The role of iron in ACD

Iron therapy

The recognition of the role of functional iron deficiency in the pathogenesis of ACD, together with the development of new formulations of parenteral iron, have led to a re-evaluation of iron supplementation in the management of this anemia. As already discussed, IDA frequently co-exists with ACD, and it is clearly important that true deficiency of iron is corrected. However, even in patients with ‘pure’ ACD, iron supplementation may theoretically be beneficial. Iron deficiency may also develop during the treatment of ACD with EPOs and limit the hematological response to these agents.

Oral iron supplements are often poorly tolerated, and patients frequently show poor compliance: in addition, patients with ACD will usually have raised hepcidin levels, which would be expected to inhibit intestinal iron absorption. However, oral iron is cheap, widely available, and easy to give, and given the difficulties in ruling out concomitant IDA in many patients with ACD, a trial of oral iron will be undertaken by many clinicians treating ACD. It must however be recognized that failure to respond to oral iron rules out neither true, nor functional iron deficiency.

There is little literature on the use of intravenous iron supplementation alone in the treatment of ACD. Cazzola et al on the beneficial effects of intravenous iron in 20 consecutive patients with juvenile chronic arthritis, although it is likely that a significant proportion of these patients also had true iron deficiency. Studies in patients with gynaecological cancer also showed a benefit in terms of reduced transfusion requirements for those receiving intravenous iron supplementation. However baseline iron status was not reported in either of these papers, and clearly larger studies are needed.

Much of the literature concerning intravenous iron supplementation has come from the field of renal medicine, where the superiority of parenteral over oral iron supplementation is now well established, and not only improves the responses to EPOs but can also lead to reduced doses of EPOs being used. The DRIVE (Dialysis Patients’ Response to IV iron and with Elevated Ferritin) trial randomized selected hemodialysis patients with elevated ferritin and reduced transferrin saturation to receive or not receive intravenous ferric gluconate together with EPO. The patients who received IV iron showed more rapid and better responses in Hb level than the controls, and similar responses were seen in patients with transferrin saturations above and below 19%, leading the authors to conclude that functional iron deficiency was a significant contributor to anemia in this setting, and that this could be overcome by intravenous iron supplementation.

There is now evidence that intravenous iron can enhance the effects of EPOs in patients with other forms of ACD, particularly cancer-related anemia. Auerbach et al randomized 155 patients being treated with EPOs for chemotherapy-related anaemia to no iron, oral iron or intravenous iron: there were significant improvements in hematological responses in patients receiving intravenous iron compared with those receiving either no iron or oral iron. These observations have been confirmed in several subsequent studies. Criteria for exclusion of co-existent IDA varied between these trials, and it is possible that significant numbers of patients included were in fact iron deficient, but the study by Hedenus et al is of particular interest as it enrolled only patients with lymphoproliferative malignancies not receiving chemotherapy, and all patients had detectable bone marrow iron stores.

In contrast, a recent study by Steensma et al randomized patients with chemotherapy-associated anemia to no iron, oral iron or intravenous iron plus darbepoietin: all had serum ferritin >20 μg/l and transferrin saturations <60%. There was no difference in erythropoietic response between the three groups. The mean pre-treatment ferritin levels in this study were higher than in the other studies, suggesting this population was less likely to have co-existent IDA, and the doses and scheduling of iron infusions were lower. Both these observations may partly explain the different results observed, but it is clear that further prospective studies, with better characterization of baseline iron stores are needed to define the role of intravenous iron supplementation in this setting. The ASH/ASCO guidelines recommend periodic monitoring of iron status in patients receiving treatment with EPOs but fall short of recommending intravenous supplementation to augment responses.

It is not yet known how intravenous iron might overcome the reticuloendothelial blockade on iron utilization thought to be fundamental to the pathogenesis of ACD, but it is possible that the infused iron may become bound directly to transferrin rather than being taken up by macrophages, and is thus available to the erythron. There are however no in vitro data to support this hypothesis.

Safety issues also need to be considered when using intravenous iron, particularly as older preparations were associated with significant adverse events, including anaphylaxis. Recent pharmacological developments have led to the release of several new iron formulations including low molecular weight iron dextran (Cosmofer), iron sucrose (Venofer), ferric carboxymaltose (Ferinject) and sodium ferric gluconate (Ferrlecit). In the trials above, no excess of adverse effects was observed with these newer intravenous iron preparations. One hypothesis for the hypoferremia seen in ACD is that low iron levels might inhibit bacterial growth, as iron is essential for the growth and survival of intracellular bacteria, but there is no evidence to date that supplemental iron increases the risk of infections. However, the long-term effects of intravenous iron administration on other parameters, for example tumor growth and cardiovascular disease, have not been studied.