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Therapy

Addition of intravenous iron to epoetin beta increases hemoglobin response and decreases epoetin dose requirement in anemic patients with lymphoproliferative malignancies: a randomized multicenter study

A Corrigendum to this article was published on 13 February 2008

Abstract

This randomized study assessed if intravenous iron improves hemoglobin (Hb) response and permits decreased epoetin dose in anemic (Hb 9–11 g/dl), transfusion-independent patients with stainable iron in the bone marrow and lymphoproliferative malignancies not receiving chemotherapy. Patients (n=67) were randomized to subcutaneous epoetin beta 30 000 IU once weekly for 16 weeks with or without concomitant intravenous iron supplementation. There was a significantly (P<0.05) greater increase in mean Hb from week 8 onwards in the iron group and the percentage of patients with Hb increase 2 g/dl was significantly higher in the iron group (93%) than in the no-iron group (53%) (per-protocol population; P=0.001). Higher serum ferritin and transferrin saturation in the iron group indicated that iron availability accounted for the Hb response difference. The mean weekly patient epoetin dose was significantly lower after 13 weeks of therapy (P=0.029) and after 15 weeks approximately 10 000 IU (>25%) lower in the iron group, as was the total epoetin dose (P=0.051). In conclusion, the Hb increase and response rate were significantly greater with the addition of intravenous iron to epoetin treatment in iron-replete patients and a lower dose of epoetin was required.

Introduction

Results of randomized controlled trials of erythropoiesis-stimulating agents (ESAs; epoetin or darbepoetin) have led to their recognition in several US and European guidelines as an appropriate treatment for cancer-related anemia.1, 2, 3 However, although ESA treatment is effective, only 40–70% of patients with cancer achieve a hematological response.2

A major reason for patients not responding to ESA treatment is likely to be functional iron deficiency (FID), defined as a failure to provide iron to the erythroblasts despite sufficient iron stores. One cause of this failure is iron trapped in the macrophages owing to a cytokine-mediated increase in hepcidin, which in turn reduces the normal function of ferroportin as the exporter of iron from the cells.4, 5 This is seen in anemia of chronic disease, both in chronic inflammatory disease and cancer, and is aggravated when ESA treatment increases the demand for iron transport to the erythron.6, 7 Blood transfusion leads to a rise in plasma iron and thus has an impact on hepcidin production and iron kinetics,5 hindering studies on iron metabolism in transfused patients.

To avoid FID, it has been suggested that ESAs should be administered with iron support.6, 8, 9 Intestinal iron absorption is often reduced in malignant disease7 and oral iron treatment is associated with poor patient compliance. In contrast, intravenous iron supplementation improves response to epoetin and decreases epoetin dose requirements in patients with chronic kidney disease (CKD) and anemia.10 Consequently, it is routinely used in CKD patients with anemia and iron deficiency.11

Some guidelines for anemia management of patients with cancer also suggest iron supplementation during ESA treatment.1, 3 However, definitive recommendations regarding the role and optimal form or schedule of iron supplementation cannot be made until data from prospective, randomized studies are available. Such data are starting to emerge, with demonstrations that intravenous iron optimizes the response to epoetin alfa treatment in patients with cancer and chemotherapy-induced anemia.12, 13

Iron status is commonly assessed using serum ferritin and transferrin saturation (TSAT) values. As inflammation has an influence on these variables, other more specialized markers have come into use, such as serum soluble transferrin receptor (sTfR), the percentage of hypochromic red blood cells (RBCs) and reticulocyte hemoglobin (Hb) concentration. However, even with these markers, the evaluation of iron status is still problematic in anemia of chronic disease.14, 15 Therefore, the gold standard for the diagnosis of iron deficiency is still considered to be the assessment of a bone marrow aspirate stained with Prussian blue.

