IV iron sucrose for cancer and/or chemotherapy-induced anemia in patients treated with erythropoiesis-stimulating agents

1 Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA; 2 Nashat Cancer Center, Canton, OH; 3 Kentucky Cancer Clinic, Hazard, KY; 4 Florida Cancer Specialists, Fort Myers, FL; 5 Hematology/Oncology Group of Fresno, Fresno, CA; 6 Newland Medical Associates, Southfield, MI; 7 Oncology/Hematology Associates, Indianapolis, IN; 8 AAI Pharma, Inc., Natick, MA; and 9 Luitpold Pharmaceuticals/American Regent, Inc., Norristown, PA

Manuscript received January 2, 2011; accepted June 16, 2011.

This work was presented at the 43rd Annual Meeting of the American Society of Clinical Oncology; June 1–5, 2007 in Chicago, IL, and was supported by Luitpold Pharmaceuticals/American Regent, Inc., Shirley, NY.

Correspondence to: Lowell B. Anthony, MD, LSUHSC New Orleans, Ochsner Kenner Medical Center, 200 West Esplanade, Kenner, LA 70065; e-mail: lantho@lsuhsc.edu.

Conflicts of interest: Ms. Niforos was a fulltime salaried employee of AAI Pharma, Inc., contracted to perform all biostatistical services for the clinical trial. Dr. Mangione was a fulltime salaried employee of the trial sponsor, Luitpold Pharmaceuticals/American Regent, Inc. Drs. Anthony, Gabrail, Ghazal, Woytowitz, Flam, Drelichman, and Loesch have nothing to disclose.

Mild-to-moderate anemia occurs in up to 75% of cancer patients undergoing either single- or multimodality therapy and may contribute to an increased morbidity and reduced quality of life (QOL).1–4 This form of anemia resembles anemia of chronic disease, with a blunted erythropoietin response and inadequate erythropoietin production.5 Increasing hemoglobin (Hgb) concentrations and reducing red blood cell (RBC) transfusions while improving QOL and tolerance to cancer therapies are the treatment-related goals.

Intravenous (IV) iron is commonly administered with ESAs in CKD-associated anemia.12,13 Most studies regarding IV iron replacement in cancer and/or chemotherapy-induced anemia (CCIA) are positive, with one exception: Steensma et al14 reported no benefit in adding IV ferric gluconate to an ESA in a phase III randomized trial in which an oral placebo and iron were used as comparators. Practice guidelines are inconsistent, as the National Comprehensive Cancer Network (NCCN) recommends the IV route when iron is prescribed,6 and the American Society of Hematology/ American Society of Clinical Oncology considers the evidence insufficient to support routine IV iron use.15,16 Auerbach et al17 demonstrated that IV iron dextran results in a greater Hgb level increase than oral iron in ESAtreated patients. Approved formulations of IV iron in the United States include iron dextran, iron sucrose, and ferric gluconate, with the majority of published data with iron dextran.15,18,19 However, the iron dextrans have black-box warnings, and test doses are recommended. Henry et al20 reported that IV ferric gluconate significantly increased Hgb response when compared with oral iron or no iron and was well tolerated in CCIA.

Early work with IV iron sucrose includes a trial evaluating 67 lymphoma patients randomized between ESA or ESA with IV iron sucrose.21 Despite adequate bone marrow iron stores, the Hgb response was greater (91% vs 54%) and the time to reach a Hgb level > 2 g/dL was less (6 vs 12 weeks) in the IV iron-treated group.21 Another trial randomized 398 CCIA patients between fixed IV iron doses (mean weekly dose, 64.8 mg) with ESA versus standard practice (2% received IV iron).22 IV iron resulted in a trend toward a higher ferritin level, but transferrin saturation (TSAT) remained similar between the two groups.22 A study in patients with noniron-deficient anemic solid tumors receiving chemotherapy also demonstrated an increase in hemoglobin levels statistically favoring the darbepoetin alfa (Aranesp)/iron group.23 As additional information is needed, this study was performed to determine whether IV iron sucrose combined with ESA increases Hgb levels in CCIA patients who have been previously treated with an ESA.

