Intravenous iron failed to improve erythropoietic response in patients with chemotherapy-induced anemia

Steensma DP. J Clin Oncol. 2010;doi:10.1200/JCO.2010.30.3644.

Issue: December 25, 2010

The addition of intravenous ferric gluconate to darbepoetin alfa did not improve the erythropoietic response rate in patients with nonmyeloid malignancies who have chemotherapy-induced anemia, according to researchers from the Mayo Clinic.

“One of the most common reasons for a lack of response to erythropoiesis-stimulating agent treatment is iron deficiency,” the researchers wrote. “… In the nephrology/hemodialysis setting, parenteral iron administration is a standard practice, but use of IV iron is currently infrequent in oncology clinics.”

The prospective, multicenter, randomized trial included 502 patients with hemoglobin levels of less than 11 g/dL who were undergoing chemotherapy for nonmyeloid malignancies. All patients were being treated with darbepoetin alfa, once every 3 weeks. The patients were randomly assigned to receive 187.5 mg of ferric gluconate intravenously every 3 weeks, 325 mg of oral daily ferrous sulfate or oral placebo for 16 weeks.

The primary endpoint was an erythropoietic response, defined as a 2 g/dL or more improvement in hemoglobin levels. Secondary endpoints included transfusion requirements, ESA dose used, safety and quality of life.

The erythropoietic response rates were similar in all three groups. In the IV iron group, 69.5% of the patients achieved a response vs. 66.9% of those who received oral iron and 65% of those who received the placebo. The number of blood transfusions required was similar in all of the groups. There were no significant differences in quality of life or ESA dose among the three groups. Adverse events were more common in the IV iron arm, but this was not significant.

The erythropoietic response rates were similar in all three groups. In the IV iron group, 69.5% of the patients achieved a response vs. 66.9% of those who received oral iron and 65% of those who received placebo. The number of blood transfusions required was similar in all of the groups. There were no significant differences in quality of life or ESA dose among the three groups. Adverse events were more common in the IV iron arm, but this was not significant.

Steensma DP. J Clin Oncol. 2010;doi:10.1200/JCO.2010.30.3644.

This was a well-done, randomized, placebo-controlled trial and the largest trial of its kind. But why was the outcome of this study negative when others were not? First, the mean dose of iron actually delivered was around 650 mg, which is considerably lower than the mean dose in previous studies. Second, there are considerable data that the amount of iron given at any time may affect the ability of the delivered iron to synergize with the ESA to improve erythropoiesis in patients with iron lack and functional iron deficiency, which many patients with chemotherapy-induced anemia have. In this trial, patients received 187.5 mg every 3 weeks, which is 62.5 mg per week. In a previous study, patients received 200 mg every 3 weeks, and it turned out positive. But in that study, the mean dose of iron delivered was significantly higher by about 400 mg. It’s possible that the iron dose given in this study was too low, due to an unexplained number of patients who did not complete the planned course. This was supported by the greater transferring saturation increments in the oral iron group compared with the IV iron group, when typically the reverse has been seen. Another possibility is that they enrolled patients with higher transferrin saturations (<60%) than were permitted in previously published trials, which may have skewed the response rate to some degree. Most physicians agree that 60% transferrin saturation is reflective of neither absolute nor functional iron deficiency. It would have been interesting to see the response rates stratified by transferrin saturations.

The data showed an increased rate of grade-3 or -4 adverse events for IV iron — the rate was 55%, which caused premature closure of the trial. But for placebo, there was a 47% adverse event rate. One wonders what the real adverse event rate was. We just don’t see anything that remotely resembles that rate in practice. I’ve given thousands of doses of IV iron, and adverse events are extremely uncommon. In addition, the investigators allowed the use of premedication such as antihistamines, and it’s possible, as the authors appropriately suggested, that this contributed to the high adverse event rate, since the oral iron patients could not have been premedicated. In summary, the conduct of the study was very good and the data are what they are. Two meta-analyses presented at the ASH Annual Meeting concluded that IV iron, when added to ESAs for chemotherapy-induced anemia, was associated with improved response rates, decreased ESA exposure to target hemoglobin levels, and decreased transfusions without an increase in adverse events. With new IV iron products that promise to allow full iron replacement dosing in an hour or less, more well-done corroborating studies are likely to be seen.

– Michael Auerbach, MD
Clinical Professor of Medicine, Georgetown University School of Medicine

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