Intravenous iron in chemotherapy-induced anemia
Authors: Michael Auerbach
Journal: American Journal of Hematology (2014)

To the Editor: This is the seventh in a series of short articles concerning iron deficiency and the role of intravenous iron. At a time when resources are scarce and restrictions on the use of erythropoiesis stimulating agents (ESAs) 1 have resulted in a significant increment in transfusions among patients with chemotherapy-induced anemia (CIA) 2, it remains puzzling why guidelines incorporating intravenous (IV) iron as a standard in CIA vary among the different governing bodies. To date, 12 of 12 prospective studies examining the role of intravenous iron as an adjunct to ESAs or as sole therapy have shown benefit. One negative trial which demonstrated no synergy in hemoglobin response or symptomatic improvement 3 resulted in changed conclusions after a re-analysis of the intention to treat population revealed those randomized to intravenous iron who actually received at least 80% of the planned dose enjoyed similar benefits seen in the previously published prospective trials 4. Therefore, based on all prospective published evidence, co-administration of intravenous iron or intravenous iron alone improves responses to ESAs and hemoglobin respectively, in the treatment of CIA without appreciable clinically significant adverse events. Space does not permit an in-depth description of the trials. Interested readers are referred to two recent reviews 5, 6. Six studies encompassing 1,768 patients received ESAs plus or minus intravenous iron for CIA. All showed increments in hemoglobin response rates, decreased transfusions, decreased time to reach target hemoglobin and when examined, a decrease in ESA dose for similar benefits observed without intravenous iron. In one study in patients with lymphoproliferative disease not on chemotherapy, a positive hemosiderin stain on a bone marrow aspirate, the gold standard for iron repletion, was an entrance requirement 7. As observed in the CIA studies, IV iron added to ESAs resulted in a significant improvement in response rate as well as an 11,000 unit per week reduction in ESA usage for a similar benefit. In another study, 127 subjects were examined, who underwent autologous bone marrow transplant 8. IV iron when added to ESAs showed a significant benefit in hemoglobin response compared to ESA alone. A unique aspect of this trial was the five year follow-up of those enrolled. At that time there was no statistically significant difference in relapse rate or change in progression-free survival in the IV iron group compared to controls. Four studies evaluated the ability of intravenous iron without ESAs to decrease significant anemia progression or increase hemoglobin. While hemoglobin responses were smaller than in the trials examining the synergy between intravenous iron and ESAs, in all four trials, intravenous iron alone resulted in improved hemoglobin responses compared to no treatment. As was the case in the other trials, the benefits seen were independent of baseline iron parameters supporting the notion that intravenous iron is beneficial in CIA even if iron replete at commencement of therapy. In the largest of these trials, Steinmetz et al. examined 135 patients with CIA and noted a substantial increase in hemoglobin levels and stabilization to the 11–12 g/dl range without ESAs 9. Intravenous iron may also have a salutary effect on the incidence of venous thromboembolism, the most clinically significant adverse event associated ESA therapy. In an animal model, Loo and Beguin showed a statistically significant reduction in platelet counts in rats given intravenous iron compared to controls 10, which in a post hoc exploratory analysis of CIA patients randomized to ESA alone or with IV iron translated to a reduction in thromboembolic events and platelet counts in patients given IV iron with ESAs compared to ESAs alone 11. All of the above conclusions were supported by a large meta-analysis which searched 1,118 relevant trails of which 56 were included including two presented abstracts 6. The meta-analysis did not take into account the recant of the one negative study with intravenous iron in CIA which would have strengthened the conclusions. ESAs were administered in all but two. Most included most solid tumors but one with lymphoproliferative diseases not on chemotherapy and another post-autologous bone marrow transplant. Irrespective of the method of intravenous iron administration, a clear improvement in response rates was observed. A statistically significant decrement in transfusions was also reported which applied to those who received IV iron alone or with ESAs. In conclusion, studies comprising thousands of patients demonstrate intravenous iron synergizes with ESAs for those being treated for CIA with improvements in hemoglobin responses, time to target, decreased red cell transfusion, improvement in quality of life parameters, and cost savings. Most importantly, these observations occurred without treatment related clinically significant toxicity. Intravenous iron as sole therapy for CIA promises to overcome a significant portion of the gap created by the 2007 CMS decision memo restricting ESA usage. Compared to the cost of ESAs, the cost of intravenous iron is negligible. Based on the preponderance of published evidence, failure to add intravenous iron to the standard treatment paradigm of CIA is suboptimal. Michael Auerbach* Auerbach Hematology and Oncology, Baltimore, Maryland