The aim of the present study was to investigate, in a prospective, randomized fashion, the impact of intravenous iron supplementation on the effectiveness and dose requirement of epoetin in iron-replete, moderately anemic patients with indolent lymphoproliferative malignancies. By investigating a well-defined anemic population of patients with stainable iron in the bone marrow, not receiving chemotherapy or blood transfusion, we were able to study iron kinetics in the absence of major confounding factors.

Materials and methods

Patients

Patients were recruited from 15 medical centers in Sweden between December 2003 and December 2005. Eligible patients were adults with a diagnosis of clinically stable lymphoproliferative malignancy (indolent non-Hodgkin's lymphoma (NHL), chronic lymphocytic leukemia (CLL) or multiple myeloma (MM)) not requiring chemotherapy or blood transfusions, an Hb level of 9–11 g/dl (measured on two occasions within 1 month and an interval of at least 2 weeks), and demonstration of stainable iron in a bone marrow aspirate within 1 month before inclusion. Patients were randomized within 4 weeks of first Hb measurement. Patients with anemia attributable to factors other than cancer (such as vitamin B12 or folate deficiency, hemolysis or active inflammatory or infectious disease), serum ferritin >800 μg/l, serum creatinine >175 μmol/l, serum bilirubin >40 μmol/l, and an Eastern Cooperative Oncology Group performance status of >2 were not eligible. Other exclusion criteria included prior antitumor therapy within 8 weeks before randomization or expected within 16 weeks following inclusion, prior epoetin treatment within 12 weeks of enrollment, iron therapy within the previous 4 weeks, uncontrolled hypertension or cardiac disease, neurological or psychiatric disorders, and pregnancy.

Study procedures

This was a prospective, open-label, randomized, multicenter study. The protocol and conduct of the study complied with the ethical principles of good clinical practice, in accordance with the Declaration of Helsinki and Swedish legal requirements. The study was approved by each institution's Ethics Committee. All patients provided written, informed consent before enrollment. Baseline information was obtained at an initial screen conducted within 7 days of enrollment and included complete blood count, reticulocyte count, TSAT, and serum levels of iron, ferritin, sTfR and erythropoietin. Reticulocyte Hb concentration and percentage hypochromic RBCs were omitted. Patients were stratified according to malignancy type (MM versus NHL or CLL) and serum erythropoietin level (100 versus >100 IU/l). Participants were randomized to one of two groups: no iron or intravenous iron. It was planned that all patients would receive 16 doses of 30 000 IU epoetin beta (NeoRecormon, Roche AB, Sweden) by subcutaneous injection once weekly.16 Concomitantly, on the same day iron sucrose 100 mg (Venofer, Renapharma AB, Sweden) was given once weekly by intravenous injection from weeks 0 to 6, followed by 100 mg every second week from weeks 8 to 14. The total study period was 16 weeks.

If patients failed to show an increase of Hb >1 g/dl after 4 weeks, the dose of epoetin beta was increased to 60 000 IU once weekly from week 5. If Hb level exceeded 14 g/dl, epoetin beta therapy was suspended until the Hb declined to <13 g/dl and was reinstated at 75% of the previous dose. If serum ferritin level exceeded 1000 μg/l, iron sucrose was suspended until it declined to <500 μg/l. The upper limit for ferritin level was chosen to be somewhat higher than that recommended in guidelines for patients with CKD (<800 μg/l)11 based on the inclusion/exclusion criteria that patients were allowed to have serum ferritin levels up to 800 μg/l at study entry. Blood transfusions were to be avoided at Hb levels above 8.5 g/dl, or given when clinically indicated and were documented throughout the course of the study.

Hb levels were measured weekly and iron variables (reticulocyte count, TSAT, and serum levels of iron, ferritin and sTfR) were followed throughout the study. Apart from Hb, which was analyzed at local laboratories, all laboratory tests were performed at a central location. Bone marrow aspirate smears were stained with Prussian blue. Each sample was examined regarding the presence or absence of iron granules in erythroblasts or reticuloendothelial iron stores. The results were verified by two people independently.

