Michael Auerbach

Intravenous Iron Optimizes the Response to Recombinant Human Erythropoietin in Cancer Patients With Chemotherapy-Related Anemia: A Multicenter, Open-Label, Randomized Trial

PURPOSE Recombinant human erythropoietin (rHuEPO) is the standard of care for patients with chemotherapy-related anemia. Intravenous (IV) iron improves hemoglobin (Hb) response and decreases dosage requirements in patients with anemia of kidney disease, but its effect has not been studied in randomized trials in cancer patients. METHODS This prospective, multicenter, open-label, randomized trial enrolled 157 patients with chemotherapy-related anemia (Hb <or= 105 g/L, serum ferritin <or= 450 pmol/L or <or= 675 pmol/L with transferrin saturation <or= 19%) receiving subcutaneously rHuEPO 40000 U once weekly to: (1). no-iron; (2). oral iron 325 mg twice daily; (3) iron dextran repeated 100mg IV bolus; or (4) iron dextran total dose infusion (TDI). Hb and quality of life (QOL) were measured at baseline and throughout. RESULTS All groups showed Hb (P <.0001) increases from baseline. Mean Hb increases for both IV iron groups were greater (P <.02) than for no-iron and oral iron groups. The percentage of patients with hematopoietic responses was higher (P <.01) in both IV iron groups (each case 68%) compared with no-iron (25%) and oral iron (36%) groups. IV iron groups showed increases in energy, activity, and overall QOL from baseline, compared with a decrease in energy and activity for no-iron group and no change in activity or overall QOL for oral iron group. CONCLUSION rHuEPO increases Hb levels and improves QOL in patients with chemotherapy-related anemia. Magnitude of Hb increase and QOL improvement is significantly greater if IV iron is added.

Clinical Use of Intravenous Iron: Administration, Efficacy, and Safety

This section reviews the history, pharmacology, administration, efficacy, and toxicity of intravenous iron. Intravenous iron offers advantages over oral iron for the treatment of iron deficiency anemia across a wide range of disease states associated with absolute and functional iron deficiency. However, there remain concerns about the acute safety profiles of the available preparations and the potential for long-term toxicity with their repeated administration. Seven intravenous iron formulations are available. Confusion concerning the relative toxicities of the different formulations abounds. The similarities and differences are discussed. Iron repletion has been associated with adverse outcomes in infections. The relationship, if any, between intravenous iron administration and infections is reviewed. The potential advantages of total dose infusion (TDI), complete repletion in a single setting, are highlighted. A new paradigm for iron replacement therapy in iron deficiency anemia is presented.

Clinical update: intravenous iron for anaemia

For nearly half a century, parenteral iron has been considered dangerous and for use only in extreme situations and when oral iron was not tolerated. This proscription was based largely on poorly characterised and infrequent anaphylactoid reactions to the high-molecular-weight dextran preparation (Imferon) that for most of this time was the only product available. Moreover, when parenteral iron was necessary, the recommended approach was small intramuscular doses (≤100 mg), even after intravenous administration of the total iron defi cit as a single dose or as repetitive boluses was shown to be as safe and eff ective as the intramuscular route. This mindset persists despite the subsequent introduction of low-molecular-weight iron dextran and two iron salt preparations, ferric gluconate and iron saccharate (the latter is also known as iron sucrose), all of which are associated with fewer serious adverse events than the high-molecular-weight dextran. The introduction of recombinant erythropoietin for dialysis patients was associated with the development, in some individuals, of functional iron defi ciency that limited effi cacy. Intravenous iron, unlike oral iron, improves erythropoietic response in dialysis patients, and is now routinely used. The discovery of the iron regulatory peptide, hepcidin, has improved our understanding of the anaemia of chronic infl ammatory states, including cancer. Hepcidin is upregulated in these conditions, resulting in increased synthesis by the liver. Hepcidin inhibits iron transport across cell membranes, which decreases the accessibility of storage iron and gastrointestinal absorption of dietary iron, leading to an increased frequency of iron-restricted erythropoiesis, especially during therapy with recombinant erythropoietin. The most frequent laboratory fi ndings during the anaemia of chronic infl ammation are hypoferraemia and a low percent transferrin saturation, although these fi ndings are not always present. The increasing use of recombinant erythropoietin to treat anaemia in patients with chronic diseases has expanded the population of patients with functional iron defi ciency and increased interest in safe rational approaches to parenteral iron therapy. There is mounting evidence that anaemic patients with cancer undergoing chemotherapy and receiving recombinant erythropoietin respond better when parenteral iron is administered. This benefi t is independent of baseline iron variables, such as ferritin, low percentage transferrin saturation, and stainable marrow haemosiderin, leaving the clinician in need of laboratory variables to reliably detect iron-restricted erythropoiesis in patients with infl ammatory illnesses and to predict improvement of erythropoietic response to parenteral iron in the setting of infl ammatory illness. Two new laboratory measures look promising: percent hypochromic red blood cells and reticulocyte haemoglobin content. These tests are reliable and accurate correlates of functional iron defi ciency. Although these investigations are not yet widely available, their use will probably expand and guide identifi cation of functional iron defi ciency and rational intervention with parenteral iron. Currently, four parenteral iron preparations are available (table). No randomised trials have compared the safety and effi cacy of any of these agents. The largest retrospective review of dialysis experience suggests that most serious adverse events have been associated with the high-molecular-weight iron dextrans (Imferon, which is no longer available and the current preparation, Dexferrum) and are rare (<1:200 000) with the low-molecular-weight iron dextran or the two iron salts (fi gure). Adverse event rates might be somewhat higher in patients with infl ammatory diseases in which immune-mediated drug reactions may be observed more commonly than in dialysis patients. Some of the adverse clinical experience with parenteral iron is due to inappropriate supportive care. Myalgias, when they include chest and back discomfort, are mistakenly described as anaphylaxis, prompting Low–molecular–weight iron dextran Iron saccharate Ferric gluconate High–molecular–weight iron dextran

