Purpose: Limited data are available to describe the effectiveness of darbepoetin alfa (DA) in terms of hemoglobin (Hb) and transfusion outcomes when initiated at Hb <= 10 g/dL (the threshold specified in the summary of prescribing characteristics). We assessed DA, initiated according to current labeling (Hb <= 10 g/dL), in chemotherapy-induced anemia (CIA).Methods: Data for patients with cancer and CIA who initiated DA at Hb <= 10 g/dL were extracted from a database of Amgen-sponsored trials. A comparative analysis was limited to randomized, controlled trials in patients treated with DA or control (placebo/best supportive care). Data for the DA arm(s) of randomized, multiple-arm, or prospective, single arm trials were also extracted (DA-only analysis; non front-loaded studies only). Outcomes included Hb increase >= 1 g/dL or >= 2 g/dL during the first 12 weeks of treatment. Crude and Kaplan Meier proportions of patients who experienced each outcome and time (days) to each outcome were summarized by treatment arm. Meta-analysis (fixed-effects inverse variance method) was performed to compare outcomes for DA with control.Findings: The comparative analysis included 4 studies (2 in lung cancer, 1 in lymphoproliferative disease, and 1 in non-myeloid malignancy: DA, n = 261; control, n = 273). The DA-only analysis included 15 studies (n = 3768). In comparative analyses, more patients who received DA than placebo achieved Hb increase of >1 g/dL (fixed-effects hazard ratio [HR] = 2.07; 95% CI, 1.62-2.63) or >= 2 g/dL (HR = 2.91; 95% CI, 2.09-4.06). Median times to >= 1 g/dL or >= 2 g/dL increase were 43 or 78 days for DA (not evaluable for placebo). Transfusions were less common in patients who received DA (HR = 0.58; 95% CI, 0.44-0.77). Addition of 2 dose-finding studies did not change the findings of the main comparative analysis. Results were similar in the DA-only analyses.Implications: This is the first patient-level meta analysis, to our knowledge, to evaluate the efficacy in terms of Hb response of DA treatment when initiated according to current product labeling in patients with CIA. Limitations include the small number of studies and patients eligible for inclusion in the comparative analyses and the absence of non-Amgen trials of DA. The results of the comparative analysis confirm that DA is more effective than placebo at increasing serum Hb levels and at reducing the need for transfusion in patients with CIA when treatment is initiated at Hb 10 g/dL, as per current product labeling. (C) 2016 The Authors. Published by Elsevier HS Journals, Inc.

We investigated rituximab maintenance therapy in patients with diffuse large B-cell lymphoma (n=662) or follicular lymphoma grade 3b (n=21) in first complete remission. Patients were randomized to rituximab maintenance (n=338) or observation (n=345). At a median follow-up of 45 months, the event-free survival rate (the primary endpoint) at 3 years was 80.1% for rituximab maintenance versus 76.5% for observation. This difference was not statistically significant for the intent-to-treat population (likelihood ratio P=0.0670). The hazard ratio by treatment arm was 0.79 (95% confidence interval 0.57–1.08; P=0.1433). The secondary endpoint, progression-free survival was also not met for the whole statistical model (likelihood ratio P=0.3646). Of note, rituximab maintenance was superior to observation when treatment arms only were compared (hazard ratio: 0.62; 95% confidence interval 0.43–0.90; P=0.0120). Overall survival remained unchanged (92.0 versus 90.3%). In subgroup analysis male patients benefited from rituximab maintenance with regards to both event-free survival (84.1% versus 74.4%) (hazard ratio: 0.58; 95% confidence interval 0.36–0.94; P=0.0267) and progression-free survival (89.0% versus 77.6%) (hazard ratio: 0.45; 95% confidence interval 0.25–0.79; P=0.0058). Women had more grade 3/4 adverse events (P=0.0297) and infections (P=0.0341). Men with a low International Prognostic Index treated with rituximab had the best outcome. In summary, rituximab maintenance in first remission after R-CHOP-like treatment did not prolong event-free, progression-free or overall survival of patients with aggressive B-non-Hodgkin lymphoma. The significantly better outcome of men warrants further studies prior to the routine use of rituximab maintenance in men with low International Prognostic Index. This trial is registered under EUDRACT #2005-005187-90 and www.clinicaltrials.gov as #NCT00400478.

