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Management of anaemia in oncohaematological patients treated with biosimilar epoetin alfa: results of an Italian observational, retrospective study:

Management of anaemia in oncohaematological patients treated with biosimilar epoetin alfa:... Giovanni Rosti, MD Background: Many patients with solid tumours or nonmyeloid haematopoietic tumours Oncologia, Policlinico San Matteo IRCCS, Pavia, Via develop symptomatic anaemia, which has a major impact on quality of life (QoL). The efficacy Scarpa 1, 31100 Treviso, Italy of erythropoiesis-stimulating agents (ESAs) in improving QoL and reducing blood transfusions rosti.giovanni@gmail.com has been widely demonstrated. Binocrit (biosimilar epoetin alfa) is an ESA indicated in the Mario Petrini, MD Azienda Ospedaliera European Union for treating chemotherapy-induced anaemia. The aim of this study was to Universitaria Pisana, Pisa, investigate the effect of Binocrit on haemoglobin (Hb) levels in anaemic cancer patients in Italy Italian clinical practice. Alberto Bosi, MD Department of Methods: The ANEMONE study was a national, longitudinal, retrospective, multicentre Hematology, Careggi Hospital and University of observational study. Patients had to be 18 years or older, with a solid tumour or non-Hodgkin’s Florence, Firenze, Italy lymphoma, Hodgkin’s disease or multiple myeloma, receiving chemotherapy, and treated Piero Galieni, MD Ospedale C. e G. Mazzoni, with Binocrit to manage chemotherapy-induced anaemia. The primary outcomes were Ascoli Piceno, Italy the proportion of patients with a Hb increase ⩾1 g/dl during the first 4 weeks and with a Hb Daniele Bernardi, MD increase ⩾2 g/dl during the first 12 weeks. ULSS 10 ‘Veneto Orientale’, San Donà di Results: A total of 245 patients were enrolled and 215 patients were evaluable for statistical Piave, Italy analysis. In the first 4 weeks, 49.3% of patients showed an increase in Hb of ⩾1 g/dl: 45.5% in Gianfranco Giglio, MD Ospedale Cardarelli, patients with solid tumours and 52.1% in patients with haematological malignancies. In the Campobasso, Italy first 12 weeks, 51.6% of patients showed an increase in Hb of ⩾2 g/dl (48.4% solid tumours, Laura Dorotea, MD ® Ospedale Riuniti Padova 54.2% haematological diseases). Treatment with Binocrit was well tolerated. Sud, Monselice, Italy Conclusions: These results confirm the effectiveness and safety of Binocrit for Brunangelo Falini, MD Ospedale Santa Maria chemotherapy-induced anaemia in routine practice in patients with solid tumours, lymphoma della Misericordia, and myeloma. Perugia, Italy Elvira Scelzi, MD Ospedale di Castelfranco Veneto (ULSS), Keywords: biosimilar, chemotherapy-induced anaemia, epoetin alfa, erythropoiesis- Castelfranco Veneto, Italy stimulating agents, erythropoietin Enzo Veltri, MD Ospedale S. Maria Goretti, Latina, Italy Roberto Castelli, MD Fondazione Cà Granda Introduction 1995]. About two-thirds of cancer patients under- Ospedale Maggiore About 50% of patients with solid tumours or non- going chemotherapy developed anaemia during Policlinico, Milano, Italy myeloid haematopoietic tumours develop symp- treatment in the European Cancer Anaemia Chiara Longagnani, MD MediNeos surl, Modena, tomatic anaemia during the course of their disease Survey (ECAS) [Ludwig et al. 2004]. Italy [Bokemeyer et al. 2004]. In cancer patients, anae- Tommaso Raggi, MSc mia may have multiple causes; it can result from Anaemia has a substantial impact on patients’ Sandoz S.p.A., Origgio, Italy cancer itself, concomitant diseases, older age, quality of life (QoL), and is largely responsible for Federico Simonetti, MD inflammation, malnutrition, low iron levels and the fatigue reported by many cancer patients. An Versilia Azienda ULSS 12, treatment with chemotherapy [Skillings et  al. increase in haemoglobin (Hb) level can produce a Lido di Camaiore, Italy 22 http://tam.sagepub.com G Rosti, M Petrini et al. meaningful improvement in fatigue, with related The Anaemia Cancer Treatment (ACT) study improvement in physical, functional, emotional assessed ESA treatment response rates in anae- and overall well-being [Cella et al. 2004]. In cases mic patients (Hb ⩽ 11 g/dl). It demonstrated that of severe anaemia, red blood cell (RBC) transfu- 65% of patients showed an increase in Hb of ⩾1 sions may be needed [Ludwig et al. 2004]. These g/dl over 8–10 weeks after initiation, while a rise are effective, but inconvenient, in short supply of Hb ⩾2 g/dl was observed in 34% of