Patients and methods
Patient eligibility
his was an open-label, phase III, randomized, institutional review board-approved, multicenter study at 56 US centers. After signing informed consent, patients ≥ 18 years of age with a histologic diagnosis of cancer (acute leukemia or myeloproliferative syndrome excluded) receiving ongoing or planned chemotherapy, with a Hgb level ≤ 10.0 g/dL, body weight > 50 kg, and a Karnofsky performance status of ≥ 60%, were eligible. Patients were excluded if they had iron depletion, active infection, myelophthisic bone marrow (except for hematologic malignancy), hypoplastic bone marrow, uncontrolled hypertension, bleeding, or planned surgery. To ensure a stable baseline Hgb value, no IV iron within 2 months of consent or RBC transfusions within 3 weeks of randomization were allowed.

Treatment
After 8 weeks of fixed ESA doses in stage 1, patients were classified as either ESA responders (≥ 1 g/dL Hgb level increase from baseline) or nonresponders (< 1 g/dL Hgb level increase from baseline), with each group separately randomized centrally using block randomization to receive either IV iron sucrose or no iron treatment (Figure 1). At the time of randomization (beginning of stage 2), patients were stratified according to malignancy type (solid tumor vs hematologic) and Hgb level (< 12 g/dL vs ≥ 12 g/dL for ESA responders; < 9.5 g/dL vs ≥ 9.5 g/dL for ESA nonresponders).

The calculated dose of the study drug (iron sucrose [Venofer]; 7 mg/kg up to 500 mg maximum) was added to 500 mL of normal or half-normal saline and administered IV over 4 hours.24 Patients randomized to receive iron sucrose were scheduled to receive up to three infusions at 1- to 3-week intervals during the first 9 weeks of stage 2, with the first dose administered as soon as possible after randomization. The last dose of ESA was given on or before week 12 of stage 2.

Outcome measures
The primary endpoint for efficacy was the change from baseline (end of stage 1) to the maximum Hgb level achieved during stage 2 in patients who responded to ESA. Major secondary endpoints included changes in Hgb levels when iron sucrose was added to ESA nonresponders as well as the percentage of all randomized patients with Hgb level increases > 1 g/dL, > 2 g/dL, and > 3 g/dL; changes in Hgb levels and iron indices from baseline at each visit; and changes in the 13-item Functional Assessment of Chronic Illness Therapy (FACIT) fatigue scale. Hgb levels were obtained weekly, and iron indices were measured every 3 weeks. The FACIT fatigue scale was measured during stage 1 at consent, weeks 4, and 8 and during stage 2 weeks 3, 6, 9, and at the end of the study.

Adverse events were recorded hourly during iron sucrose administration and from the day of randomization through study completion or 30 days following the last dose of study drug, whichever was later. Investigators provided the date of onset, severity, relationship, date of resolution, action taken, and adverse event outcome. Adverse drug events were events considered by the investigator to be possibly, probably, or definitely related to the study drug.

Statistical method
The sample size was based on the hypothesis that iron-treated ESA responders (group A) would have a 1.0 g/dL or higher mean increase in Hgb levels than would ESA responders who did not receive iron (group B). The standard deviation (SD) of the difference was assumed to be ≤ 1.5 g/dL. Targeting a 1.0 g/dL change in Hgb level to be significant, 49 patients/ group were required (alpha = 0.05; beta = 0.10). Assuming that the ESA response rate in stage I was at least 40% and that the stage I and stage 2 dropout rates were no more than 10% and 25%, respectively, 325 patients were the targeted number for stage I enrollment, with adjustments made by monitoring the stage I response rate.

The intent-to-treat (ITT) population included patients randomized into stage 2 based on actual treatment. The evaluable population included ITT patients who completed at least 10 weeks of stage 2 or who had interventions (RBC transfusions or nonstudy iron) prior to week 10.

Continuous variables were assessed using analysis of covariance and t-tests. Ordinal responses were analyzed with the Fisher’s exact test and Cochran-Mantel-Haenszel statistics. Changes from baseline to each visit for all FACIT scores were assessed for treatment groups with the unpaired two-sample t-test.