Intravenous (IV) iron therapy is widely used in iron deficiency anaemias when oral iron is not tolerated or ineffective. Administration of IV‐iron is considered a safe procedure, but severe hypersensitivity reactions (HSRs) can occur at a very low frequency. Recently, new guidelines have been published by the European Medicines Agency with the intention of making IV‐iron therapy safer; however, the current protocols are still non‐specific, non‐evidence‐based empirical measures which neglect the fact that the majority of IV‐iron reactions are not IgE‐mediated anaphylactic reactions. The field would benefit from new specific and effective methods for the prevention and treatment of these HSRs, and the main goal of this review was to highlight a possible new approach based on the assumption that IV‐iron reactions represent complement activation‐related pseudo‐allergy (CARPA), at least in part. The review compares the features of IV‐iron reactions to those of immune and non‐immune HSRs caused by a variety of other infused drugs and thus make indirect inferences on IV‐iron reactions. The process of comparison highlights many unresolved issues in allergy research, such as the unsettled terminology, multiple redundant classifications and a lack of validated animal models and lege artis clinical studies. Facts and arguments are listed in support of the involvement of CARPA in IV‐iron reactions, and the review addresses the mechanism of low reactogenic administration protocols (LRPs) based on slow infusion. It is suggested that consideration of CARPA and the use of LRPs might lead to useful new additions to the management of high‐risk IV‐iron patients.

This randomized trial evaluated ferric carboxymaltose without erythropoiesis-stimulating agents (ESA) for correction of anemia in cancer patients with functional iron deficiency. Patients on treatment for indolent lymphoid malignancies, who had anemia [hemoglobin (Hb) 8.5–10.5 g/dL] and functional iron deficiency [transferrin saturation (TSAT) ≤20 %, ferritin >30 ng/mL (women) or >40 ng/mL (men)], were randomized to ferric carboxymaltose (1,000 mg iron) or control. Primary end point was the mean change in Hb from baseline to weeks 4, 6 and 8 without transfusions or ESA. Difficulties with patient recruitment led to premature termination of the study. Seventeen patients (8 ferric carboxymaltose and 9 control) were included in the analysis. In the ferric carboxymaltose arm, mean Hb increase was significantly higher versus control at week 8 (p = 0.021). All ferric carboxymaltose-treated patients achieved an Hb increase >1 g/dL (control 6/9; p = 0.087), and mean TSAT was >20 % from week 2 onwards. No treatment-related adverse events were reported. In conclusion, ferric carboxymaltose without ESA effectively increased Hb and iron status in this small patient population.

