title: A phase I trial of recombinant human interleukin-6 in patients with myelodysplastic syndromes and thrombocytopenia.
abstract: To evaluate the hematologic effects of recombinant human interleukin-6 (rhIL-6, Escherichia coli, SDZ ILS 969, IL-6), and determine its toxicity profile, we performed a phase I trial of IL-6 in 22 patients with various myelodysplastic syndromes (MDS), platelet counts < 100,000/microL, and < 5% bone marrow (BM) blasts. Patients received one of four doses of IL-6 (1.0, 2.5, 3.75, and 5.0 micrograms/kg/d) as a subcutaneous injection on day 1, followed by a 7-day wash-out period, and then 28 days of IL-6 therapy. Dose-limiting toxicities of fatigue, fever, and elevated alkaline phosphatase were seen at 5.0 micrograms/kg/d; the maximum tolerated dose was 3.75 micrograms/kg/d. All patients experienced at least grade II fever and all had an increase in acute phase proteins. Eight patients (36%) experienced at least a transient improvement in platelet counts; three fulfilled the criteria for response, whereas five others had clinically significant increases that failed to meet response criteria. Various IL-6-related toxicities prevented more than three patients from receiving maintenance therapy. Two of the three patients who received maintenance IL-6 therapy had a persistent increase in platelet counts, during 3 and 12 months of IL-6 therapy, respectively. Laboratory studies indicated that IL-6 increased the frequency of higher ploidy megakaryocytes but did not significantly increase the number of assayable megakaryocytic progenitor cells, suggesting that IL-6 acts as a maturational agent rather than a megakaryocyte colony-stimulating factor. Although IL-6 therapy can promote thrombopoiesis in some MDS patients, its limited activity and significant therapy-related toxicity preclude its use as a single agent in this patient population. Further studies, combining low doses of IL-6 with other hematopoietic growth factors, are underway.
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, USA.
authors.forename: M S
authors.initials: MS
authors.lastname: Gordon
authors.forename: J
authors.initials: J
authors.lastname: Nemunaitis
authors.forename: R
authors.initials: R
authors.lastname: Hoffman
authors.forename: R L
authors.initials: RL
authors.lastname: Paquette
authors.forename: C
authors.initials: C
authors.lastname: Rosenfeld
authors.forename: S
authors.initials: S
authors.lastname: Manfreda
authors.forename: R
authors.initials: R
authors.lastname: Isaacs
authors.forename: S D
authors.initials: SD
authors.lastname: Nimer
mesh_terms: D000209:Acute-Phase Proteins / Q000032:analysis; D000293:Adolescent; D000328:Adult; D000368:Aged; D001853:Bone Marrow / Q000473:pathology; D015331:Cohort Studies; D005260:Female; D005334:Fever / Q000139:chemically induced; D006261:Headache / Q000139:chemically induced; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use*; D007279:Injections, Subcutaneous; D015850:Interleukin-6 / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*; D007518:Isoantibodies / Q000097:blood; D007677:Kidney Function Tests; D008111:Liver Function Tests; D008297:Male; D008533:Megakaryocytes / Q000187:drug effects; D008875:Middle Aged; D009135:Muscular Diseases / Q000139:chemically induced; D009190:Myelodysplastic Syndromes / Q000150:complications / Q000401:mortality / Q000628:therapy*; D010976:Platelet Count / Q000187:drug effects; D011003:Ploidies; D011994:Recombinant Proteins / Q000627:therapeutic use; D013921:Thrombocytopenia / Q000209:etiology / Q000401:mortality / Q000628:therapy*; D016896:Treatment Outcome
chemical_list: D000209:Acute-Phase Proteins; D007155:Immunologic Factors; D015850:Interleukin-6; D007518:Isoantibodies; D011994:Recombinant Proteins