Clinical experience with ferric carboxymaltose in thetreatment of cancer- and chemotherapy-associatedanaemiaT. Steinmetz1*, B. Tschechne2, O. Harlin3, B. Klement4, M. Franzem5, J. Wamhoff6, H. Tesch7,R. Rohrberg8 & N. Marschner91Outpatient Clinic for Oncology and Haematology, Cologne; 2Klinikum Neustadt am Rbenberge, Neustadt am Rbenberge; 3Vifor Pharma, Munich, Germany; 4ViforPharma, Glattbrugg, Switzerland; 5iOMEDICO AG; 6Oncology Practice, Osnabrueck; 7Outpatient Clinic, Im Prueing, Frankfurt; 8Oncology Outpatient Clinic,Halle/Saale; 9Practice for Oncology and Hematology, Freiburg, German

Received 16 April 2012; revised 5 July 2012; accepted 12 July 2012

Background: Intravenous (i.v.) iron can improve anaemia of chronic disease and response to erythropoiesis-stimulating agents (ESAs), but data on its use in practice and without ESAs are limited. This study evaluatedeffectiveness and tolerability of ferric carboxymaltose (FCM) in routine treatment of anaemic cancer patients.Patients and methods: Of 639 patients enrolled in 68 haematology/oncology practices in Germany, 619 receivedFCM at the oncologists discretion, 420 had eligible baseline haemoglobin (Hb) measurements, and 364 at least onefollow-up Hb measurement. Data of transfused patients were censored from analysis before transfusion.Results: The median total iron dose was 1000 mg per patient (interquartile range 6001500 mg). The median Hbincrease was comparable in patients receiving FCM alone (1.4 g/dl [0.22.3 g/dl; N = 233]) or FCM + ESA (1.6 g/dl[0.72.4 g/dl; N = 46]). Patients with baseline Hb up to 11.0 g/dl and serum ferritin up to 500 ng/ml beneted from FCMtreatment (stable Hb 11.0 g/dl). Also patients with ferritin >500 ng/ml but low transferrin saturation beneted fromFCM treatment. FCM was well tolerated, 2.3% of patients reported putative drug-related adverse events.Conclusions: The substantial Hb increase and stabilisation at 1112 g/dl in FCM-treated patients suggest a role fori.v. iron alone in anaemia correction in cancer patients.Key words: anaemia, cancer-induced anaemia, chemotherapy-induced anaemia, ferric carboxymaltose, intravenousiron, iron deciency

introductionIron deciency (ID) and anaemia are frequent comorbidities inpatients with a variety of cancers, particularly when receivingchemotherapy [13]. The negative impact of anaemia onphysical performance and anti-tumour therapy is well known[2, 4, 5]. ID, even in the absence of anaemia and other medicalconditions, is associated with impaired physical function,weakness and fatigue; symptoms which can be improved withiron supplementation [68]. Factors contributing to thedevelopment of anaemia in cancer patients include chronicbleeding, nutritional deciencies, anaemia of chronic disease,myelosuppressive chemotherapy, and metastatic inltration ofthe bone marrow [9]. Notably, ID may not only be dened bydepleted iron stores (serum ferritin

(ferinject [FCM], Vifor Pharma), a non-dextran parenteraliron preparation, in routine treatment of an unselectedanaemic and iron-decient cancer patient population. Thisobservational study provides the rst, large database on the useof FCM in an oncological setting. In other therapeutic areas,FCM has already shown its effectiveness in correcting IDanaemia [2628].

methods

patients and study designAdult anaemic cancer patients with active malignancy and absolute orfunctional ID (indicated by laboratory values or symptoms such as fatigueand impaired physical function) who received FCM as i.v. iron treatmentin haematology and oncology practices across Germany and providedinformed consent were registered to this prospective, non-interventionalstudy. The study was registered at the Association of Research-basedPharmaceutical Companies in Germany (Study no: 27-10-08; http://www.vfa.de) and conducted following Good Clinical Practice criteria and theDeclaration of Helsinki.