Efficacy assessments

The primary efficacy variable was defined as the mean change in Hb concentration from baseline to end of treatment. For patients who did not complete the study, the last recorded Hb level was used for analysis. Secondary efficacy variables included Hb response (defined as an increase in Hb of 2.0 g/dl versus baseline without transfusion until the end of treatment at week 15), time to Hb response, dose of epoetin and effect on iron variables.

Data analysis and statistical methods

The size of the study population (30 patients in each group) was chosen based on the assumption that mean increase in Hb level would be 1 g/dl higher in the iron group than the no-iron group, with a coefficient of variation of 80%, a significance level of 5% (two-sided) and a statistical power of 80%. It was planned to enroll up to 66 patients to allow for patients not valid for efficacy analysis. For all efficacy analyses, the intention-to-treat (ITT) population and per-protocol (PP) population were assessed. The ITT population was defined as all randomized patients. The PP population was defined as patients who received treatment for 16 weeks without receiving any RBC transfusion or chemotherapy.

The primary comparison, the difference in the increase in Hb level between the two groups, was made using the Student's t-test for uncorrelated means. The within-group analysis was performed using the paired pairwise Student's t-test for correlated means. Repeated measurements analysis was used to analyze time-dependent data and multiple comparisons of continuous data were performed by analysis of variance. The procedure proposed by Fisher was used to control for multiplicity. To evaluate hypotheses of variables in contingency tables, the χ2 test was used or, in the case of small expected frequencies, Fisher's exact test. The same statistical methods were used to evaluate the hypotheses of the variables in the secondary end points. For safety data, the ITT population was analyzed. Safety was assessed by summarizing the frequency and grade of adverse reactions. In addition to that, descriptive statistics were used to characterize the data.

All analyses were carried out using the SAS system, version 8.2 (SAS Institute, NC, USA) and 5, 1 and 0.1% levels of significance were considered.

Results

Patients

One hundred and seven patients were screened; the most common reasons for screening failures were Hb values not fulfilling the inclusion criteria and no demonstrable iron in the bone marrow. A total of 67 patients were randomized to receive epoetin beta only (no-iron group, n=34) or epoetin beta plus intravenous iron (iron group, n=33). Sixty patients completed the study. Of the seven patients who did not complete the protocol, three experienced adverse events, two died, one discontinued because of ineligibility and one discontinued owing to progressive disease. All but one discontinued the study in the first half of the study (up to week 8). Three patients (one patient in the no-iron group, two in the iron group) received blood transfusion. Therefore, 57 patients were included in the PP population (no-iron group, n=30; iron group, n=27).

Baseline demographic characteristics were similar between the two groups (Table 1). Forty-two (63%) patients had a confirmed diagnosis of indolent NHL or CLL, and 25 patients (37%) had MM. The mean Hb level at baseline was 10.3 g/dl, median serum ferritin level was 128 μg/l and median TSAT 22%.

Table 1 Baseline clinical characteristics (all randomized patients)

Hemoglobin response

Both groups showed significant (P<0.05) increase in mean Hb during the study (Figure 1). The increase from baseline was faster and significantly (P<0.05) greater from week 8 onwards in the iron group than in the no-iron group. There was a significant (P<0.0001) difference in mean Hb at the end of treatment between the iron and no-iron groups of the PP population (13.0 and 11.8 g/dl, respectively; difference 1.24 g/dl (95% confidence interval (CI) 1.82, 0.65) (Figure 1). The mean change in Hb from baseline to end of treatment in the PP population was 2.91 versus 1.50 g/dl (P<0.0001). Similar results were seen in the ITT population; the difference in mean Hb between the two groups at the end of treatment was 0.99 g/dl (95% CI 1.61, 0.37; P=0.0023). The mean change in Hb from baseline was 2.76 in the iron group versus 1.56 g/dl in the no-iron group (P=0.0002).