patients and not without associated risks and cost [Ludwig et  al. 2009]. This study confirmed the [Abraham and Sun, 2012]. Furthermore, low importance of anaemia in real-life clinical practice levels of Hb before or during chemotherapy and suggested that that the treatment response cycles may require dose reductions or delays in rates were lower than reported in randomized administration, resulting in a decrease in the controlled trials. Observational studies are there- overall treatment intensity. fore important to assess the real-world effective- ness of these agents in the context of a rapidly Anaemia is defined as a Hb level <10 or 11 g/dl, evolving disease management framework. with severe anaemia defined as a Hb level <8 g/dl [Bokemeyer et  al. 2007]. Although considerable Binocrit (biosimilar epoetin alfa) is an ESA indi- progress has been made in preventing or alleviat- cated for the treatment of anaemia as a result of ing many of the common toxicities associated chronic kidney disease or chemotherapy-induced with cancer and its therapy, anaemia continues anaemia [Binocrit® Summary of Product to be relatively undertreated [Loney et al. 2000]. Characteristics (available at http://www.ema. The efficacy of erythropoiesis-stimulating agents europa.eu/docs/en_GB/document_library/ (ESAs) in correcting anaemia in cancer patients EPAR_-_Product_Information/human/000725/ has been widely demonstrated [Littlewood et al. WC500053680.pdf)]. However, data on the use 2003; Bohlius et  al. 2006]. These substances of Binocrit for the treatment of chemotherapy- improve QoL and reduce the need for transfu- induced anaemia in clinical practice are limited sion. The administration of ESAs in cancer [Weigang-Köhler et  al. 2009; Kerkhofs et  al. patients has been reported to be associated with 2012; Rodriguez Garzotto et al. 2014]. an increased risk of thromboembolic events, reduced survival and reduced time to disease The aim of this retrospective study was to investi- progression [Bennett et  al. 2008]. However, in gate the effect of Binocrit on Hb levels in anae- many studies ESAs had been used with target Hb mic cancer patients in Italian clinical practice. levels significantly higher than those currently Secondary aims were to describe: (i) the charac- recommended by guidelines. According to cur- teristics of the treated population; (ii) all adverse rent guidelines, ESAs should be used only in events (AEs) over the 12-week observational patients with chemotherapy-induced anemia, period; (iii) factors related to improvement of and treatment should be discontinued once the anaemia; and (iv) key factors considered by clini- chemotherapy course is completed, and these cians in the management of anaemia. agents should not be used when the aim of treat- ment is cure. Materials and methods Recently, the UK National Institute for Health and Care Excellence (NICE) found ESA usage Study design in cancer-induced anaemia to be cost-effective, The ANEMONE (Anaemia management in largely due to the availability of lower cost bio- oNcohaEMatological patients treated with similar ESAs. Treatment guidelines and recom- binOcrit: an italiaN retrospective obsErvational mendations have been published regarding the study) study was designed as a national, longitudi- safe use of ESAs [Bokemeyer et  al. 2007; Rizzo nal, retrospective, multicentre observational study. et al. 2002]. Although the evidence for specifying It involved 23 Italian oncology or haematology cen- the optimal strategy of monitoring iron and insti- tres. The study was approved by the Institutional tuting iron repletion is not optimal, the majority Review Boards of all participating centres. Patients of these guidelines also suggest the importance included in the study were those who started treat- of using intravenous (IV) iron in combination ment with Binocrit according to normal clinical with ESAs to ensure patients are iron replete practice before site activation, in order to manage [Bokemeyer et al. 2007; Rizzo et al. 2002]. chemotherapy-induced anaemia. http://tam.sagepub.com 23 Therapeutic Advances in Medical Oncology 9(1) For each patient included, the decision to pre- (e.g. other ESAs or transfusion) in the 28 days ® ® scribe treatment with Binocrit was taken by their preceding the start of treatment with Binocrit . doctor regardless of enrolment in the ANEMONE study. Data were retrospectively collected from clinical medical records over a 12-week observa- Study aims and sample size tional period (± 1 