Unexplained fatigue is often left untreated or treated with antidepressants. This randomized, placebo-controlled, single-blinded study evaluated the efficacy and tolerability of single-dose intravenous ferric carboxymaltose (FCM) in iron-deficient, premenopausal women with symptomatic, unexplained fatigue.Fatigued women (Piper Fatigue Scale [PFS] score ≥5) with iron deficiency (ferritin <50 µg/L and transferrin saturation <20%, or ferritin <15 µg/L) and normal or borderline hemoglobin (≥115 g/L) were enrolled in 21 sites in Austria, Germany, Sweden and Switzerland, blinded to the study drug and randomized (computer-generated randomization sequence) to a single FCM (1000 mg iron) or saline (placebo) infusion. Primary endpoint was the proportion of patients with reduced fatigue (≥1 point decrease in PFS score from baseline to Day 56).The full analysis included 290 women (FCM 144, placebo 146). Fatigue was reduced in 65.3% (FCM) and 52.7% (placebo) of patients (OR 1.68, 95%CI 1.05-2.70; p = 0.03). A 50% reduction of PFS score was achieved in 33.3% FCM- vs. 16.4% placebo-treated patients (p<0.001). At Day 56, all FCM-treated patients had hemoglobin levels ≥120 g/L (vs. 87% at baseline); with placebo, the proportion decreased from 86% to 81%. Mental quality-of-life (SF-12) and the cognitive function scores improved better with FCM. 'Power of attention' improved better in FCM-treated patients with ferritin <15 µg/L. Treatment-emergent adverse events (placebo 114, FCM 209; most frequently headache, nasopharyngitis, pyrexia and nausea) were mainly mild or moderate.A single infusion of FCM improved fatigue, mental quality-of-life, cognitive function and erythropoiesis in iron-deficient women with normal or borderline hemoglobin. Although more side effects were reported compared to placebo, FCM can be an effective alternative in patients who cannot tolerate or use oral iron, the common treatment of iron deficiency. Overall, the results support the hypothesis that iron deficiency can affect women's health, and a normal iron status should be maintained independent of hemoglobin levels.ClinicalTrials.gov NCT01110356.

Intravenous iron is widely used for the treatment of iron deficiency anemia when oral iron is inappropriate, ineffective or poorly tolerated. Acute hypersensitivity reactions during iron infusions are very rare but can be life-threatening. This paper reviews their frequency, pathogenesis and risk factors, and provides recommendations about their management and prevention. Complement activation-related pseudo-allergy triggered by iron nanoparticles is probably a more frequent pathogenetic mechanism in acute reactions to current formulations of intravenous iron than is an immunological IgE-mediated response. Major risk factors for hypersensitivity reactions include a previous reaction to an iron infusion, a fast iron infusion rate, multiple drug allergies, severe atopy, and possibly systemic inflammatory diseases. Early pregnancy is a contraindication to iron infusions, while old age and serious co-morbidity may worsen the impact of acute reactions if they occur. Management of iron infusions requires meticulous observation, and, in the event of an adverse reaction, prompt recognition and severity-related interventions by well-trained medical and nursing staff.

PURPOSE:Patients with cancer frequently experience chemotherapy-induced anaemia (CIA) and iron deficiency. Erythropoiesis-stimulating agents (ESAs), iron supplementation and blood transfusions are available therapies. This study evaluated routine practice in CIA management.METHODS:Medical oncologists and/or haematologists from nine European countries (n=375) were surveyed on their last five cancer patients treated for CIA (n=1,730). Information was collected on tests performed at diagnosis of anaemia, levels of haemoglobin (Hb), serum ferritin and transferrin saturation (TSAT), as well as applied anaemia therapies.RESULTS:Diagnostic tests and therapies for CIA varied across Europe. Anaemia and iron status were mainly assessed by Hb (94%) and ferritin (48%) measurements. TSAT was only tested in 14%. At anaemia diagnosis, 74% of patients had Hb ≤ 10 g/dL, including 15% with severe anaemia (Hb <8 g/dL). Low-iron levels (ferritin ≤ 100 ng/mL) were detected in 42% of evaluated patients. ESA was used in 63%of patients, blood transfusions in 52 % and iron supplementation in 31% (74% oral, 26% intravenous iron). Only 30% of ESA-treated patients received a combination of ESA and iron supplementation. Blood transfusions formed part of a regular anaemia treatment regimen in 76% of transfused patients. Management practices were similar in 2009 and 2011.CONCLUSION:Management of anaemia and iron status in patients treated for CIA varies substantially across Europe. Iron status is only assessed in half of the patients. In contrast to clinical evidence, iron treatment is under utilised and mainly based on oral iron supplementation. Implementation of guidelines needs to be increased to minimize the use of blood transfusions.

