CHICAGO – Serum hepcidin levels may help predict which cancer patients would benefit from the combination of erythropoiesis-stimulating agents and supplemental iron in the treatment of chemotherapy-associated anemia, new data suggest.
Investigators found a positive association between serum hepcidin levels and clinical response to the combination of darbepoetin alfa (Aranesp) and intravenous iron in a planned analysis of 489 patients in a randomized, phase III trial. The original study did not find a benefit from the combination, but the new analysis showed it was effective with higher doses of intravenous iron in people who had lower levels of hepcidin.
Overall, the analysis showed that patients who received four or five 187.5-mg doses of intravenous iron were the most likely to achieve a hemoglobin response (80%, vs. 65% for placebo, 67% for oral iron, and 56% for fewer than four doses of IV iron – all given in addition to darbepoetin). They also had the least need of red blood cell transfusions (9% vs. 13%-17% in the other groups).
The highest hemoglobin response rates in the study (92%-95%) occurred in 47 patients who had serum hepcidin levels below 64.3 ng/mL and received four to five doses of IV iron – and these patients required no red blood cell transfusions, Dr. David P. Steensma of Dana-Farber Cancer Institute, Boston, and his coauthors reported in a poster at the annual meeting of the American Society of Clinical Oncology.
"We found, interestingly, that patients who have lower hepcidin levels were much more likely to have positive response to the IV iron plus darbepoetin combination," Dr. Steensma said in an interview.
Hepcidin, a peptide made by hepatocytes, is a critical regulator of systemic iron homeostasis, and low serum hepcidin concentrations may predict iron deficiency, according to the poster.
This planned analysis followed a Mayo Clinic Cancer Research Consortium study which compared darbepoetin with darbepoetin plus oral iron and darbepoetin plus IV iron (ferrous sulfate) in two doses. The investigators reported that supplemental IV iron provided no additional benefit compared with oral placebo or oral iron in the trial (J. Clin. Oncol. 2011;29:97-105).
Serum hepcidin concentration was measured from samples taken before treatment from 405 (83%) of the 489 eligible patients. Stratification by tertiles showed the lowest tertile had up to 20.2 ng/mL, the middle greater than 20.ng/mL to 64.3 ng/mL, and the highest greater than 64.3 ng/mL.
"The conclusions from this evaluation were that lower pretreatment serum hepcidin was associated with better clinical response. Serum hepcidin measurements may help predict response to ESAs plus supplemental iron in future trials," Dr. Patricia Ganz of the University of California Los Angeles schools of medicine and public health said in an invited discussion of the study.
"The relative underdosing of IV iron in the [original] trial may explain the negative results, but the potential risks of higher doses of IV iron, e.g., iron overload, must also be considered," she said.
Asked whether this research would change his clinical practice, Dr. Steensma said that no serum hepcidin assay is commercially available, but that one is in development.
"I think that in the future I’ll probably use serum hepcidin to help distinguish a subset of patients who may have relative iron deficiency, or who may benefit from IV iron, and perhaps use that to help target patients who should receive combination therapy, versus those [for whom] maybe an ESA alone would be just fine," he said. "Especially if this is confirmed in other data sets."
The study was sponsored by Amgen. Dr. Steensma disclosed a consultant or advisory role with Amgen, maker of ESAs darbepoetin alfa and erythropoietin alfa. Dr. Ganz disclosed that her husband, Dr. Tomas Ganz, discovered hepcidin (Blood 2003;102:783-8), and that he has employment and stock ownership in Intrinsic LifeSciences, which is developing a test for hepcidin, has received research funding from Amgen, and has been a paid consultant to several companies including Ortho Biotech, which markets erythropoietin.