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Emerging Concepts in the Management of Iron Deficiency Anemia

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - 54th Annual Meeting of the American Society of Hematology

Atlanta, Georgia / December 8-11, 2012

Atlanta - It is estimated that as many as 1.6 billion people have iron deficiency anemia (WHO Global Database on Anaemia. 2008;1-40, WHO anaemia fact sheet. 2001;114). Oral iron remains the preferred first-line treatment for iron deficiency anemia, but for various reasons, some patients cannot take iron or do not achieve adequate responses. The only approved alternatives to oral iron in North America are iron dextrans, which have potential drawbacks related to safety and patient convenience. Progress in the development of a new generation of intravenous iron preparations may address many of the limitations of currently available treatment options.

Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec

Alternatives to Oral Therapy

A substantial proportion of patients with iron deficiency anemia (IDA) achieve inadequate hemoglobin (Hb) responses to oral iron: intolerance, suboptimal response to therapy and poor absorption, among the chief reasons (Am J Medicine 2000;109:27-32). In North America, options for intravenous (IV) iron supplementation in patients without chronic kidney disease (CKD) have been limited to iron dextran products. The U.S. Food and Drug Administration has required these products to carry boxed warnings related to potential anaphylactic reactions. Moreover, IV iron dextrans have inconvenient dosing schedules involving IM injections, multiple IV infusions or a lenghty total dose infusion over many hours that may discourage patient adherence. “Therefore, many of these patients do not get IV iron and remain inadequately treated and symptomatic,” Dr. Saroj Vadhan-Raj, University of Texas MD Anderson Cancer Center, Houston, noted in a poster presentation.

Recently, ferumoxytol, a new IV iron formulation approved for treatment of IDA in patients with CKD, has been investigated in IDA patients without CKD who have a history of unsatisfactory oral iron therapy or in whom oral iron cannot be used.

Dr. Vadhan-Raj presented results from a multicentre, randomized, placebo-controlled trial in non-CKD patients with IDA who could not tolerate or had not responded adequately to oral iron supplementation.

The IDA-301 study involved 808 patients with a baseline Hb level of 7-10 g/dL randomized 3:1 to two doses of ferumoxytol 510 mg or placebo, each administered 2-8 days apart and followed for 5 weeks. The primary end point was the proportion patients achieving Hb improvement of ≥2 g/dL.

The primary analysis showed that 81% of patients treated with ferumoxytol had ≥2 g/dL increase from baseline in Hb vs. 5.5% of patients in the placebo group (P<0.0001). Moreover, ferumoxytol-treated patients had a mean Hb improvement of 2.7 g/dL from baseline, as compared with 0.1 g/dL in the placebo group (P<0.0001) (Abstract 2098).

Safety data showed the IV iron supplement was generally well tolerated and the trial produced no new safety signals, reported Dr. Vadhan-Raj. Adverse event rates were similar with ferumoxytol (49.2%; 2.6% serious) and placebo (43%; 3% serious). “Two doses of ferumoxytol were shown to be highly effective in raising Hb and iron parameters in non-CKD patients with iron deficiency anemia who had a history of unsatisfactory oral iron therapy,” she remarked. “We believe ferumoxytol could provide an important new treatment option for patients with iron deficiency with a history of unsatisfactory oral iron therapy or in whom oral iron could not be used,” Dr. Vadhan-Raj concluded.

Preserving Quality of Life

Iron deficiency anemia can profoundly affect quality of life (QoL), and many patients report high levels of fatigue, dyspnea and loss of energy or vitality. As part of the IDA-301 protocol, patients completed a series of questionnaires that assessed the impact of IDA on patient-reported outcomes, including changes in response to treatment.

Instruments used to assess patient-reported outcomes included the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale, the Linear Analog Scale Assessment (LASA) of energy and the vitality component of the 36-item Short Form Health Survey (SF-36) (Abstract 478).

The baseline mean FACIT-Fatigue score was 24.1 in the ferumoxytol group and 24.7 in the placebo group. After 5 weeks of treatment, the fatigue score had improved by an average of 10.6 points vs. 5.7 points in placebo arm (P<0.0001). The difference of 4.9 exceeded the 3.0 threshold reported to be clinically important in cancer patients with anemia.

