title: Recombinant human interleukin-6 induces a rapid and reversible anemia in cancer patients.
abstract: 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.
authors.affiliation: Department of Internal Medicine, University Hospital Groningen, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Nieken
authors.forename: N H
authors.initials: NH
authors.lastname: Mulder
authors.forename: J
authors.initials: J
authors.lastname: Buter
authors.forename: E
authors.initials: E
authors.lastname: Vellenga
authors.forename: P C
authors.initials: PC
authors.lastname: Limburg
authors.forename: D A
authors.initials: DA
authors.lastname: Piers
authors.forename: E G
authors.initials: EG
authors.lastname: de Vries
mesh_terms: D000209:Acute-Phase Proteins / Q000378:metabolism; D000328:Adult; D000740:Anemia / Q000139:chemically induced*; D001810:Blood Volume / Q000187:drug effects; D002292:Carcinoma, Renal Cell / Q000188:drug therapy*; D005260:Female; D006242:Haptoglobins / Q000378:metabolism; D006410:Hematopoiesis / Q000187:drug effects; D006801:Humans; D015850:Interleukin-6 / Q000009:adverse effects* / Q000627:therapeutic use; D007501:Iron / Q000097:blood; D007680:Kidney Neoplasms / Q000188:drug therapy*; D008297:Male; D008545:Melanoma / Q000188:drug therapy*; D008875:Middle Aged; D010976:Platelet Count / Q000187:drug effects; D011994:Recombinant Proteins; D013997:Time Factors
chemical_list: D000209:Acute-Phase Proteins; D006242:Haptoglobins; D015850:Interleukin-6; D011994:Recombinant Proteins; D007501:Iron