A Phase III, Randomized Study of the Effects of Parenteral Iron, Oral Iron, or No Iron Supplementation On the Erythropoietic Response to Darbepoetin Alfa for Patients with Chemotherapy-Associated Anemia: A Study of the Mayo Clinic Cancer Research Consortium (MCCRC).

Erythropoiesis stimulating agents (ESAs) improve hemoglobin (Hb) levels and reduce red blood cell (RBC) transfusion requirements in patients (pts) with chemotherapy-associated anemia (CAA), but many pts with CAA do not respond to ESAs. Functional iron deficiency due to inflammation-related hepcidin production and pathological sequestration of bioavailable iron may be an important reason for lack of ESA response in iron-replete pts. The common clinical practice of co-administering oral iron with ESAs does not appear to alter the disordered iron processing in CAA. We conducted a prospective trial to evaluate whether parenteral iron might overcome functional iron deficiency and benefit iron-replete pts with CAA undergoing ESA treatment.

Eligible pts were receiving chemotherapy for a non-myeloid neoplasm and had Hb level <11.0 g/dL, ferritin >20 ng/mL, transferrin saturation <60%, and ECOG performance score ≤2. All pts received darbepoetin alfa (DA) 500 mcg subcutaneously q3wks until Hb reached >11 g/dL, and thereafter DA 300 mcg q3wks; DA was held for Hb >13 g/dL until Hb fell to <12 g/dL, then restarted with 25% dose reduction. Pts were randomized 1:1:1 to receive either sodium ferric gluconate complex in sucrose (Ferrlecit) 187.5 mg intravenously q3wks (total dose 1,125 mg), oral ferrous sulfate 325 mg once daily, or oral placebo. Quality of life (QOL) was measured using the Symptom Distress Scale, Brief Fatigue Inventory, FACT-An, and LASA instruments. The primary endpoint was the proportion of patients achieving Hb ≥12.0 g/dL or ≥2.0 g/dL Hb increment from baseline by the end of the 16-week study. Secondary endpoints included transfusion requirements. changes in QOL, changes in iron parameters, and adverse events (AEs).

Planned enrollment was 582 pts, but the study met an early stopping rule due to an excess of serious AEs in the IV iron arm; 502 pts enrolled at 14 MCCRC sites between February 2006 and December 2008. The median age of the 490 evaluable pts was 64 years; 65% were female and 94% white; 6% had hematological neoplasms (lymphoma or multiple myeloma), 25% had severe anemia (Hb <9.5 g/dL), 48% received platinum-containing therapy, and 66% completed all 16 weeks of the study. Baseline characteristics were comparable between groups. With respect to the primary endpoint, 69.5% of IV iron-treated pts achieved a Hb response (median Hb increase from baseline to end of study, 2.7 g/dl), compared to 66.9% with oral iron (median increase, 2.4 g/dL) and 65.0% with placebo (median increase 2.3 g/dl) (p=0.73). There were no significant differences in the proportion of patients requiring RBC transfusion (12.8% for IV iron, 12.9% for oral iron, 13.5% for placebo; p=0.87) or QOL changes. A total of 17 pts (3%) died on study–8 in the IV iron arm, 6 oral iron, 3 placebo (p=0.22). Grade 3 or higher AEs occurred in 54% of IV iron pts compared to 43% for oral iron and 45% placebo (p=0.03). The end-of-study ferritin level was higher in the IV iron arm (median 501 ng/mL) compared to the oral iron (229 ng/mL) and placebo (193 ng/mL) arms (p=0.0022). The median total DA dose administered was similar between arms (p=0.71).

Co-administration of DA with intravenous ferrous gluconate q3wks did not result in improvement in Hb levels, reduce transfusions, improve QOL endpoints, or allow lower doses of DA, compared with DA + oral iron or DA + placebo. IV iron increased AEs. The reason for discordant results with 5 previous smaller studies is unclear.

The study was supported by a grant from Amgen (Thousand Oaks, CA) to the MCCRC.

Off Label Use: Ferrlecit, chemotherapy-associated anemia.