week) after starting Binocrit The primary aim of the study was to describe the administration. Alive and reachable patients were trend of Hb levels in a 12-week observational consecutively enrolled at their normal scheduled period in patients receiving chemotherapy for a visits, during which they signed the informed con- solid tumour, lymphoma or myeloma and treated sent to the study and to retrospective data collec- with Binocrit . tion from existing clinical medical records. During the second half of the enrolment period, deceased/ In detail, the two primary outcomes considered unreachable patients were also consecutively for the evaluation of the primary objective were: included in descending order of Binocrit start date according to the list of all potentially eligible 1. the proportion of patients who, during the patients generated by each site at the time of acti- first 4 weeks after the start of treatment vation. This study was retrospective and observa- with Binocrit , showed an increase in Hb of tional, and did not affect the relationship between ⩾1 g/dl; clinicians and patients or standard patient follow- 2. the proportion of patients who, during the up patterns. Clinicians in the study remained free first 12 weeks after the start of treatment to decide on the treatment of their patients. The with Binocrit , showed an increase in Hb of enrolment period lasted 10 months. Data were ⩾2 g/dl. collected using an electronic data collection sheet, which automatically checked for possible data Secondary objectives of the study were to describe entry errors and inconsistencies. Site monitoring the treated population, to assess AEs occurring visits were performed at six participating centres, during the 12-week observational period, the where all data were validated with source data. evaluation of demographic and clinical factors potentially related to improvement of anaemia, and the description of the key factors considered Eligibility criteria by clinicians in the management of anaemia. To be eligible for inclusion, patients (both males and females) had to be 18 years or older at initia- According to feasibility considerations based on tion of Binocrit , presenting with a solid tumour, clinicians’ opinions, a total of 300 patients were non-Hodgkin’s lymphoma, Hodgkin’s disease or expected. Sample size was not based on the power multiple myeloma. They were to be receiving to investigate a formal statistical hypothesis but chemotherapy (alone or in combination with the achievable estimate precision was evaluated other treatments). Treatment to manage chemo- based on literature data. In the ACT study therapy-induced anaemia with Binocrit had to [Ludwig et  al. 2009], the proportion of patients have been started before site activation and data who showed an increased level of Hb ⩾ 1 g/dl was in medical records had to be available for the 65.0%, with a median time to response of 4.7 period from the start of treatment with Binocrit weeks, while the proportion of patients who for the following 12 weeks. showed an increased level of Hb ⩾ 2 g/dl was 33.7%, with a median time to response of 6 Patients were not eligible if they received treat- weeks. Starting from these results, we assumed ments for their cancer or anaemia in the context that the two proportions of interest at 4 and 12 of a clinical trial during the retrospective observa- weeks would be 32.5% and 33.7%, respectively. tional period, if they were in treatment only with Thus, considering 32.5% as the expected value of radiotherapy or molecular targeted therapy, if the primary outcome, with a sample size of 300 they presented with acute leukaemia or a chronic patients (corresponding to 270 evaluable patients, myeloproliferative syndrome, if they presented assuming 10% of patients as not evaluable due to with uncorrected haemolytic anaemia or anaemia screening failures, missing data, etc.), the 95% due to a deficiency not related to cancer (e.g. confidence interval (CI) for the expected propor- deficiency of iron, vitamin B12 or folic acid), or if tion would be 32.5% ± 5.6%. A smaller sample they received any other treatment for anaemia size would mean lower estimated precision, but 24 http://tam.sagepub.com G Rosti, M Petrini et al. the precision was acceptable (relative error ⩽ factors of interest (age, gender, Karnofsky perfor- 20%), even for 200 evaluable patients. mance status, baseline Hb level, tumour type). For the description of key factors considered by Statistical analysis clinicians in