Figure 1
figure1

Mean (±s.e.m.) Hb changes from baseline (week 0) to end of treatment (week 15) by treatment group for the per-protocol patient population.

Hb response was achieved by significantly (P=0.0012) more patients in the iron group than in the no-iron group (93 versus 53%, PP population; Figure 2). A similar difference in Hb response was observed in Kaplan–Meier proportions for the ITT population (87 versus 53%, P=0.0014). The time to achieve an Hb response was also shorter in the iron group. For the PP population, the median time to achieve an Hb response was 6 weeks in the iron group compared with 12 weeks in the no-iron group.

Figure 2
figure2

Hemoglobin (Hb) response (%) in relation to treatment time in each treatment group (per-protocol population).

Epoetin beta dosing

Dose doubling was more common in the no-iron group compared with the iron group (185 versus 106 doses, respectively) whereas reductions or withholding of dose were less frequent in the no-iron group (40 versus 80 doses, respectively). Although the number of missed doses was low in both groups, indicating good compliance with treatment, it was somewhat higher in the no-iron than in the iron group. The total amount of missed epoetin beta dose was 240 000 versus 90 000 IU, respectively.

From week 5 onwards, there was an increasing difference in mean weekly epoetin beta dose in favor of the iron group (Figure 3), reaching significance at week 13 (P=0.029). At week 15, the average difference was more than 10 000 IU or approximately 25% lower in the iron group than in the no-iron group. For the PP population, the mean total cumulative patient dose of epoetin was 511 400 IU in the iron group versus 626 600 IU in the no-iron group (P=0.051). Corresponding mean total doses for the ITT population were 532 000 and 629 000 IU (P=0.059), respectively.

Figure 3
figure3

Mean (95% CI) weekly epoetin beta patient dose in each treatment group (per-protocol population).

Iron metabolism and reticulocytes

Of the 57 PP patients, 39% (n=11 in each treatment group) had a baseline TSAT <20% despite proven iron deposits in the bone marrow, indicating FID. Eight of these had serum ferritin >100 μg/l, indicating sufficient iron stores.

The mean baseline serum ferritin concentration was about 190 μg/l and 32% had a baseline serum ferritin <100 μg/l. In the no-iron group, there was a rapid decrease in mean serum ferritin at week 1, and this continued to decrease to a mean of 112 μg/l at the end of the study (Figure 4). One-third of these patients reached subnormal serum ferritin levels. In contrast, in the iron group, the mean ferritin level almost doubled during the study (Figure 4).

Figure 4
figure4

Mean (±s.e.m.) values of iron metabolism variables by treatment week (per-protocol population).

In both treatment groups, the mean TSAT level decreased after starting epoetin treatment (Figure 4). The mean TSAT in the no-iron group was approximately 20% during the treatment period compared with 30% in the iron group. In the no-iron group, TSAT decreased to a subnormal level (<20%) in all 14 patients with a normal TSAT at baseline. Of all 30 patients in this treatment arm, 26 patients (87%) had TSAT <20% (indicating FID) during more than 75% of the treatment period. Nine of these patients (35%) failed to respond with an increase in Hb. Eleven of the 27 patients (41%) in the iron group had subnormal baseline TSAT values. In seven of these, after an initial decrease, TSAT values increased well above 20%. During the study, all patients in the iron group with TSAT <20% (n=19) at any time responded with an increase in Hb>2 g/dl compared with only 54% of patients in the no-iron group (P<0.001).

The mean serum level of sTfR increased in both groups (Figure 4) was significantly higher than baseline after 1 week, and reached a maximum value at week 8, with similar levels in both groups. Mean levels remained elevated during the rest of the study, but tapered down in the iron group at the end of the study.

There was a rapid increase in mean reticulocyte count in both groups to double the baseline level within 1 week (Figure 4). The levels remained elevated throughout the study, and there was no statistically significant difference between the treatment groups.