Pharmacovigilance (PV) is the science and activities relating to the detection, assessment, understanding, and prevention of adverse effects or other problems related to medical products after they have been licensed for marketing. The purpose of PV is to advance the safe use of marketed medical products. Regulatory agencies and license holders collaborate to collect data reported by health care providers, patients, and the public as well as data from systematic reviews, meta-analyses, and individual clinical and nonclinical studies. They validate and analyze the data to determine whether safety signals exist, and if warranted, develop an action plan to mitigate the identified risk. Erythropoiesis-stimulating agents (ESAs) provide an example of how PV is applied in reality. Among other approved indications, ESAs may be used to treat anemia in patients with chemotherapy-induced anemia. ESAs increase hemoglobin levels and reduce the need for transfusions; they are also associated with a known increased risk of thromboembolic events. Starting in 2003, emerging data suggested that ESAs might reduce survival. As a result of PV activities by regulatory agencies and license holders, labeling for ESAs addresses these risks. Meta-analyses and individual clinical studies have confirmed that ESAs increase the risk of thromboembolic events, but when used as indicated, ESAs have not been shown to have a significant effect on survival or disease progression. Ongoing safety studies will provide additional data in the coming years to further clarify the risks and benefits of ESAs.

Rationale. Improved outcome of female patients treated with rituximab (R) has been reported for first-line diffuse large B-cell lymphoma (DLBCL) (Müller C, et al. Blood 2012; 119: 3276-84), maintenance treatment of relapsed DLBCL (Gisselbrecht C, et al. J Clin Oncol 2012; 30: 4462-9), and induction as well as maintenance treatment of follicular lymphoma (Jäger U, et al. Haematologica 2012; 97: 1431-8; Salles G, et al. Lancet 2011; 377: 42-51.). This sex-specific response has been attributed to lower body weight or a smaller volume of distribution of the drug in women. Rituximab maintenance in DLBCL and FL grade 3 in complete remission (CR) or CR unconfirmed (CRu) after R-CHOP-like therapy did not significantly prolong EFS or PFS in the NHL13 trial conducted by the Austrian Study Group (AGMT) (http://www.clinicaltrials.gov/ct2/show/NCT00400478?term=ML+18223&rank=1). However, a trend for improved EFS (p value = 0.067), a 44% reduction of relapses, as well as a particularly good outcome in patients with an International Prognostic Index (IPI) of 0 or 1 was noted (Jaeger U, et al. Hematol Oncol 2013; 31 (Suppl. 1): 96-150 (abstract 119)). In the second interim analysis imbalances in toxicity between male and female patients treated with R were observed. This prompted us to analyse sex specific outcome in the final analysis.

BACKGROUND:Prior to the approval of the first erythropoiesis-stimulating agent (ESA) in the early 1990s, red blood cell transfusions were the primary means of treating severe chemotherapy-induced anemia (CIA), with little recourse for those with more mild forms of the condition. The introduction of the ESAs allowed treatment of mild-to-moderate CIA in patients with cancer. It has been a decade since darbepoetin alfa (DA), a second-generation ESA with a longer half-life, became available to patients with CIA.OBJECTIVE AND METHODS:We present a review of studies on DA in CIA, from its development through to the present day. Medline was searched for randomized clinical trials on DA. Additional trials and meta-analyses on ESAs were incorporated into this review when relevant.RESULTS:The first publications on DA generally focused on optimal dosing, efficacy and tolerability. In these, it was shown that DA is an effective and well tolerated treatment option to achieve hematopoietic response, regardless of dosing interval. Subsequently, the focus shifted towards meta-analyses on survival data of all ESAs. These reported conflicting results regarding mortality and/or disease progression. However, guidelines for ESA use were updated and, when followed, these make ESAs a well tolerated and effective tool for managing CIA.CONCLUSIONS:As the past decade has broadened our knowledge on the benefits and risks of CIA management, continued high-quality studies will help to optimize treatment with ESAs in order to maximize quality of life for these patients. The limitation of a literature review of this nature is the complete reliance on previously published research and the availability of these studies using the methodology outlined above.

