Prediction of Survival in Patients with Non-Hodgkin’s Lymphoma: Role of Tumor Necrosis Factor Ligand-Receptor and Extracellular Protein Kinase A.

Backgrounds: The International Prognostic Index (IPI) is the most commonly used survival parameter for patients with Non-Hodgkin’s lymphoma (NHL). To investigate an another factor to predict survival, we studied the role of tumor necrosis factor receptor with molecular weight of 75 kd (p75-R-TNF) and extracellular protein kinase A (ECPKA). TNF has a central role in inflammatory processes, and its receptor is constitutively found in the circulation and is elevated in a variety diseases. The cAMP-dependent protein kinase (PKA) is critically involved in the regulation of metabolism, cell growth and differentiation, and gene expression. PKA is a predominantly intracellular enzyme, but it has been shown that cancer cells of various cell types excrete PKA into the conditioned medium. This extracellular form i.e., ECPKA is known to be upregulated in the serum of cancer patients as compared with normal serum. The aim of this prospective study was to evaluate p75-R-TNF and ECPKA as feasible prognostic factors for patients with NHL.

Methods: From October 2003 to May 2005, chemotherapy-naive patients with NHL who were planned to receive CEOP-B or R-CHOP chemotherapy at Guro Hospital, Korea University were enrolled. Blood sampling for p75-R-TNF and ECPKA was done before chemotherapy initiation and was stored at −70°C until the assay. The level of p75-R-TNF was measured using ELISA kit. ECPKA was measured by RIA method. A total of 20 serum samples from normal people were used as control.

Results: A total of 45 patients were enrolled. The male to female ratio was 22:23, and the median age was 58 years old (range: 29–87). Indolent histologic type and aggressive type were 4 and 41 patients, respectively. Twenty-two patients were limited stage (stage I, II) and 23 patients were advanced stage (stage III, IV). The level (mean±SD) of p75-R-TNF was 1066.6±1174.9 pg/ml for patient group and that of control group was 678.2±312.4 pg/ml. ECPKA activity of patient group was 87.6±21.1 mU/ml as compared with 40.6±21.5 mU/ml in control group. During the median follow-up period of 8.5 months, 12 patients died and 33 patients were alive. As a result of univariate analysis, serum albumin (p=0.005), hemoglobin (p=0.054), the IPI score [0–2 vs 3–5] (p=0.006), occurrence of febrile neutropenia (p=0.01), and level of p75-R-TNF (p=0.003) were significantly associated with survival. By logistic regression testing, p75-R-TNF level was identified as an independent predictive factor for survival (p=0.037). Median survival of patients with elevated p75-R-TNF (cutoff: 678.2 pg/ml) was 10.5 months. For patients with p75-R-TNF < 678.2 pg/ml, median value was not reached yet.

Conclusions: This study indicates that in addition to the IPI, high baseline levels of p75-R-TNF can predict the survival of patients with NHL. The levels of ECPKA were elevated in patient group than those of normal controls, but its level could not predict the prognosis.