the management of anaemia, clini- Quantitative variables were described in terms of cians were asked to report the key criteria they th th mean, standard deviation, median, 25 and 75 take into account in management of anaemia and percentile [interquartile range (IQR)], minimum in initiating treatment with Binocrit (for exam- and maximum. Qualitative variables were described ple maintenance of QoL, reduction of transfu- in terms of absolute and relative frequency, with sions, expected improvement of Hb level and bilateral 95% CI (where relevant). patient request). These were described in terms of frequency. For both primary outcomes, the last available value in the month preceding the first administra- All the analyses were performed using SAS for tion of Binocrit was considered as the Hb level at Windows, release 9.2 (SAS Institute Inc., US). the start of treatment. The first outcome was calculated as the number Results of patients who, during the first 4 (+1) weeks From June 2013 to March 2014, 245 patients after the start of treatment, showed at least one were enrolled in the study. Of these, 30 were Hb level which exceeded the level at the start of excluded due to violations of the eligibility criteria treatment by ⩾1 g/dl in absence of blood trans- or unavailability of at least one Hb value during fusion or other ESA treatment during the 28 the Binocrit monitoring period. Thus, 215 days preceding that value, divided by the num- patients were evaluable for statistical analysis. ber of evaluable patients with at least one Hb value in that period. If an increased level of Hb The main demographic and clinical characteristics ⩾ 1 g/dl in the first 4 weeks occurred when the of the patients are shown in Table 1. Median age patient had undergone blood transfusion or was 68 years in females, and 71.5 years in males. other ESA treatment within 28 days before that Half of patients presented with at least one relevant increased value, the patient was still considered comorbidity. Overall, 95 (44.2%) patients pre- in the analysis but as a patient who did not show sented with a primary solid tumour, while 120 that increase. (55.8%) had lymphoma or myeloma. Among patients with primary solid tumours, the most fre- The second outcome was calculated as the num- quent sites were lung, prostate and breast, and ber of patients who, during the first 12 (+1) 26.3% of patients had received prior radiotherapy weeks after the start of treatment, showed at least while 44.2% had received previous chemotherapy. one Hb level which exceeded the level at the start of treatment by at least 2 g/dl, with the same cave- Among patients with haematological malignan- ats as above. Moreover, the mean and standard cies, non-Hodgkin’s lymphoma was most com- deviation of Hb level at each time point was pro- mon. A total of 5% of haematological patients vided and tested by repeated-measure analysis of had received previous radiotherapy and 30.8% of variance (ANOVA). patients had received previous chemotherapy. All AEs (serious related or unrelated, non-serious Among all patients, the median Hb level at related or unrelated) arising during the 12-week Binocrit treatment initiation was 9.6 g/dl (IQR observational period were described. Incidence of 8.9, 10.1 g/dl). During the 12-week observation AEs was calculated for all events overall and by period, 42 patients (19.5%) received iron supple- event type. mentation: 21 (9.8%) received IV iron, and 27 (12.6%) received oral supplementation. Figure 1 The association between demographic and clini- shows iron administration at each time point. cal factors and the improvement of anaemia was studied by means of univariate logistic regression models. The dependent variable of these models Treatment with Binocrit was anaemia improvement (present versus absent), Mean [± standard deviation (SD)] starting dose while the independent variables were each of the of Binocrit was 35,673 ± 8449 IU/injection, and http://tam.sagepub.com 25 Therapeutic Advances in Medical Oncology 9(1) Table 1. Baseline characteristics of evaluable patients. Age Median (range) 70 22–89 Gender, n (%) Male 102 47.4 Female 113 52.6 Weight, kg, median (IQR) 68 60–78 Karnofsky score, median (IQR) 90 80–90 Main relevant comorbidities, n (%) Any relevant comorbidity 108 50.2 Arterial hypertension 64 29.8 Cardiovascular/cardiac 15 7.0 Diabetes 14 6.5 Myocardial infarction 13 6.0 Type of neoplastic disease Primary solid tumour, n (%) 95 44.2 Lung 15 15.8 Prostate 14 14.7 Breast 13 13.7 