Advanced cancer is often accompanied by anaemia, which may worsen with concomitant administration of chemotherapy. Serum erythropoietin (EPO) concentrations are lower in cancer patients than in patients with iron deficiency, suggesting that the anaemia observed in cancer patients is at least partially due to a relative deficiency of EPO. Consequently, we studied the effects of recombinant human erythropoietin (r-HuEPO) therapy in three populations of anaemic cancer patients: patients not receiving concomitant chemotherapy or radiotherapy; patients receiving cyclic, non-cisplatin-containing chemotherapy, and patients receiving cyclic cisplatin-containing chemotherapy. Therapy with r-HuEPO was well tolerated; it increased haematocrit levels and corrected anaemia, irrespective of concomitant chemotherapy or the type of chemotherapy administered. A dose of 150 U/kg r-HuEPO given subcutaneously 3 times weekly decreased transfusion requirements after the 1st month of therapy; improved functional capacity was noted in patients who achieved a significant increase in haematocrit in response to r-HuEPO therapy.

A double-blind, placebo-controlled study of the pharmacokinetics and safety of multiple doses of recombinant human erythropoietin [rHuEPO 150 or 300 U/kg either by intravenous (IV) bolus or subcutaneously (SC)] in normal male subjects demonstrated that rHuEPO had a dose- related effect on the hematocrit independent of the route of administration and that multiple doses of rHuEPO had no direct pressor effects. When rHuEPO was injected IV, a monoexponential decrease in serum EPO level was evident for 18 to 24 hours postdose. Absorption of SC injected rHuEPO occurred more slowly, with relatively low serum EPO levels being maintained for 48 hours. All rHuEPO antibody titer determinations were negative. With the exception of significant increases in hemoglobin and hematocrit, no clinically significant changes occurred. No hypertensive, convulsive, or thrombotic events were observed. Of the adverse experiences observed in 10 subjects, none was considered clinically significant, and none of the subjects dropped out because of adverse experiences.

A double-blind, placebo-controlled study of the pharmacokinetics and safety of multiple doses of recombinant human erythropoietin [rHuEPO 150 or 300 U/kg either by intravenous (IV) bolus or subcutaneously (SC)] in normal male subjects demonstrated that rHuEPO had a dose- related effect on the hematocrit independent of the route of administration and that multiple doses of rHuEPO had no direct pressor effects. When rHuEPO was injected IV, a monoexponential decrease in serum EPO level was evident for 18 to 24 hours postdose. Absorption of SC injected rHuEPO occurred more slowly, with relatively low serum EPO levels being maintained for 48 hours. All rHuEPO antibody titer determinations were negative. With the exception of significant increases in hemoglobin and hematocrit, no clinically significant changes occurred. No hypertensive, convulsive, or thrombotic events were observed. Of the adverse experiences observed in 10 subjects, none was considered clinically significant, and none of the subjects dropped out because of adverse experiences.

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Twenty patients with myelodysplastic syndromes (MDS) entered a randomized, placebo-controlled, double-blind trial designed to evaluate the efficacy and toxicity of high doses of recombinant human erythropoietin (rhEPO). Patients completing the trial were eligible to receive rhEPO as part of an open-label study. Eighteen patients were transfusion dependent; 10 had refractory anemia (RA), and 10 had refractory anemia with ringed sideroblasts (RARS). A response to rhEPO was defined as an increase in hematocrit of 4 percentage points or more over baseline, or the elimination of all transfusions with the hematocrit stable at the baseline level. In the double-blind trial, 1 patient (12.5%) receiving rhEPO responded, as compared with no responses in the placebo group. Overall, responses occurred in 4 of 17 patients (24%) receiving rhEPO at a dose of 1,200 to 1,600 U/kg intravenously (IV) twice weekly. Changes in granulocyte or platelet counts were not observed. Despite the administration of high doses of rhEPO, toxicity attributable to rhEPO was not observed in either the double-blind or open-label study. Response to rhEPO was not significantly related to age, gender, type of MDS, time since diagnosis, time since initiation of transfusion therapy, or baseline serum EPO. These studies indicate that rhEPO can be administered safely in very high doses to patients with MDS and that 24% of these patients will respond with increased erythropoiesis.