Elevated circulating levels of TNF alpha and its p55 soluble receptor are associated with an adverse prognosis in lymphoma patients

In 88 newly diagnosed lymphoma patients, tumour necrosis factor alpha (TNF alpha) and soluble TNF type I receptor (p55-R-TNF) were prospectively determined in plasma by immunoradiometric assay (IRMA) and ELISA methods respectively. These 88 patients included 19 with centrocyto-centroblastic lymphoma, 13 patients with other low-grade lymphoma, and 56 with high-grade lymphoma, Median TNF alpha plasma values were 20 pg/ml (range 5-380 pg/ml) in patients versus 7 pg/ml (range 4-9 pg/ml) in 20 healthy control subjects. Presence of TNF alpha level greater than or equal to 20 pg/ml was significantly associated with elevated LDH level (P < 0.0001), serum beta 2-microglobulin level greater than or equal to 3 mg/l (P < 0.0001), haemoglobin less than or equal to 12 g/dl (P = 0.0001), Ann Arbor stage III or IV disease (P < 0.005), and with bulky tumour (P = 0.01). High level of TNF alpha was also associated with B symptoms (P < 0.005), poor performance status (P < 0.05), and serum albumin less than or equal to 35 g/l (P < 0.05), Levels of p55-R-TNF were also markedly elevated in these lymphoma patients (median of 3.5 ng/ml, range 0.8-18.8 ng/ml) versus 1.45 ng/ml in control subjects (range 1.1-2.3 ng/ml). Level of p55-R-TNF greater than or equal to 3.5 ng/ml was significantly associated with poor performance status (P < 0.0001), B symptoms (P < 0.0001), P2-microglobulin levels greater than or equal to 3 mg/l (P < 0.0001), serum albumin less than or equal to 35 g/l (P = 0.0001), C-reactive protein > 6 mg/l (P = 0.0003), elevated (> 20 pg/ml) IL-6 level (P < 0.005), haemoglobin less than or equal to 12 g/dl (P < 0.005), and bulky tumour (P < 0.001). In the whole group of 88 patients, both high TNF alpha and p55-R-TNF levels strongly predicted short progression-free survival (P < 0.005 for both variables) and overall survival (P < 0.001 and P < 0.0001 respectively). In multivariate analyses the elevation of p55-R-TNF retained a higher significance over the other variables and therefore improved the predictive value of the International Prognostic Index. This study suggests that elevated TNF alpha and p55-R-TNF levels have a high correlation with other adverse prognostic factors in lymphoma patients and may predict a poor outcome.