Colorectal 11 11.6 Ovary 8 8.4 Head and neck 3 3.2 Other 31 32.6 Haematological malignancies, n (%) 120 55.8 Non-Hodgkin’s lymphoma 77 64.2 Multiple myeloma 22 18.3 Hodgkin’s disease 19 15.8 Non-Hodgkin’s lymphoma type B-cell-chronic 2 1.7 lymphocytic leukaemia Hb level at Binocrit® treatment initiation: 9.6 8.9–10.1 median (25–75 percentiles), g/dl Relevant comorbidities with frequency >5% are reported. Percentages are computed out of the number of evaluable pa- tients (N = 215). For primary solid tumour site and type of haematological malignancy, percentages are computed out of the number of evaluable patients with solid tumour (N = 95) and with haematological malignancy (N = 120), respectively. Hb, haemoglobin; IQR, interquartile range. almost all patients (95.2%) started treatment with (range 1–13 weeks). No AEs leading to adjust- one injection per week (N = 104 patients with ment of dosage of Binocrit or temporary suspen- data available for the three time points). Almost sion of treatment with the drug were reported. half of patients (103, 47.9%) discontinued Initial Binocrit dosage was increased during Binocrit within 12 weeks; in 14.6% of these treatment in two patients, who continued the cases treatment was discontinued because chem- increased dosage until the end of the observation otherapy was discontinued and in 75.7% because period. targeted values were attained (i.e. anaemia improvement was reached). In particular mean (SD) Hb values at treatment start were 9.34 Primary outcomes (1.02) versus 9.83 (0.94) in patients who did not Of 205 patients with at least one Hb value in the versus did discontinue because anaemia was first 4 (+1) weeks after Binocrit start (88 with improved (Student’s t-test p value = 0.0187). solid tumours and 117 with haematological malig- nancies), 101 (49.3%) showed a ⩾1 g/dl increase Binocrit was administered to half of the patients in Hb in the first 4 weeks of treatment: 45.5% in for at least 10 weeks during the observation period patients with solid tumours, 52.1% in patients 26 http://tam.sagepub.com G Rosti, M Petrini et al. Figure 1. Iron administration during the observation period. The proportion of patients who received iron at each time point is shown. Percentages are computed out of the number of evaluable patients (N = 215). OS, by mouth. Figure 2. Increase of haemoglobin level during the observation period. The proportion of patients who showed at least one ⩾1 increased Hb value during the first 4 (+1) weeks/at least one ⩾2 increased Hb value during the first 12 (+1) weeks/ at least one ⩾1 increased Hb value during the first 12 (+1) weeks. 95% CI of the proportion is shown with error bars. CI, confidence interval; Hb, haemoglobin. with haematological malignancies (Figure 2). g/dl increase in Hb level (62.5% in patients with Considering all evaluable patients (N = 215) in solid tumours, 68.8% in patients with haemato- the first 12 weeks after treatment initiation, 72.6% logical malignancies), while 46.4% showed a of patients showed a ⩾1 g/dl increase in Hb ⩾2 g/dl increase in Hb level (39.6% in patients (69.5% in patients with solid tumours, 75.0% in with solid tumours, 51.6% in patients with hae- patients with lymphoma/myeloma) and 51.6% of matological malignancies). Considering only patients showed a ⩾2 g/dl increase in Hb level patients who did not discontinue Binocrit or (48.4% in patients with solid tumours, 54.2% in who discontinued it after the first 5 weeks (N = patients with haematological malignancies). 150), 72.0% of patients showed a ⩾1 g/dl increase in Hb (66.7% in patients with solid Considering the first 12 weeks after treatment tumours, 75.6% in patients with haematological initiation and only patients who did not discon- malignancies), and 51.3% showed a ⩾2 g/dl tinue Binocrit (N = 112), 66.1% showed a ⩾1 increase in Hb (45.0% in patients with solid http://tam.sagepub.com 27 Therapeutic Advances in Medical Oncology 9(1) Figure 3. Haemoglobin level during the observation period. Hb mean (± SD) level (g/dl) at each time point is shown. Only patients with all available values at each time point were considered (N = 48 for solid tumours and N = 75 for haematological malignancies). p value refers to repeated measures ANOVA. ANOVA, analysis of variance; Hb, haemoglobin; SD, standard deviation. Table 2. Univariate logistic regression models for improvement of anaemia. Independent variable Odds ratio (point Wald 95% CI estimate) Age Continuous variable 1.015 0.994–1.037 Gender Female versus male 1.330 0.767–2.307 Hb level before starting Continuous variable 0.572 0.423–0.773 Binocrit Karnofsky performance Continuous variable 1.005 0.985–1.026 status Tumour type Malignant blood dyscrasia 1.114 0.805–1.541 versus primary solid tumour Note: The dependent variable was anaemia improvement (present versus absent), defined as either ⩾1 g/dl increased Hb ® ® level after 4 (+1) weeks from Binocrit treatment start or ⩾2 g/dl increased Hb level after 12 (+1) weeks from Binocrit treatment start. CI, confidence interval; Hb, haemoglobin. tumours, 55.6% in patients with haematological of obtaining an improvement (odds ratio 0.572, malignancies). 