Serum Soluble Tumor Necrosis Factor Recepter 2 Levels Is Associated with the Outcome of Patients with Diffuse Large B-Cell Lymphoma Treated with R-CHOP Regimen

We have previously reported that serum concentration of serum-soluble tumor necrosis factor receptor 2 (sTNF-R2) predicts the clinical outcome of patients with aggressive non-Hodgkin's lymphoma (NHL) treated with CHOP without rituximab (Goto et al. 2005). We extracted the diffuse large B-cell lymphoma (DLBCL) patients from aggressive NHL, used in our previous study, and extended our observation period. We found that serum sTNF-R2 level was a strong independent prognostic factor even for long-term observation in the CHOP era (8-year overall survival (OS); high serum sTNF-R2 group: 17.6%, low sTNF-R2 group: 69.8%, P<0.0001). Based on the result, we analyzed serum sTNF-R2 for patients with DLBCL who had received the CHOP plus rituximab (R-CHOP) regimen.

We aim to re-assess the prognostic significance of serum sTNF-R2 for DLBCL patients treated with R-CHOP regimen, and to assess sTNF-R2 with subtype of DLBCL, such as germinal center B cell type (GCB type) and non-GCB type which were classified by Hans et al. method (Hans et al. 2004).

Consecutive 154 untreated patients with DLBCL prospectively participated in this study between 2002 and 2008. The patients were treated with R-CHOP.

In all patients with DLBCL, the median of serum sTNF-R2 level was 13.72 ng/ml (range 2.66–112.5 ng/ml). Various poor prognostic indicators, such as elderly age, poor performance status, increased LDH, multiple extranodal involvement sites, advanced disease, and existence of B-symptoms, were strongly associated with high serum sTNF-R2 levels. Serum sTNF-R2 levels significantly correlated with the increasing grade of international prognostic index (IPI), revised-IPI (R-IPI) (Sehn et al. 2007), and subtype, respectively (P<0.0001, P<0.0001, P=0.0058). We established the cut-off value for sTNFR2 at 20 ng/ml which was determined by ROC analysis. Patients with high sTNF-R2 (20 ng/ml and over) at onset had significantly lower OS rate (5-year: 29%), than that with low sTNF-R2 (5-year: 83%), respectively (P <0.0001). Multivariate analysis involving R-IPI, subtypes of DLBCL and serum sTNF-R2 revealed that sTNFR-2 significantly correlated with OS and progression free survival (PFS) (OS: P = 0.0001, PFS: P= 0.0085). Additionally, as the OS rate was about 50% even in the poor prognosis group of R-IPI, we tried to divide risk categories of R-IPI into low and high sTNF-R2 groups, resulting actually in five groups: very good risk group, good risk group with high sTNF-R2, good risk group with low sTNF-R2, poor risk group with high TNF-R2, and poor risk group with low sTNF-R2. A strong significant difference was observed. (5-year OS; very good risk group: 100%, good risk group with high sTNF-R2: 20%, good risk group with low sTNF-R2: 85%, poor risk group with high TNF-R2: 28.6%, and poor risk group with low sTNF-R2: 77.8%.)

These results suggest that a high serum sTNF-R2 level predicts a poor prognosis in DLBCL and may be a useful biomarker for selecting appropriate treatment. Upfront high dose chemotherapy or alternative therapy of first line chemotherapy instead of R-CHOP might be well indicated for DLBCL patients with high serum sTNF-R2.

No relevant conflicts of interest to declare.