Darbepoetin alfa (DA) is an erythropoiesis-stimulating agent (ESA) approved for treating chemotherapy-induced anemia (CIA). Safety concerns have prompted changes to the ESA-product information, which now recommends initiating ESAs at hemoglobin (Hb) levels <10 g/dL (US) or ≤10 g/dL (EU). The present exploratory analysis of a DA trial examined how baseline-Hb levels at ESA initiation affect transfusion rates, Hb response, and safety outcomes in CIA patients. Data were retrospectively analyzed from a phase 3 trial of CIA patients randomised to 500 mcg DA every 3 weeks (Q3 W) or to 2.25 mcg/kg DA weekly (QW) for 15 weeks. In the current analysis, data were reanalyzed by baseline-Hb categories of <9 g/dL (n = 126), 9 to <10 g/dL (n = 225), and ≥10 g/dL (n = 354). The Q3 W and QW groups were combined. Transfusion rates were highest in the <9 g/dL baseline-Hb group in all time periods examined. The Kaplan–Meier percentage (95% CI) of patients achieving Hb ≥10 g/dL was 68% (59, 78) and 88% (82, 92) in the <9 g/dL and 9 to <10 g/dL baseline-Hb groups, respectively. With lower baseline-Hb, incidence of a ≥1 g/dL-Hb rise in 14 days progressively decreased. Incidence of venous thromboembolic events was similar in all baseline-Hb groups and similar between patients with or without a ≥1 g/dL-Hb rise in 14 days. Overall, transfusion risk increased and Hb response decreased at lower baseline-Hb levels in this exploratory analysis. When following ESA-product information to initiate ESAs at Hb ≤ 10 g/dL, the greatest benefit may be achieved when initiating close to 10 g/dL. Prospective studies are needed to further examine this hypothesis.

Erythropoiesis-stimulating agents (ESAs) are approved to treat anemia in patients with non-myeloid malignancies receiving myelosuppressive chemotherapy. ESAs reduce transfusion rates, but some clinical studies suggest that ESAs may reduce survival or increase disease progression. This study-level meta-analysis examined the effects of darbepoetin alfa, epoetin alfa or epoetin beta on mortality, disease progression and transfusion incidence in patients with lymphoproliferative malignancies, using randomized, controlled trials of patients receiving chemotherapy and ESAs or standard of care. The odds ratio (OR) for mortality was 1.04 (95% confidence interval [CI], 0.81-1.34, random-effects model, 10 studies); the risk difference was - 0.01 (95% CI, - 0.03-0.02). The OR for disease progression was 1.02 (95% CI 0.81-1.30, random-effects model, five studies). A lower proportion of ESA-treated patients than controls received transfusions (seven studies). In this meta-analysis, ESAs reduced transfusions with no clear effect on mortality or disease progression in patients with lymphoproliferative malignancies receiving chemotherapy.

International Journal of Gynecology & ObstetricsVolume 119, Issue S3 p. S858-S859 Poster presentations W472 A SINGLE 1000 MG IRON DOSE OF FERRIC CARBOXYMALTOSE IMPROVES FATIGUE IN IRON DEFICIENT, NON-ANAEMIC PREMENOPAUSAL WOMEN – RESULTS OF THE RANDOMISED, PLACEBO-CONTROLLED PREFER STUDY B. Favrat, B. FavratSearch for more papers by this authorK. Balck, K. BalckSearch for more papers by this authorC. Gasche, C. GascheSearch for more papers by this authorM. Hedenus, M. HedenusSearch for more papers by this authorA. Mezzacasa, A. MezzacasaSearch for more papers by this authorC. Küng, C. KüngSearch for more papers by this authorC. Breymann, C. BreymannSearch for more papers by this author B. Favrat, B. FavratSearch for more papers by this authorK. Balck, K. BalckSearch for more papers by this authorC. Gasche, C. GascheSearch for more papers by this authorM. Hedenus, M. HedenusSearch for more papers by this authorA. Mezzacasa, A. MezzacasaSearch for more papers by this authorC. Küng, C. KüngSearch for more papers by this authorC. Breymann, C. BreymannSearch for more papers by this author First published: 22 October 2012 https://doi.org/10.1016/S0020-7292(12)62191-2Citations: 1AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat No abstract is available for this article.Citing Literature Volume119, IssueS3Abstracts of XX FIGO World Congress of Gynecology and ObstetricsOctober 2012Pages S858-S859 RelatedInformation