Results
Patient disposition and demographics
Of the 375 patients enrolled during the run-in stage 1 period (between July 2003 and October 2005), 132 patients discontinued treatment (the most common reasons were a required intervention [50], withdrawn consent [23], and adverse events [17]). Fourteen patients completed stage 1 but did not enter stage 2. Figure 2 shows the numbers of patients who were randomly assigned to the two treatment groups and were evaluated for safety and efficacy as well as reasons for study discontinuation. Table 1 shows the patient numbers assigned to the various treatment groups (A to D) based on ESA response in stage I and the study population; it also demonstrates the similar baseline demographic characteristics between the treatment groups. At baseline (ie, prior to randomization), there were no statistically significant differences in Hgb level, TSAT, and ferritin level between the ESA responders (A vs B) and nonresponders (C vs D).

Efficacy of iron sucrose
Mean maximum improvement in Hgb levels (Table 2). Among ESA responders (groups A and B), a statistically significantly greater mean maximum Hgb level increase was observed among patients who received iron sucrose (group A) than among those who did not (group B), achieving the primary endpoint (ITT, P = 0.004; evaluable, P = 0.008). A statistically significant greater increase in the mean maximum Hgb level was observed following iron sucrose (groups A and C) when compared with no iron treatment (groups B and D), regardless of prior ESA response. In the ESA nonresponder group, a significant increase (P = 0.027) in the mean maximum Hgb level was observed between those who received iron sucrose (group C) and those who did not (group D) in the ITT population; a statistical difference was not seen in the evaluable population (P = 0.082).

With regard to tumor subtypes, breast cancer and other tumor types, but not lung cancer, were associated with statistically significant increases in maximum Hgb levels following iron sucrose, regardless of prior ESA response.

Absolute increases in Hgb levels (Table 2). A greater proportion of patients assigned to IV iron sucrose achieved a ≥ 2 g/dL and ≥ 3 g/dL increase in Hgb level during the study than did those who did not receive iron. These differences were statistically significant for all the groups except for the evaluable ≥ 3 g/dL nonresponder group. The only statistically significant difference in the proportion achieving a ≥ 1 g/dL Hgb level increase occurred in the ESA nonresponder groups. In addition, baseline hematologic characteristics and iron indices did not predict the efficacy of IV iron treatment (as defined by a > 1 g/dL or > 2 g/dL increase in Hgb level). In the IV iron sucrose-treated group, there was no statistical difference in these baseline characteristics in the patients who demonstrated a > 1 g/dL (data not shown) or a > 2 g/dL treatment response to IV iron.

Changes from baseline in Hgb and ferritin levels and in TSAT. Figure 3 summarizes the Hgb level, ferritin level, and TSAT responses by study visit after IV iron sucrose compared with no iron in the ITT population. Between treatment groups, statistically significant differences (P < 0.05) were present by weeks 7, 3, and 13 for Hgb level, ferritin level, and TSAT, respectively. At the end of the study, week 13, the mean Hgb level increase from baseline was 2.3 g/dL versus 1.2 g/dL (P < 0.002), the mean ferritin level increase from baseline was 419 ng/mL versus a decrease of 50 ng/mL (P < 0.001), and the mean TSAT increase from baseline was 8.8% versus 0.2% (P < 0.005) in the iron sucrose versus no iron group.

Changes in fatigue levels (FACIT fatigue scale). There was a statistically significant decrease in the level of fatigue at the end of the study compared with at baseline (end of stage 1) in the iron sucrose-treated patients in the ITT but not in the evaluable population (–3.3 iron sucrose/–2.1 no iron, P = 0.022 ITT; –3.0 iron sucrose/–1.7 no iron, P = 0.058 evaluable population). No significant decrease in the level of fatigue was experienced by the patients who received no iron. There were no statistically significant differences between the groups in changes from baseline at each visit..

Safety of iron sucrose
Extent of exposure. In the ITT population, the mean per patient total dose of iron sucrose administered was 1,123 (SD, 402) mg in group A (responders) and 1,113 (SD, 387) mg in group C (nonresponders).

Adverse drug events (ADEs). All safety analyses were performed using the ITT population. Serious ADEs were experienced by three patients in the iron sucrose group (chest pain, hypersensitivity, and hypotension, one patient each) and by no patients in the ESA-only group. One ESA-only group patient (arthralgia) and four iron sucrose patients (hypersensitivity; abdominal pain; arthralgia and muscle cramps; myalgia, nausea, and vomiting) were prematurely discontinued from the study drug due to the occurrence of an ADE.