95% CI 0.423–0.773). Among patients with available Hb values at each Among 21 patients who received IV iron adminis- time point, a statistically significant increase in tration, 16 (76.2%) experienced anaemia improve- Hb levels in both patients with solid tumours and ment; among the 194 patients who did not receive in patients with haematological malignancies was IV iron administration, 116 (59.8%) experienced observed (Figure 3). anaemia improvement (not statistically signifi- cant). A total of 38 patients received RBC transfu- In univariate logistic regression models, improve- sions during the observation period: 23 (10.7%) ment in Hb level was not significantly associated by 4 weeks, and 25 (11.6%) by 12 weeks. with age, gender or Karnofsky performance sta- tus, tumour type (Table 2). The only variable that was significantly associated with improve- Adverse events ment in Hb level was baseline Hb level: patients Overall, 29 (13.5%) patients experienced one or with higher baseline Hb level had a lower chance more AEs during the observation period, for a 28 http://tam.sagepub.com G Rosti, M Petrini et al. Table 3. Key factors in the management of anaemia as reported by clinicians. First key factor Second key factor Third key factor Maintenance of quality 155 (72.1%) Maintenance of 80 (37.2%) International 78 (36.3%) of life chemotherapy dosages recommendations Maintenance of 36 (16.7%) Reduction of 66 (30.7%) Maintenance of 40 (18.6%) chemotherapy dosages transfusions chemotherapy dosages Reduction of 14 (6.5%) Maintenance of quality 40 (18.6%) Expected efficacy 30 (14.0%) transfusions of life Expected efficacy 5 (2.3%) Expected efficacy 17 (7.9%) Reduction of 18 (8.4%) transfusions Other factor 5 (2.3%) Other factor 8 (3.7%) Other factor 28 (13.0%) No other key factor – No other key factor 4 (1.9%) No other key factor 21 (9.8%) Percentages are computed out of the number of evaluable patients (N = 215). total of 63 AEs. The most commonly observed patients undergoing chemotherapy for solid AEs were asthenia (nine events) and dyspnoea tumours or lymphoma and myeloma was associ- (six events), followed by oedema, diarrhoea, nau- ated with a clinically relevant increase in Hb level sea and anorexia (three events each). Out of 63 (⩾1 g/dl) in the first 4 weeks after treatment initia- events, 40 (63.5%) were mild, 15 (23.8%) were tion in nearly half (49%) of patients. This propor- moderate and 8 (12.7%) were severe. Overall, tion was similar in the two groups: 45% in patients four patients experienced one or more serious with primary solid tumours and 52% in patients AEs (a total of six serious AEs): all these events with haematological disorders. Furthermore, in the were judged unrelated to Binocrit . There were first 12 weeks after treatment initiation, 73% of two patients that experienced adverse drug reac- patients achieved a Hb increase of ⩾1 g/dl and 52% tions: one superficial venous thrombosis and one achieved an increase of ⩾2 g/dl. These proportions deep venous thrombosis, both considered possi- were also similar in patients with solid tumours and bly related to Binocrit administration. Antibody haematological malignancies. formation to biosimilar epoetin alpha was not specifically evaluated, in any case no patients These results are largely consistent with literature developed pure red cell aplasia (PRCA) during about the activity of ESAs. In the ACT study, an this study. Hb increase of >1 g/dl was obtained in 65% of patients [Ludwig et  al. 2009]. The ACT study was run before the 2008 ESA-class label change Key factors taken into account by clinicians in and United States Food and Drug Administration the management of anaemia (FDA) black box warning, so one could postulate Key considerations reported by clinicians in that treatment habits in Italy are likely to be more the management of anaemia are summarized