Total and individual iron doses, dosing frequency, use of ESAs or bloodtransfusions, and the frequency of study visits were left to the investigatorsdiscretion following their routine practice. The rst day of FCM treatmentwas dened as baseline, and the observation period was scheduled for 12

weeks.The safety population consisted of all patients who had received at least

one FCM dose during the study. The effectiveness population includedpatients with an available baseline Hb value assessed between 7 days priorand 3 days after the rst FCM administration to ensure that Hb levels wereindependent of iron administration and other inuences. Normal Hb (12g/dl [females], 13 g/dl [males] [29]), absence of active malignancy, or age

effectivenessThe median Hb increase versus baseline ranged from 1.4 to1.6 g/dl (Table 3) and was statistically signicant in all groups(P < 0.0001). Hb increases in FCM-treated patients receiving ornot receiving additional ESAs were not substantially different.Only minor differences in baseline Hb or Hb increase wereseen between data censored for transfusions (All, censored)versus uncensored data (All, uncensored). The Hb increasewas also comparable for patients who received no or at leastone anti-anaemia pre-treatment such as transfusion, ESA, oriron (1.4 [0.32.3] versus 1.2 [02.4] g/dl; uncensoredeffectiveness population).The median total iron dose per patient was 1000 (600

1500) mg and comparable for patients that had been treated

with FCM only (1000 [6001400] mg) or concomitantly withan ESA (1000 [7001500] mg). Median Hb differences werecomparable in subpopulations stratied by the total iron doseand infusion frequency (range 1.31.8 g/dl). Heterogeneity ofthe subpopulations did not allow for a more detailed statisticalanalysis or interpretation.Hb levels improved steadily after the rst FCM

administration until the EOS (Figure 1AC). From week 5onwards, median Hb levels remained stable in the range of 1112 g/dl and were comparable between patients treated withFCM alone and those also receiving an ESA (Figure 1A).Increase in median Hb levels was more pronounced in patientswith moderate-to-severe anaemia (baseline Hb

between the investigated groups (Table 3). Median ferritinlevels among censored patients raised up to 893 ng/ml (week3). Patients with available TSAT values presented with lowmedian TSAT at baseline. Notably, median TSAT was very lowat baseline (11.0%) but almost doubled (+10.8%) in patientstreated with FCM alone. Median TSAT of patients treated withFCM plus ESA was only slightly below normal at baseline(16.8%) and showed only a modest median increase (+0.86%)over the study period.A total of 119 patients in the effectiveness population

(28.3%) received 1 transfusion at any time during the studyor within 4 weeks before the study (median 3, range 122).The proportion of patients receiving their rst transfusion afterthe initiation of FCM decreased from 13.8% during weeks 14to 9.1% after week 4 (Table 4).

tolerabilityA total of 354 (60.2%) patients in the safety populationcompleted the 12-week observation period. Forty-three (7.3%)patients were lost to follow-up, 42 (7.1%) died, and 31 (5.3%)withdrew consent. For 118 (20.1%) patients, no or otherreasons for termination were recorded (e.g. some physiciansstopped data collection after 6 weeks without recording areason, if a patient experienced a satisfactory Hb response).

FCM at total iron doses of 6001500 mg was well toleratedand blood counts (thrombocytes, leukocytes, erythrocytes)were comparable at baseline and EOS. ADRs were recorded foronly 14 (2.3%) patients. These were mainly related to thegastrointestinal tract, and only nausea and diarrhoea werereported more than once (Table 5). One allergy/immunologyreaction (ush) that was mild and resolved on the day of onsetwas reported. One possibly related serious adverse drugreaction was recorded for a 66-year-old male patient receivingthird-line cytotoxic chemotherapy for a head/neck tumourwith pulmonary metastasis and experienced hypoxia resultingin death. The patient received the second iron dose (200 mg, 6days after the rst dose) and died the same day.In a survey evaluating the satisfaction with FCM, a very

good or good rating for efcacy and for tolerability was givenby 97.4% and 81.0% of 390 responding investigators.Furthermore, 81.5% planned to use FCM again in thesepatients, if required.

discussionThis is the rst published dataset that documents the use andoutcomes of FCM treatment in cancer patients andcomplements available data in patients with chronic kidneydisease [27, 30], inammatory bowel disease [28, 31], chronic

Table 3. Baseline Hb and increase in Hb from baseline until end of the study or termination visit

All, uncensored All, censoreda FCM onlya FCM+ ESAa

Baseline Hb (g/dl)Patients (n) 420 328 277 51Mean Hb SD 9.9 1.1 10.0 1.1 10.1 1.0 9.6 1.1Median (Q1, Q3) 10.0 (9.110.6) 10.0 (9.310.6) 10.0 (9.410.7) 9.6 (8.910.4)

Hb increase (g/dl)b,c

Patients (n) 364 279 233 46Mean SD 1.4 1.7 1.4 1.5 1.3 1.5 1.7 1.5Median (Q1, Q3) 1.4 (0.22.3) 1.4 (0.32.3) 1.4 (0.22.3) 1.6 (0.72.4)

Baseline ferritin (ng/ml)Patients (n) 312 246 204 42Mean ferritin SD 399 566 356 500 334 500 461 491Median (Q1, Q3) 188 (32509) 169 (27480) 150 (21444) 309 (102645)