Safety

Forty-four patients in the safety population experienced 107 adverse events, distributed evenly between the two treatment groups. The most commonly reported adverse events were upper respiratory infections, skeletal or back pain, and vertigo. Twenty-five serious adverse events were reported in 17 patients. The incidence of thromboembolic (one fatal suspected pulmonary embolism and one thrombophlebitis related to iron injection) and serious cardiovascular events (four events in three patients) was as expected in the patient population studied. Four deaths unrelated to the study drug were reported, all in the no-iron group; two patients died during the study (one from disease progression and one from a suspected pulmonary embolism, occurring at an Hb concentration of 9.4 g/dl at week 5 in a non-responding patient not judged to be study drug related by the investigator) and a further two died within 4 weeks of the end of the study (one each from disease progression, pneumonia).

Mean changes (decreases rather than increases) from baseline to end of study in systolic and diastolic blood pressure were similar between the two groups. Seven (21%) patients in the no-iron group and 13 (39%) patients in the iron group had Hb >14 g/dl during the study (P=0.090). The highest Hb level recorded was 15.8 g/dl in the iron group.

Discussion

This randomized, prospective trial clearly demonstrates the benefit of combining epoetin treatment with intravenous iron supplementation. Both treatment groups showed increases in mean Hb level during the study; however, the increase was faster and of significantly greater magnitude in the iron group than in the no-iron group, and importantly this was achieved with a lower dose of epoetin beta in the iron group. Despite less dose doubling and more epoetin doses being withheld or reduced in the iron group, the mean change in Hb from baseline to end of treatment was almost twice as high in this group compared with the no-iron group (2.91 versus 1.50 g/dl).

The proportion of patients responding (Hb increase 2.0 g/dl) after 16 weeks of treatment was also almost twice as high (93 versus 53%) in the iron group compared with the no-iron group. This is comparable to response rates seen in patients with CKD. The proportion of Hb responders increased substantially after week 5 in the iron group despite dose doubling in only 11 patients in this group compared with 17 in the no-iron group. The Hb response rate in the iron group in our study is higher than that reported in similar trials.12, 13 This might be due to the inclusion criteria in the present study, which may have favored response to epoetin; all patients were moderately anemic, transfusion independent, had clinically stable disease, were not receiving concomitant chemotherapy, and all were iron replete. However, the response rate in the no-iron group (53%) was comparable with that of other randomized studies on patients with lymphoproliferative malignancies receiving chemotherapy in which intravenous iron administration was uncommon.17, 18, 19 In contrast, another study of epoetin beta (30 000 IU once weekly versus 10 000 IU three times weekly) in lymphoid tumors, in which approximately 40% of patients received intravenous iron supplementation, reported higher response rates of 72–75%.16

In patients with CKD, concomitant intravenous iron has been shown to allow ESA dose reduction.10, 11 The results of the present study suggest that these findings can be extended to the cancer patient population. Despite more missed epoetin doses in the no-iron group, the mean weekly epoetin dose after 15 weeks of treatment was at least 10 000 IU (25%) lower in the iron group than in the no-iron group, translating into a weekly cost saving of at least US $100 per patient according to the Swedish pharmacy price list in November 2006. The implications of this reduction, achieved by co-administering a relatively inexpensive supplement, imply that this result is of clinical and economic significance, although costs for extra admissions to healthcare for administration of intravenous iron have to be taken into consideration.

A third of patients in the PP population had limited iron stores with serum ferritin levels <100 μg/l. In the no-iron group, a third of patients developed depleted iron stores and only half of these had an increase in Hb of >2 g/dl. In contrast, serum ferritin levels increased steadily in the iron group, and all patients with signs of FID at baseline responded with an Hb increase >2 g/dl. TSAT levels, reflecting iron availability, were below 20% during the treatment period in most patients in the no-iron group in comparison with only three patients in the iron group. Thus, several variables indicate that better iron availability was the reason for the superior Hb response in the iron group and that the dose given was sufficient.