At least one ADE was experienced by 37.4% of the patients in the iron sucrose group and 0.8% in the control group. The most common (³ 5%) ADEs were nausea (8.1%), dysgeusia (8.1%), back pain (6.1%), arthralgia (6.1%), muscle cramp (6.1%), and peripheral edema (5.1%). Within the ESA-only group, the only ADE reported was hypertension (one subject, 0.8%).

Eleven grade 3 (National Institutes of Health/National Cancer Institute– Common Terminology Criteria, version 2.0) ADEs occurred in iron sucrose-treated patients and included nausea (2.0%), hypotension (2.0%), abdominal pain (1.0%), chest pain (1.0%), hypersensitivity (1.0%), arthralgia (1.0%), dizziness (1.0%), dyspnea (1.0%), and hypertension (1.0%). A serious grade 3 hypotensive event occurred in a 49-year-old woman weighing 50 kg who experienced dizziness, nausea, vomiting, and transient hypotension (110/60 mm Hg to 70/40 mm Hg) after her first iron sucrose dose of 375 mg. Ninety minutes later, following IV steroids, iron sucrose was restarted and the hypotension recurred. The patient received two subsequent lower iron sucrose doses (200 mg over 4 hours), with no further adverse reactions.

Deaths and thrombotic events. These events are summarized in Table 3. None of these events was judged by the investigators to be related to the study drug.

Laboratory results. Statistically greater mean increases in ferritin levels, TSAT, Hgb levels, hematocrit, mean corpuscular hemoglobin, mean corpuscular volume, and monocytes oc curred in the iron sucrose-treated group. There were no significant differences between treatment groups in clinical chemistry safety laboratory results.

Discussion
This study is the first to evaluate IV iron in CCIA patients who have received prior ESA therapy. IV iron sucrose administered with ESAs significantly increased Hgb levels in CCIA patients. Prior ESA response did not predict Hgb level response to iron sucrose, as benefit was demonstrated in both ESA responders and nonresponders. Baseline hematologic/ iron indices also did not predict IV iron responsiveness, as these characteristics were similar in IV iron responders and nonresponders. Improvement in QOL, as measured by fatigue levels at study completion, was also observed after IV iron but not in the no iron group. IV iron studies are commonly open-label because of the difficulty in blinding iron’s viscous dark-colored solution.

This study design limits the significance of QOL measurements in IV iron studies, where primary endpoints are typically objective measurements. Even though transfusion rates were lower in the IV iron groups (5.1% in groups A and C [A = 1.7%; C = 10%]) than in the no iron groups (10.4% in groups B and D [B = 2.6%; D = 22.9%]), this difference was not statistically significant (Fisher’s exact test, P = 0.215). Our findings support the prior observations that IV iron replacement in combination with ESAs effectively increases Hgb levels and is safe.17,20,21,25,26

Combining IV iron with ESA increases the Hgb level response and may either shorten the time to response and/or decrease the ESA requirement. Approximately 30%–50% of patients are nonresponders after 12–24 weeks of ESA therapy.8,9,17,27,28 Iron deficiency may be a major factor accounting for ESA resistance. Decreased ESA responsiveness in the dialysis population can be corrected by providing adequate iron supplementation. 11,18 Also, ESA nonresponders may become responders with IV iron replacement while continuing the ESA. ESA treatment in responders can produce a functional iron deficiency, because the ESA produces a rapid initiation of erythropoiesis. Inducing functional iron deficiency with ESA therapy implies that the iron supply to the erythron may be the rate-limiting step in erythropoiesis, and the IV iron dose may be important.25 As ESA responders and nonresponders experienced improvement in Hgb levels with IV iron therapy in this trial, IV iron supplementation may be required to achieve and/or maintain a response to ESA therapy.

Iron available for erythropoiesis is derived from the balance between dietary sources and that in the usable pool within the reticuloendothelial system.29 ESA therapy can result in RBC production that exceeds the rate of iron mobilization, even with adequate iron stores. Inflammatory cytokines may also hinder the release of stored iron from macrophages by inducing hepcidin and thus further contribute to an inadequate rate of RBC production.30–34

Of note, baseline ferritin levels were higher in the ESA nonresponders (groups C and D) than in the ESA responders (groups A and B), although these differences were not statistically significant. This finding may be consistent with elevated inflammatory cytokines impairing the availability of iron, leading to a failed ESA response. ESA resistance is multifactorial, with these factors contributing to the rapid depletion of the usable iron pool, thus blunting the ESA response. Identifying factors that allow for maximizing ESA therapy in CCIA patients may result in greater ESA efficiency. The IV route of iron replacement is superior to oral administration and accounts for one of these variables.17,21,25,26