Ferritin increase (ng/ml)b

Patients (n) 193 150 125 25Mean SD 581 1077 585 1148 481 675 1105 2344Median (Q1, Q3) 306 (64767) 302 (57767) 291 (46711) 386 (213839)

Baseline TSAT (%)Patients (n) 225 170 140 30Mean TSAT SD 18.0 20.3 17.3 19.8 15.3 16.4 26.8 29.9Median (Q1, Q3) 12.1 (7.718.7) 12.2 (7.918.2) 11.0 (7.516.8) 16.8 (11.624.7)

TSAT increase (%)b

Patients (n) 128 94 74 20Mean SD 11.0 26.9 10.8 22.3 14.0 20.2 1.0 26.3Median (Q1, Q3) 9.9 (1.420.1) 9.9 (1.419.9) 10.8 (3.020.5) 0.9 (8.35.5)

aData from patients who received blood transfusions were censored from analysis before the transfusion.bOnly patients who had Hb data available from baseline and at least one follow-up visit during week 4 to end of the study were included.cP for Hb increase

Figure 1. Median Hb levels over the course of the study period and stratied by different patient characteristics. *Data were censored for transfusion use.(A) Median Hb stratied by concurrent ESA use and censorship of data following a blood transfusion. (B) Median Hb levels stratied by baseline Hb. (C)Median Hb levels stratied by baseline serum ferritin (cut-offs

heart failure [32], preoperative anaemia correction [33], andheavy menstrual bleeding [34] or postpartum anaemia [35, 36].In addition, this study, although of observational nature,presents the largest subset of data on cancer patients treatedwith i.v. iron as the primary anti-anaemia therapy.Overall, median Hb levels of anaemic cancer patients

receiving FCM treatment in routine clinical practice improvedand stabilised >11 g/dl within 5 weeks of the rst FCMadministration. The extent of the nal improvement in Hb wascomparable in patient groups stratied by concomitant ESAuse and different baseline characteristics such as Hb or serumferritin levels. Detailed analysis of the Hb increase did notreveal an effect of anti-anaemia pre-treatments (e.g. ESAs orblood transfusions) on the study results. Most important, theeffectiveness of FCM without an additional ESA in this largecancer patient population conrms former results of clinicalstudies showing higher Hb levels [12] and less transfusionrequirements in cancer patients with i.v. iron as sole anaemiatherapy [24, 25].As expected, Hb increase was higher in patients with low

initial Hb levels (11 g/dl. In morethan one-third of patients, Hb levels remained 11 g/dl at baseline. These ndings seem toconrm that i.v. iron has no major inuence on the regulationof erythropoiesis and suggest that there is no risk of increasingHb levels beyond recommended ranges as seen with ESAs andreected in ESA dosing recommendations [11, 23].Since patients with baseline serum ferritin levels

current uncertainty in selecting appropriate diagnosticparameters for cancer-related anaemia. Accordingly, awarenessabout iron homeostasis in cancer patients needs to beincreased. Notably, the assessment of baseline ferritin andTSAT in 74% and 54% of patients in this study is already animprovement compared with ndings of the German CancerAnaemia Registry (20042005) or a survey on the managementof chemotherapy-induced anaemia (20092010), wherebaseline ferritin was assessed in only 44% or 47% and TSAT in33% or 14% of patients [37, 38].Overall, the results of this observational study and the

satisfaction of the physicians with FCMs effectiveness andtolerability suggest a role for i.v. iron alone in the correction ofanaemia in cancer patients with ID and provide a rationale forfurther investigations on this topic.

acknowledgementsThe authors acknowledge the contribution of all investigatorsat all participating study sites. Medical writing support wasprovided by Walter Frst (SFL Regulatory Affairs & ScienticCommunication Ltd., Switzerland). The manuscript wasreviewed and commented by Beate Rzychon and Marcel Felder(Vifor Pharma Ltd., Glattbrugg, Switzerland) and Garth Virgin(Vifor Pharma, Munich, Germany).

fundingThis work was supported by Vifor Pharma DeutschlandGmbH who sponsored the study and supported thedevelopment of the study design. Medical writing support andthe Oxford Open Access licence for publication were fundedby Vifor Pharma Ltd. Interpretation of the data as well as thereview and decision to submit the manuscript for publicationhave been carried out independently by all authors.

disclosuresTS disclosed membership in speaker bureaus and/or advisoryboards of Vifor Pharma, Medice, Amgen, Ortho Biotech, andRoche; and conduct of research for Vifor Pharma Ltd., Amgenand Roche. BT disclosed consultancy for Vifor Pharma Ltd.OH and BK are employees of Vifor Pharma Ltd.

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