“Ferumoxytol-treated patients had a greater improvement in the FACIT-Fatigue scores compared to placebo at all time points,” stated Dr. Vadhan-Raj. “A statistically significant difference between groups was observed within the first week.” Moreover, the magnitude of improvement in the FACIT-Fatigue score tracked the improvement in Hb in response to treatment with ferumoxytol, she added.

Comparison of LASA scores showed significantly greater improvement with ferumoxytol compared with the placebo group at all time points and for the subscales of energy, activities of daily living and QoL (P=0.0106 to P<0.0001). The results also showed a statistically significant 10.7-point improvement in the SF-36 vitality scale as compared with minimal change in the placebo arm (P<0.0001).

IV Options

In another randomized clinical trial, ferumoxytol was compared with IV iron sucrose in non-CKD patients with anemia and a history of inadequate response to oral iron supplements.

Investigators randomized 605 patients 2:1 to ferumoxytol or iron sucrose and followed for 5 weeks (Abstract 2099). Patients randomized to ferumoxytol received a 510 mg (17 mL) injection on day 1 and a second dose 2 to 8 days later. Those randomized to iron sucrose received 200 mg (10 mL) on 5 non-consecutive days over a 14-day period.

The primary end point was the proportion of patients who had ≥2 g/dL increase in Hb from baseline to 5 weeks. The results showed that 84% of the ferumoxytol group and 81% of the iron sucrose group met the primary end point.

Patients treated with ferumoxytol had an improvement in Hb that averaged 2.7 g/dL compared with 2.4 g/dL for iron sucrose, reported Dr. David Hetzel, Royal Adelaide Hospital, Australia.

Overall, the two IV iron formulations had similar safety profiles and no new safety signals were identified, Dr. Hetzel reported.

Searching for Marker of Response

For assessment of iron status, the role of hepcidin in regulating iron availability for erythropoiesis has attracted considerable interest as a potential novel biomarker.

“Traditional biochemical assays are limited in evaluation of patients’ iron status, since they are affected by inflammation,” explained Dr. Lawrence Goodnough, Stanford University, California. “Hepcidin is a major regulator of iron homeostasis and affects availability of iron for erythropoiesis. Hepcidin may therefore serve as a biomarker for responsiveness to oral iron therapy in patients suspected to have IDA.”

To examine the potential of hepcidin assay as a means of monitoring therapy for IDA, investigators in a randomized trial of IV ferric carboxymaltose included a screening assay for hepcidin in the evaluation and monitoring of a subgroup of patients (Abstract 484). The primary objective was to determine whether hepcidin levels predict responsiveness to iron therapy.

Patients underwent hepcidin screening at baseline and after a 14-day run-in of oral iron supplementation. Patients who did not achieve ≥1 g/dL increase in Hb were considered nonresponders and randomized to receive IV ferric carboxymaltose or an oral iron supplement.

Dr. Goodnough and colleagues compared hepcidin values for 22 patients who did not respond to the 14-day trial of iron supplementation and 22 patients who did respond. The nonresponding patients had significantly higher hepcidin levels (33.2 vs. 8.7 ng/mL, P=0.0036). Of patients subsequently randomized to an additional 4 weeks of oral iron, only 20% achieved ≥1 g/dL increase in serum Hb compared with 65.3% of patients randomized to ferric carboxymaltose.

“Nonresponsiveness to oral iron therapy does not rule out iron deficiency,” noted Dr. Goodnough. “IV ferric carboxymaltose produced high responses in two thirds of patients who had no previous response to a 14-day trial of oral iron therapy. These findings suggest that in patients with inflammation, IV iron may be the preferred route of iron therapy.”

Summary

Iron deficiency anemia affects one fourth of the world’s population. Many patients remain inadequately treated with currently available oral iron and IV iron dextrans. Development of a new generation of IV iron products has led to therapeutic strategies that offer promise for improving IDA in the non-CKD patient population.    

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