AMG 114 is a novel, hyperglycosylated erythropoiesis-stimulating agent. In preclinical studies, AMG 114 demonstrated increased potency and longer half-life than darbepoetin alfa and epoetin alfa. This phase I/II, randomised, double-blind, placebo-controlled, dose-escalation study evaluated safety, pharmacokinetics, and efficacy of AMG 114 in patients with non-myeloid malignancies and chemotherapy-induced anaemia. Patients were randomised (1:5) to receive subcutaneous placebo or AMG 114 Q3W for 6 weeks in 3 dose cohorts of 15 μg (cohort A1), 50 μg (cohort A2), or 200 μg (cohort A3). Safety endpoints included incidence of adverse events and dose-limiting toxicities (DLTs). The PK profile of AMG 114 was evaluated. Efficacy was assessed by change in haemoglobin from baseline to end of treatment. Forty-eight patients enrolled: 8 received placebo, 40 received AMG 114. No DLTs were observed; adverse events were consistent with underlying malignancies. The PK profile was dose-proportional over the dose range tested; terminal half-life of AMG 114 was approximately 130 h. Mean change (range) in haemoglobin from baseline in AMG 114-treated patients was −0.16 (−1.8 to 1.3), 0.21 (−1.5 to 3.4), and 0.76 (−1.0 to 2.9) g/dl in cohorts A1, A2, and A3, respectively. AMG 114 appeared to be well tolerated, but the study was halted, in part because of modest efficacy.

e19557 Background: Chemotherapy-induced anemia (CIA) is a frequent complication in cancer patients. Intravenous (I.V.) iron in conjunction with an erythropoiesis-stimulating agent (ESA) is a well tolerated and effective therapy. This study evaluated current practice in diagnosis and treatment of CIA in nine European countries.METHODSOnco-hematologists completed records on their last five patients treated for CIA within six months prior to the survey. Data were collected from Jun-Oct 2009 (France, Germany, Spain, Switzerland, UK) and Aug-Nov 2010 (Austria, Italy, Netherlands, Sweden). Results are presented as median [range] between countries.RESULTS1,730 cases were recorded by 375 physicians (321 hospital and 54 office-based). Lymphoma, myeloma, breast and lung cancer accounted for 60% [50-66%] of cases; 52% [30-60%] had metastatic disease. Blood tests at diagnosis of anemia included hemoglobin (Hb, 96% [86-99%]), ferritin (49% [23-60%]) and transferrin saturation (TSAT, 12% [2-25%]). Median Hb before treatment was comparable between countries (9.1 g/dL [9.0-9.6 g/dL]), but ferritin (127 µg/L [50-243 µg/L]) and TSAT (26% [15-35%]) varied more. At diagnosis, 75% [65-89%] had an Hb <10 g/dL and 14% [8-25%] an Hb <8g/dL, 44% [21-65%] had a ferritin <100 µg/L and 20% [8-41%] had a ferritin <30 µg/L. 73% [15-100%] of CIA patients were treated with an ESA and iron was given to 22% [11-61%]. Although iron was mainly given in combination with an ESA (57% [17-100%]), I.V. iron was used in only 19% [4-77%] of iron-treated patients. Notably, Switzerland was the sole country where more patients received I.V. than oral iron. A blood transfusion was given to 52% [11-93%] of patients at some stage of treatment.CONCLUSIONSIron status assessment and treatment of CIA vary in manner and frequency between European countries. Ferritin and TSAT, markers of absolute and functional iron deficiency (AID, FID) are underused. Only a small fraction of cancer patients with CIA receives I.V. iron therapy despite clinical evidence on the efficacy of I.V. iron compared to oral iron in supplementing ESA-based anemia treatment. Awareness of evidence on the role of I.V. iron to resolve ID and prevent FID in CIA patients needs to be broadened.