An increase in sTfR levels indicates the need for more iron to the erythroblasts, either because of true iron deficiency, FID or an increased erythropoietic rate. In this study, there was a similar increase in mean sTfR level from baseline in both groups. Although this increase may have been caused mainly by a lack of iron in the no-iron group, in the iron group, it is likely to have been largely caused by increased erythropoiesis.

Subcutaneous epoetin beta and intravenous iron were well tolerated, with no safety concerns in any of the treatment arms, supporting previous reviews of ESA or intravenous iron sucrose use in correcting anemia within normal limits.20, 21 Apart from one patient who suffered thrombophlebitis related to iron injection, there were no reports of adverse events regarded or reported as potentially related to the study drugs. The adverse events reported were as expected in this patient population and were evenly distributed between the treatment arms.

In conclusion, this open-label, randomized, prospective study of iron-replete patients with lymphoproliferative malignancies and cancer-associated anemia found that concomitant once weekly administration of subcutaneous epoetin beta and intravenous iron sucrose is markedly more effective than epoetin beta alone. Concomitant intravenous iron administration significantly increased Hb levels and the proportion of Hb responders, and produced faster Hb responses. Moreover, the weekly epoetin dose requirement was decreased by at least 25%. Thus, our data, along with those of Auerbach et al.12 and Henry et al.,13 show that intravenous iron therapy is an important consideration in the optimization of response to treatment with ESAs for cancer-related anemia and should be considered for inclusion in clinical guidelines.

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Acknowledgements

We thank the patients and study nurses for their dedication to this trial. We thank Karin Larsson for monitoring and assisting and Ulf Jansson for excellent laboratory work. We also thank the NIFe Study Group for its participation in this study; a complete membership list appears in ‘ Appendix.’ This work was supported by grants from Roche AB, Sweden, and the Research and Development Centre, Sundsvall Hospital, Sundsvall, Sweden. This investigator-initiated study was supported in part by research funding from Roche AB, Sweden.

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Correspondence to M Hedenus.

Appendix

Appendix

The NIFe study group included the following individuals and centers

Jesper Aagesen, Department of Medicine, Jönköping Hospital; Lucia Ahlberg, Department of Medicine, University Hospital, Linköping; Gunnar Birgegård, Department of Hematology, Akademiska Hospital; Margareta Carlsson, Department of Medicine, Växjö Hospital; Leif Enquist, Department of Medicine, Värnamo Hospital; Torbjörn Karlsson, Department of Medicine, St Görans Hospital; Sören Hanssen, Department of Medicine, Högland Hospital; Michael Hedenus, Department of Medicine, Sundsvall Hospital; Gerd Lärfars, Department of Medicine, Södersjukhuset; Birgitta Lauri, Department of Medicine, Sunderby Hospital; Olof Lindquist, Department of Medicine, Uddevalla Hospital; Jeanette Lundin, Departments of Hematology and Oncology, Karolinska University Hospital; Per Näsman, Center for Safety Research, Royal Institute of Technology; Göran Nilsson, Department of Medicine, Östra Hospital; Herman Nilsson-Ehle, Medical Department, Sahlgrenska University Hospital; Anders Österborg, Departments of Hematology and Oncology, Karolinska University Hospital; Fredrik Sjöö, Department of Medicine, St Görans Hospital, and Kristina Wallman, Medical Department, Falun Hospital.

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Hedenus, M., Birgegård, G., Näsman, P. et al. Addition of intravenous iron to epoetin beta increases hemoglobin response and decreases epoetin dose requirement in anemic patients with lymphoproliferative malignancies: a randomized multicenter study. Leukemia 21, 627–632 (2007). https://doi.org/10.1038/sj.leu.2404562

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Keywords

  • anemia
  • cancer
  • erythropoietin
  • intravenous iron
  • lymphoproliferative malignancies

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