The prevalence and impact of restless legs syndrome on patients with iron deficiency anemia

Restless Legs Syndrome (RLS) a common, under‐recognized disorder disrupts sleep and diminishes quality of life. Despite a clear relation between low peripheral iron and increased prevalence and severity of RLS, the prevalence and clinical significance of RLS in iron‐deficient anemic (IDA) populations is unknown. In this study all new patients referred for anemia to a community‐based hematology practice over a 1‐year period (March 2011–2012) were included if they had IDA and no RLS treatment. Patients completed a validated questionnaire identifying RLS, blood tests, and a sleep‐vitality questionnaire (SVQ). Patients with RLS were compared to patients with no RLS for differences on SVQ, blood tests, baseline characteristics, and sleep quality. Three hundred forty‐three patients were evaluated and 251 (89.2% female, average age of 45.6 years) included in the study. The prevalence of clinically significant RLS (RLS sufferers) was 23.9%, nine times higher than the general population. IDA‐RLS sufferers reported poorer quality of sleep, decreased sleep time, increased tiredness, and decreased energy during the day compared to patients with IDA without RLS. Blood tests did not relate to RLS diagnosis but RLS was less likely for African‐American than Caucasian patients. Clinically significant RLS occurs commonly with IDA producing much greater disruption of sleep and shorter sleep times than does IDA alone. This indicates the need for identification of RLS with IDA and consideration of appropriate therapeutic interventions for this sizeable subgroup: either aggressive iron treatment to reduce the RLS symptoms or medications for RLS or both. Am. J. Hematol. 88:261–264, 2013.

Intravenous iron : From anathema to standard of care

A growing body of literature supports the use of intravenous iron as a compliment to erythropoiesis stimulatory therapy and in a significant number of disease states where iron is necessary and oral iron is ineffective or not tolerated. The differences in efficacy, safety, and clinical nature of serious adverse events that occur with the various iron preparations are poorly understood. Misinterpretation of adverse events leads to underutilization of this important treatment modality. Understanding the history of the development and use of intravenous iron is crucial to appreciate its importance in the management of anemias of dialysis, cancer, and cancer chemotherapy and properly assess side effects and toxicity. The benefits seen with intravenous iron therapy are independent of the pretreatment levels of serum ferritin, iron, total iron binding capacity, and percent transferrin saturation. Intravenous iron has been shown to overcome hepcidin induced iron restricted erythropoiesis in iron‐replete patients. Available clinical and experimental data suggest that increased utilization of intravenous iron should be considered. Am. J. Hematol., 2008.

Iron management in chronic kidney disease: conclusions from a “Kidney Disease: Improving Global Outcomes” (KDIGO) Controversies Conference

Before the introduction of erythropoiesis-stimulating agents (ESAs) in 1989, repeated transfusions given to patients with end-stage renal disease caused iron overload, and the need for supplemental iron was rare. However, with the widespread introduction of ESAs, it was recognized that supplemental iron was necessary to optimize hemoglobin response and allow reduction of the ESA dose for economic reasons and recent concerns about ESA safety. Iron supplementation was also found to be more efficacious via intravenous compared to oral administration, and the use of intravenous iron has escalated in recent years. The safety of various iron compounds has been of theoretical concern due to their potential to induce iron overload, oxidative stress, hypersensitivity reactions, and a permissive environment for infectious processes. Therefore, an expert group was convened to assess the benefits and risks of parenteral iron, and to provide strategies for its optimal use while mitigating the risk for acute reactions and other adverse effects.