TO THE EDITOR: We read with interest the article by Steensma et al in the January 1, 2011, issue of Journal of Clinical Oncology on the comparison of parenteral, oral, or no iron supplementation for patients who were treated with darbepoetin alfa for chemotherapyassociated anemia. The results contrast with those of six previously published and two additionally reported clinical trials that showed a significant benefit and good tolerability of parenteral iron compared with oral or no iron supplementation in patients with cancer who were receiving a concomitant erythropoiesis-stimulating agent. We believe that the interpretation and understanding of the results of the study by Steensma et al might have been facilitated by reporting some additional information. Both the lack of benefit and the higher number of adverse events in the parenteral iron group may be related to the specific dosing schedule of ferric gluconate in this trial (187.5 mg of iron every 3 weeks). The low planned total iron dose of 937.5 mg, the second lowest dose among the published trials (750 to 3,000 mg) and the lowest dose when calculated on a weekly basis (62.5 mg/wk), may have limited the potential benefit of parenteral iron supplementation. Furthermore, the iron dose that was actually administered seems to have been even lower, namely 650 mg total iron (43.3 mg/wk), as indicated online by Auerbach. In the study by Bastit et al that was cited by Steensma et al as similar to their own study, the actually delivered total iron dose was about 400 mg higher. The increase of transferrin saturation (TSAT) from baseline to the end of the study that was reported by Steensma et al was substantially lower in the parenteral iron compared with the oral iron group, and even lower than in the placebo group ( 1.4%, 8.0%, and 1.7%, respectively). This suggests that the given total dose of parenteral iron was either too low or not effectively used. In this context, Steensma et al mention that patients who were enrolled in the parenteral iron arm were more likely to withdraw consent or discontinue treatment as a result of adverse events. No information is given on how this affected the number of administered iron doses per patient. In contrast to the low total iron dose throughout the entire study period, the single iron doses administered per treatment as ferric gluconate were rather high (187.5 mg) and may explain the excessive number of adverse events that led to early termination of the study. In fact, this dose is 50% above the recommended dose for iron repletion with ferric gluconate in adult patients receiving hemodialysis in the United States, and therefore it is in the off-label range. Data from Ferrlecit (sanofi-aventis, Bridgewater, NJ) postmarketing reports indicate that individual doses that exceed 125 mg of iron may be associated with a higher incidence and/or severity of adverse events. The high single doses of ferric gluconate in this study may have resulted in oversaturation of transferrin, formation of nontransferrinbound iron, and deposition of iron in parenchymal tissues (eg, hepatocytes) instead of in the bone marrow. Apart from the increased risk of inducing oxidative stress and thus causing associated adverse events, the described effects may have additionally decreased the amount of iron that was effectively available for erythropoiesis. Therefore, it would be relevant to know more about the time course of TSAT and especially the levels of TSAT 24 hours after ferric gluconate administration. One aspect that may have affected the statistical power is the low proportion of patients who completed the study per protocol (65% overall; 63% in the placebo and the parenteral iron arm each). Thus, given that more than one third of the patients did not complete the study, a per-protocol analysis would be informative. In summary, the lack of response to parenteral ferric gluconate in the study by Steensma et al may be attributed to a suboptimal dosing regimen (ie, a low average dose but single doses that were too high) and a high proportion of dropouts rather than a lack of effectiveness per se. The superiority of parenteral iron compared with oral or no iron supplementation in terms of better hematopoietic response and less need for blood transfusions has been confirmed by two recent meta-analyses that included data from this trial as presented by Steensma et al at the 2009 meeting of the American Society of Hematology.