 79 %), respectively (P<0.0001). and In both GCB and non-GCB subgroups, patients with high IL-18 had significantly lower progression free survival rates (GCB and low IL-18:5-ys PFS 90%, GCB and high IL-18 %:5-ys PFS 58%, non-GCB and low IL-18:5-ys PFS 65%, non-GCB and high IL-18:5-ys PFS 42% ; P<0.001). Multivariate analysis employing IL-18 and some conventional prognostic factors demonstrated that age, PS and IL-18 for PFS were poor prognostic factors.

These results suggest that, in even rituximab era, a high serum IL-18 level predicts a poor prognosis of DLBCL and may be a useful biomarker for selecting appropriate treatment. Upfront high dose chemotherapy might be well indicated for non-GCB type DLBCL patients with serum high IL-18.

No relevant conflicts of interest to declare.