Blood Concentrations of Tumor Necrosis Factor-Alpha in Malignant Lymphomas and Their Decrease as a Predictor of Disease Control in Response to Low-Dose Subcutaneous Immunotherapy with Interleukin-2

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Abstract
Tumor necrosis factor-alpha (TNF-α), a cytokine provided by both immunomodulating and inflammatory activities, has been described to be abnormally increased in the blood of patients affected by malignant lymphomas, particularly NHL. However, the biological and clinical significance of TNF-α secretion in malignant lymphomas is still controversial. The present study was carried out to further define TNF-α secretion in untreated malignant lymphomas and during low-dose IL-2 immunotherapy. The study included 80 malignant lymphoma patients, 54 of whom were affected by HD and the other 26 by NHL. The mean TNF-α serum concentrations observed in untreated lymphoma patients were significantly higher than those seen in the healthy controls, without significant differences between HD and NHL. Moreover, both HD and NHL lymphoma patients at clinical stage III-IV showed significantly higher mean TNF-α levels than those at clinical stage I-II. Finally, patients with systemic symptoms had higher mean TNF-α concentrations than those without any systemic symptoms, even though statistical significance was observed only for NHL patients. In a second study we have evaluated changes in TNF-α levels in seven evaluable lymphoma patients (NHL: 6; HD: 1) - who did not respond to conventional therapies - during subcutaneous low-dose IL-2 (3 MIU/day 6 days/week for 4 weeks). Long-term stable disease was achieved in four patients with NHL, whereas the other three progressed. In patients with stable disease the mean TNF-α concentrations significantly decreased during treatment, whereas they increased in progressing patients. This study, by showing an abnormally enhanced TNF-α secretion in both NHL and HD patients with advanced disease and systemic symptoms and a decrease in its levels in patients who achieved disease control on IL-2 immunotherapy, appears to confirm the unfavorable prognostic significance of enhanced TNF-α levels in malignant lymphomas.