SERUM INTERLEUKIN-6 LEVELS ARE ELEVATED IN LYMPHOMA PATIENTS AND CORRELATE WITH SURVIVAL IN ADVANCED HODGKINS-DISEASE AND WITH B-SYMPTOMS

Several cytokines including gamma-interferon, tumor necrosis factor al pha, interleukin 1beta (IL-1beta), and interleukin 6 (IL-6) are pyroge nic and can inhibit lipogenic processes. Because patients with lymphom a often suffer from fever, weight loss, and night sweats (B symptoms), the etiology of which is unknown, the authors investigated serum leve ls of these cytokines in normal volunteers and in patients with Hodgki n's and non-Hodgkin's lymphoma. Sixty serum samples from patients with Hodgkin's disease (28 patients) or non-Hodgkin's lymphoma (32 patient s), as well as 20 samples from normal volunteers, were collected. The majority of patients had advanced (Stage III or IV) or relapsed diseas e. The assay for gamma-interferon was a specific and sensitive radioim munoassay (lower limit of detection 0.1 unit/ml); the assays for tumor necrosis factor alpha, IL-1beta, and IL-6 were enzyme-linked immunoas says with lower limits of sensitivity of 10 pg/ml. 20 pg/ml, and 22 pg /ml, respectively. There were no statistically significant differences in gamma-interferon, tumor necrosis factor alpha, or IL-1beta levels between lymphoma patients and normal subjects. In contrast, 20 of 57 p atients (35%) with lymphoma as compared with 0 of 19 normal volunteers (0%) had detectable serum IL-6 levels (P < 0.005, chi2 test). Interes tingly, 17 of 29 lymphoma patients with B symptoms (59%) as opposed to 3 of 28 lymphoma patients without B symptoms (11%) had detectable ser um IL-6 levels (P < 0.001, chi2 test); the median IL-6 level was 28.9 pg/ml (B symptoms present) versus undetectable (no B symptoms) (P < 0. 005, Mann-Whitney U test). Analyzing Hodgkin's and non-Hodgkin's lymph oma groups separately revealed similar results. IL-6 levels showed no significant correlation with time from diagnosis, beta2-microglobulin, or lactate dehydrogenase levels. However, analysis by the method of K aplan and Meir demonstrated that the median survival of Hodgkin's dise ase patients with detectable IL-6 levels (greater-than-or-equal-to pg/ ml) was 10 mo, whereas the median survival has not been reached at a m edian follow-up time of 37.5 mo in those patients with lower values (W ilcoxon P value = 0.0012). There were too few patients in each subset of non-Hodgkin's lymphoma to determine the correlation between IL-6 an d survival but, considered as a single group, a statistically signific ant correlation was not found. We conclude that serum IL-6 levels are elevated in a substantial proportion of patients with lymphoma and tha t an association exists between endogenous over-production of IL-6 and the presence of B symptoms. Furthermore, serum levels of IL-6 of grea ter-than-or-equal-to 22 pg/ml are associated with a significantly shor ter survival in patients with advanced or relapsed Hodgkin's disease.