Safely administering IV iron is an important factor that influences the choice of iron preparations. In the United States, the only IV iron indicated for iron deficiency anemia is iron dextran. The risk of allergic reactions and the need for test doses may account for practitioners limiting the use of iron dextran, despite a compelling medical need for rapid, reliable, and safe replenishment of body iron in populations such as those with CKD35–37 and CCIA. The non–dextran- containing IV irons (iron sucrose, ferric gluconate) are currently only FDA approved for CKD indications at doses of 100–200 mg over 2–5 minutes or up to 400 mg over 2.5 hours for iron sucrose and only 125 mg over 10 minutes for ferric gluconate. 18,19

This study supports other findings that IV iron sucrose is generally well tolerated at doses of 7 mg/kg, up to a maximum of 500 mg over 4 hours, in CCIA. Caution should be exercised, however, especially in patients with a lower body weight. This concern is supported by a study of iron sucrose in nondialysis CKD, where hypotension occurred in two patients < 65 kg after 500 mg doses were administered over 4 hours.38

Conclusion
This study’s primary objective was to determine whether prior response to ESA treatment would influence response to IV iron, not to detect differences between functional and absolute iron deficiency. Our findings support that administration of IV iron while continuing ESA treatment may correct functional, as well as absolute, iron deficiency in CCIA. Baseline iron indices did not predict responsiveness to iron sucrose. Without additional data identifying predictors of ESA responsiveness in CCIA, a more proactive approach that includes IV iron may be warranted, as in CKDrelated anemia. As a better understanding of functional iron deficiency evolves, it is becoming apparent that IV iron is important to optimize the response to ESAs for CCIA. Additional studies are needed to understand the mechanisms responsible for functional iron deficiency in CCIA and to assist in identifying the optimal IV iron administration schedule.

Acknowledgments: The authors wish to thank the study coordinators; the patients at each of the participating centers; and Drs. Perry Rigby and Robert Means, for reviewing the manuscript.

*Additional members of the Iron Sucrose Study Group include Ali Ben-Jacob, MD, Cache Valley Cancer Treatment and Research Clinic, Inc., Logan, UT; Amol Rakkar, MD, Hope Center, Terre Haute, IN; Philip Chatham, MD, Granada Hills, CA; Ahmed Maqbool, MD, Welborn Clinic, Research Center, Evansville, IN; Timothy Pluard, MD, Washington University, Medical Oncology, St. Peters, MO; Nafisa Burhani, MD, Joliet Oncology- Hematology Associates, LTD, Joliet, IL; David Henry, MD, Pennsylvania Hematology and Oncology Associates, Philadelphia, PA; David Watkins, MD, Allison Cancer Center, Midland, TX; Howard Ozer, MD, University of Oklahoma Health Science Center-Hematology Oncology Section, Oklahoma City, OK; Leo Orr, MD, Leo E. Orr, Inc., Los Angeles, CA; Billy Clowney, MD, Santee Hematology Oncology, Sumter, SC, Rene Rothestein-Rubin, MD, Rittenhouse Hematology/ Oncology, Philadelphia, PA; Peter Eisenberg, MD, California Cancer Care, Greenbrae, CA; Rosalba Rodriguez, MD, Chula Vista, CA; Kumar Kapisthalam, MD, United Professional Center, Pasco Hernando Oncology, New Port Richey, FL; Jennifer Caskey, MD, Wheat Ridge, CO; Sayed E. Ahmend, MD, Sebring, FL; Patricia Braly, MD, Hematology and Oncology Specialties, New Orleans, LA; Donald Flemming, MD, Medical Center of Vincennes, The Bierhaus Center, Vincennes, IN; William Tester, MD, Albert Einstein Cancer Center, Philadelphia, PA; William Solomon, MD, SUNY Downstate Medical Center, Brooklyn, NY; Mark Hancock, MD, Mile Hile Oncology, Denver, CO; Youssef Hanna, MD, Huron Medical Center, Port Huron, MI; Scot Sorensen, MD, Prairie View Clinic, Lincoln, NE; and Mark Yoffe, MD, Raleigh, NC.

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