Darbepoetin alfa 300 or 500 μg once every 3 weeks with or without intravenous Iron in patients with chemotherapy-induced anemia†

This study evaluated efficacy and safety of darbepoetin alfa administered every 3 weeks (Q3W) at fixed doses of 300 or 500 μg with or without intravenous (IV) iron in treating anemia in patients receiving multicycle chemotherapy. This Phase 2, double‐blind, 2 × 2 factorial study randomized patients to one of four treatment arms; darbepoetin alfa 300 μg (n = 62), darbepoetin alfa 300 μg plus IV iron (n = 60), darbepoetin alfa 500 μg (n = 60), or darbepoetin alfa 500 μg plus IV iron (n = 60). Patients had nonmyeloid malignancies, hemoglobin levels ≤10 g dL−1, and no iron deficiency. Primary endpoint was achievement of target hemoglobin (≥11 g dL−1). Secondary endpoints included incidence of transfusions and change in Functional Assessment of Cancer Therapy Fatigue (FACT‐F) score from baseline to end of study. Safety was evaluated by incidence of adverse events. No evidence of a statistically significant interaction between darbepoetin alfa dose received and IV iron usage was observed, therefore, results are provided separately comparing darbepoetin alfa doses and comparing IV iron usage groups. Similar proportions of patients receiving darbepoetin alfa 300 or 500 μg achieved target hemoglobin (75 and 78%, respectively); Kaplan–Meier median time to target hemoglobin was 10 and 8 weeks, respectively. More patients receiving IV iron (82%) than not receiving IV iron (72%) achieved hemoglobin target. Adverse events profiles were similar for darbepoetin alfa treatment groups. Transient anaphylactoid reactions were reported in two patients receiving IV iron. Darbepoetin alfa at 300 μg Q3W and 500 μg Q3W showed similar benefit, while added IV iron improved treatment response in these patients. Am. J. Hematol., 2010.

Iron Deficiency Anemia—Bridging the Knowledge and Practice Gap

Despite its high prevalence, anemia often does not receive proper clinical attention, and detection, evaluation, and management of iron deficiency anemia and iron-restricted erythropoiesis can possibly be an unmet medical need. A multidisciplinary panel of clinicians with expertise in anemia management convened and reviewed recent published data on prevalence, etiology, and health implications of anemia as well as current therapeutic options and available guidelines on management of anemia across various patient populations and made recommendations on the detection, diagnostic approach, and management of anemia. The available evidence confirms that the prevalence of anemia is high across all populations, especially in hospitalized patients. Anemia is associated with worse clinical outcomes including longer length of hospital stay, diminished quality of life, and increased risk of morbidity and mortality, and it is a modifiable risk factor of allogeneic blood transfusion with its own inherent risks. Iron deficiency is usually present in anemic patients. An algorithm for detection and management of anemia was discussed, which incorporated iron study (with primary emphasis on transferrin saturation), serum creatinine and glomerular filtration rate, and vitamin B12 and folic acid measurements. Management strategies included iron therapy (oral or intravenous), erythropoiesis-stimulating agents, and referral as needed.

How we diagnose and treat iron deficiency anemia.

It is estimated that one‐third of the worlds population is anemic, the majority being due to iron deficiency (ID). In adults, ID is associated with fatigue in the absence of anemia, restless legs syndrome, pica and, in neonates, delayed growth and development. In adolescents, ID is associated with decrements in learning and behavioral abnormalities. In the absence of a clear cause, search for a source of bleeding is indicated. No single test is diagnostic of ID unless the serum ferritin is low or the percent transferrin saturation is low with an elevated total iron binding capacity. Oral iron is considered front line therapy except for conditions such as gastric bypass, heavy uterine bleeding, inflammatory bowel disease, and hereditary hemorrhagic telangiectasia. Oral iron has many unpleasant side effects, resulting in low patient adherence. For patients intolerant of, or unresponsive to, oral iron, intravenous (IV) administration is the preferred route. While early formulations were associated with a high incidence of serious adverse events (SAEs), newer formulations are much safer with SAEs occurring very infrequently. Full replacement doses can be administered in a matter of minutes to a few hours. Nevertheless, there remains a reluctance to use IV iron due to a misunderstanding of the safety of the available formulations. IV iron is safe and effective in all clinical circumstances including pregnancy. The preponderance of published evidence suggests IV iron therapy is underutilized and we believe that IV iron should be moved forward in the treatment of ID and iron deficiency anemia (IDA). Am. J. Hematol. 91:31–38, 2016.

High-Molecular Weight Iron Dextran: A Wolf in Sheep's Clothing?

Parenteral iron is given to patients in a variety of formulations, including two iron dextran products known as high- (HMW) or low- (LMW) molecular weight iron dextran. Despite more risk of adverse events, HMW iron dextran is sometimes substituted for LMW iron dextran without physician knowledge for