Recombinant human interleukin-6 induces a rapid and reversible anemia in cancer patients

Initial studies have shown that recombinant human interleukin-6 (rhIL- 6) induces anemia. Until now, the pathophysiologic mechanism of this induced anemia has been unknown. To unravel the underlying mechanism, we examined 15 cancer patients receiving rhIL-6 as an antitumor immunotherapy in a phase II study. rhIL-6 was administered subcutaneously at 150 micrograms once daily for 6 consecutive weeks. Various hematologic and biochemical parameters were measured weekly during rhIL-6 treatment and 4 weeks after rhIL-6 discontinuation. To determine plasma volume and red blood cell (RBC) volume, radioisotope dilution assays with labeled autologous RBCs and with human serum albumin were performed before rhIL-6 administration and on day 8 of rhIL-6 therapy. Hemoglobin levels decreased (mean change +/- SE) 7% +/- 1.5% within 3 days after the start of rhIL-6 therapy (P < .0001) and 19% +/- 2% at week 4. Levels had normalized at follow-up. The plasma volume increased 18% +/- 5% during the first week of rhIL-6 administration (P < .003), whereas RBC volume remained unaffected. The mean RBC corpuscular volume remained unchanged for 2 weeks and then began to decrease slowly, reaching its nadir at week 6 (5% +/- 1%; P < .01). Serum iron levels decreased 65% +/- 12% at week 4 (P < .002) and then returned to initial baseline values. Erythropoietin levels increased rapidly up to 68% at week 3 (P < .0001) and had normalized 4 weeks after rhIL-6 therapy. Levels of serum albumin, prealbumin, and transferrin decreased (P < .0001, P < .003, and P < .0001, respectively), whereas levels of serum amyloid A (P < .003), C-reactive protein, haptoglobin, and alpha-1-antitrypsin (P < .0001) increased during rhIL-6 treatment. All levels returned to pretreatment values after discontinuation of rhIL-6. No alterations in reticulocyte counts, serum lactic dehydrogenase levels, and bilirubin levels were observed. A 6-week regimen of subcutaneous rhIL-6 results in a rapid dilution anemia, caused by an acute and significant increase in plasma volume and followed by hypoferremia. This anemia is reversible after the cessation of rhIL-6 treatment.     

The modulatory impact of recombinant human interleukin-6 on the immune system of cancer patients.

To investigate the immunomodulatory impact of low-dose recombinant human interleukin-6 (rhIL-6), we examined 15 patients with metastatic renal cell carcinoma or malignant melanoma receiving rhIL-6 as an antitumor agent in a phase II trial. RhIL-6 (150 micrograms) was administered subcutaneously (s.c.) once daily for 42 consecutive days. Immunologic parameters were measured throughout therapy and at follow-up. No changes in white blood cell counts were noted. Lymphocyte subsets did not alter, nor did their expression of CD25 and HLA-DR. Immunoglobulins were unaffected. Levels of granulocyte-macrophage colony-stimulating factor, tumor necrosis factor-alpha and IL-1 beta remained below detection limits. Theoretically, subtle immunologic alterations might have been masked by increases in plasma volume, known to occur after start of therapy. Using previously published data concerning plasma volume changes in these patients, part of immunologic data were corrected for concurrent hemodilution, showing a 39% +/- 17% increase in monocytes (mean change +/- SEM [standard error of mean]; p < 0.03) within 1 week of therapy, while lymphocytes tended to increase. However, the absence of appreciable increases in cell activation markers and in monokine levels indicates insufficient immune activation, probably underlying the lack of objective antitumor responses (6 x stable, 9 x progressive disease) in these patients. In conclusion, the immunomodulatory impact of rhIL-6, if present at all, remains very limited.     

Outpatient-based subcutaneous interleukin-2 monotherapy in advanced renal cell carcinoma: an update

To minimize interleukin-2-related toxicity while retaining its efficacy, a treatment schedule utilizing subcutaneous IL-2 was evaluated in a phase II setting. Eighty unselected, consecutive patients with metastatic or recurrent renal cell carcinoma (RCC), mean age 58 years (range, 21 to 76), received IL-2 on an outpatient basis, 5 days per week for 4 or 6 consecutive weeks. During the first 5-day cycle, a dose of 18 million IU IL-2 was administered once a day; during subsequent cycles the dose in the first two days was reduced to 9 million IU. Two 6-week or three 4-week courses were given maximally. Patients who had completed at least one full course were considered evaluable. To circumvent flu-like symptoms, all patients received a maximum oral dose of 3 g acetaminophen daily. Seventy-seven patients were assessable for response. Three (4%) complete responses (CR) and 6 (8%) partial responses (PR) were observed, and 44 (57%) patients had stable disease (SD). Response durations were 64, 29, 29+ months for the CR and 2, 6, 8, 11, 32, 47 months for the PR. The median length of survival of all patients was 12 months, whereas the median survival of responders and non-responders was 35+ and 10+ months, respectively (P < 0.001). Side effects included fever, chills, nausea, vomiting, and transient inflammation and induration at the injection sites. These complications were acceptable, even in the patients with concomitant disease, and completely disappeared after cessation of IL-2. Subcutaneous IL-2 mediates antitumor responses, has limited side effects and is also suitable for elderly RCC patients with concomitant disease.     

Negative inotropic effects of recombinant interleukin 2 in patients without left ventricular dysfunction

Experimental data have shown that rIL2 has negative inotropic properties. This has not been investigated in humans with normal left ventricular function. Seventeen consecutive renal cell carcinoma patients who received rIL2 therapy because of dissemination were analyzed before and after treatment with a low dose of rIL2 subcutaneously. Left ventricular ejection fraction (echocardiography), heart rate variability parameters (24 h electrocardiography), and TNF alpha, IL1 beta and nitric oxide metabolites (NO(x)) were measured. LVEF decreased from 54+/-7 to 50+/-6% (mean+/-S.D.; P=0.012), with a concomitant increase in heart rate from 87+/-13 to 94+/-13 beats/min (P=0.031). All frequency domain HRV parameters decreased: the total power from 18.0+/-7.9 to 14.0+/-5.0 ms (P=0.001), the low frequency from 10.3+/-5.4 to 8. 3+/-3.4 ms (P=0.001), and the high frequency from 6.3+/-2.6 to 4. 5+/-1.1 ms (P=0.001). There was no measurable effect on TNF alpha, IL1 beta concentrations. Plasma levels of nitrate (NO(x)) increased from 22.8+/-14.4 to 41.8+/-26.6 micromol/l (P=0.007). CONCLUSIONS: A low dose of rIL2 has a negative inotropic effect that may be mediated by increased NO concentrations. It also reduces sympathetic activity as reflected in HRV parameters.