in conservative during the period of our later study Table 3. The main reason taken into account by (i.e. less aggressive ESA treatment); this hypoth- clinicians to treat chemotherapy-induced anaemia esis requires further evaluation. Our secondary was maintenance of patients’ QoL (72.1%), fol- analysis of potential association between demo- lowed by maintenance of chemotherapy dose graphic and clinical variables and successful treat- (16.7%) and reduction of transfusions (6.5%). ment in terms of Hb increase did not show a Key factors reported by clinicians in the decision to significant impact of sex, performance status and start Binocrit included (i) the existence of hospital age. The only variable showing a statistically sig- instructions (ESAS available in pharmacy) (38.1%) nificant association with the chance of success in and (ii) maintenance of QoL (27.9%) and (iii) Hb increase was baseline Hb level, with a signifi- expected efficacy of the chosen treatment (15.8%). cantly greater chance of benefit from Binocrit treatment in patients starting treatment with lower Hb values. This finding suggests that, even Discussion in a population of patients with a relatively low In this retrospective, observational study, treatment Hb value, with a high risk of QoL deterioration with biosimilar epoetin alfa (Binocrit ) in a series of due to anaemia and a high risk of transfusion, http://tam.sagepub.com 29 Therapeutic Advances in Medical Oncology 9(1) treatment with Binocrit is able to deliver a clini- [Abraham et  al. 2014]. The simulation showed cally meaningful benefit. that, under fixed dosing, the savings from 100% conversion were €110,592,159, translating into an Our results show a relatively low use of iron sup- additional 9770 rituximab, 3912 bevacizumab, or plementation in clinical practice, and this could 3713 trastuzumab treatments. have had a detrimental effect on the increase in Hb level obtained with Binocrit . However, this is not Another recent study evaluated the comparative the first report showing under-treatment of iron cost efficiency of different ESAs in the manage- deficiency in patients with cancer and chemother- ment of chemotherapy-induced anaemia [Aapro apy-induced anaemia. In a recent survey asking et  al. 2015]. The administration of biosimilar oncologists and haematologists from nine epoetin alfa was shown to be consistently cost- European countries about their last five patients efficient with respect to treatment with originator treated for chemotherapy-induced anaemia, iron epoetin alfa, epoetin beta and darbepoetin alfa status was measured (by serum ferritin) in less (both once weekly and once every 3 weeks), under than half (48%) of patients [Ludwig et  al. 2014]. different dosing scenarios. Despite the demonstration of iron deficiency in 42% of evaluated patients, iron supplementation Along with the increasing adoption of biosimilar was only used in 31% of the cases, with oral admin- drugs in clinical practice, patient exposure to istration in the majority of cases. While there is lit- these products continues to increase. As of tle evidence that oral iron supplements increase February 2014, the estimated exposure to response to ESAs, there is consistent evidence of a Binocrit was over 300,000 patient-years, with better response to ESAs when iron is adminis- >5000 patients studied in clinical trials [Aapro, tered IV in patients with absolute or functional 2013]. No relevant differences in safety profiles iron deficiency [Aapro et  al. 2008; Gafter-Gvili between biosimilar and reference products have et al. 2014]. Optimal treatment of chemotherapy- been demonstrated [Weigang-Köhler et al. 2009; induced anaemia should include an evaluation of Abraham and MacDonald, 2012]. From this iron status (transferrin saturation and ferritin) and point of view, our study confirmed the safety of optimal use of IV iron supplementation, when Binocrit , with a low incidence of AEs (13%) and needed, along with ESAs, in order to obtain an only two adverse reactions considered related to effective increase in Hb levels and avoid blood Binocrit administration. transfusions. A limitation of our study is that it was designed as In most countries, the sustainability of the health a retrospective, observational analysis, which can- system has been seriously challenged in recent not produce the high level of evidence associated years. Although the cost of drugs is not the only with randomized, controlled trials. On the other factor associated