Interleukin-6-associated anemia: determination of the underlying mechanism

Recombinant human interleukin-6 (rhIL-6) is a pluripotent cytokine with proinflammatory, antitumor, and growth factor effects. Clinical investigations of rhIL-6 either alone as immunotherapy or as a colony-stimulating factor in conjunction with chemotherapy have shown a dose-dependent, rapid onset, and largely reversible decrease in venous hematocrit levels. In an effort to determine the mechanism for the rhIL-6-associated anemia, we measured red blood cell volume serially in patients receiving rhIL-6 at either 30 micrograms/kg/day as a 120-hour continuous intravenous infusion (renal cell carcinoma) or 100 micrograms/kg/d intravenously over 1 hour for 5 days (melanoma) as part of two separate phase II trials. Radioisotope dilution assays with 51Cr-labeled autologous red blood cells and hemolysis screens were performed on day 1 before the initiation of therapy and on day 5 shortly before the end of therapy. In the 6 patients studied, the mean decrease in hemoglobin concentration was 1.9 +/- 0.94 g/dL. The mean decrease in the hematocrit level was 6% +/- 2% and the mean increase in total blood volume was 731 +/- 337 mL. These changes were explained by a mean decrease in red blood mass of 106 +/- 109 mL and a mean increase in plasma volume of 743 +/- 289 mL. The decrease in red blood cell mass was largely explained by phlebotomy during the hospitalization, but was not statistically significant (paired t-test, P = .06). All other changes were statistically significant (P < .05). Simple regression analysis indicated that the decrease in hematocrit level and increase in plasma volume were related (y = -1.78 - .0066X; R = -.74). Measurements of lactate dehydrogenase, bilirubin, haptoglobin, and reticulocyte counts and serial stool hemoccults did not indicate hemolysis or blood loss. We conclude that the anemia caused by IL-6 is caused by an increase in plasma volume.