with this problem, it is considered hand, its observational nature allowed confirma- a leading driver of the phenomenon [Cornes, tion of the effectiveness and safety of Binocrit 2012]. A biosimilar drug is a successor to a biologi- outside the controlled and selected conditions of cal medicine that has lost patent protection or randomized trials. Furthermore, the retrospective exclusivity [Bennett et  al. 2014]. Biosimilars are design ensured there was no interaction between approved in highly-regulated markets around the study conduct and clinician’s behaviour. Thus, world, following very stringently-defined regula- the ANEMONE study offers an overview of the tory pathways, after they have demonstrated simi- use of Binocrit to manage chemotherapy- lar safety, efficacy and quality to the reference induced anaemia in a considerable sample of product. Increase in the use of biosimilar drugs has patients from Italian clinical practice. Although been proposed as one way of controlling the esca- participating sites did not represent a random lating costs of healthcare. Using biosimilar ESAs sample of all Italian ones, an effort was made to for supportive cancer care could produce substan- represent the north, centre and south of Italy. tial cost savings, potentially increasing accessibility The consecutive enrolment procedure and inclu- to primary anticancer treatment. A recent study sion of deceased patients were performed to simulated the budget impact of biosimilar ESAs reduce the risk of selection bias. in EU countries, and estimated the number of patients who could be treated with rituximab, bev- In conclusion, the results of this retrospective, acizumab or trastuzumab from the associated cost observational experience confirm the effectiveness savings in a hypothetical panel of 100,000 patients and safety of biosimilar epoetin alfa (Binocrit ) in 30 http://tam.sagepub.com G Rosti, M Petrini et al. Treatment (A.C.T.) study: a global retrospective the treatment of anaemia in cancer patients under- study of practice patterns and outcomes in the going chemotherapy in routine practice. Our management of anaemia in cancer patients and their results can be considered reassuring about the use congruence with evidence-based guidelines. Support of Binocrit in this setting. Care Cancer 16(2): 193–200. Acknowledgements Aapro, M., Moebus, V., Nitz, U., O’Shaughnessy, J., Pronzato, P., Untch, M. et al. (2015) Safety and This study was sponsored by Sandoz S.p.A., efficacy outcomes with erythropoiesis-stimulating Italy. Scientific and technical coordination, data agents in patients with breast cancer: a meta-analysis. management, and statistical support were pro- Ann Oncol 26: 688–695. vided by MediData. Abraham, I., Han, L., Sun, D., MacDonald, K. MediData study team: Christian Amici; and Aapro, M. (2014) Cost savings from anemia Daniela Longo; Gaia Vitali; Francesca Trevisan; management with biosimilar epoetin alfa and Saide Sala; Chiara Longagnani; Luca Zanoli; increased access to targeted antineoplastic treatment: Alice Malagutti; Alessandra Ori; Lucia Simoni; a simulation for the EU G5 countries. Future Oncol Simona Sgarbi. 10: 1599–1609. ANEMONE study group: Antonio Frassoldati Abraham, I. and MacDonald, K. (2012) (A. O. U. Arcispedale S. Anna, Cona di Ferrara); Clinical safety of biosimilar recombinant human erythropoietins. Expert Opin Drug Saf 11: 819–840. Teresa Gamucci (Ospedale S. S. Trinità, Sora); Roberto Maisano (Az. Osp. Bianchi Melacrino Abraham, I. and Sun, D. (2012) The cost of blood Morelli, Reggio Calabria); Claudia Minotto transfusion in Western Europe as estimated from six (Ospedale di Mirano ULSS 13, Mirano); studies. Transfusion 52: 1983–1988. Pierosandro Tagliaferri (Fondazione Tommaso Bennett, C., Chen, B., Hermanson, T., Wyatt, Campanella, Catanzaro); Carlo Gatti (Azienda M., Schulz, R., Georgantopoulos, P. et al. (2014) ULSS 14 Chioggia, Sottomarina di Chioggia); Regulatory and clinical considerations for Riccardo Filippo Gherlinzoni (Ospedale Cà biosimilar oncology drugs. Lancet Oncol 15: Foncello, Treviso); Ghio (A. O. U. San Martino di e594–e605. Genova, Genova); Guido Moreo (Fondazione Cà Bennett, C., Silver, S., Djulbegovic, B., Samaras, Granda Ospedale Maggiore Policlinico, Milano); A., Blau, C., Gleason, K. et al. (2008) Venous Manlio Mencoboni (az. Ospedale Villa Scassi ASL thromboembolism and mortality associated with 3, Genova); Francesco Angelini (Ospedale Regina recombinant erythropoietin and darbepoetin Apostolorum, Albano Laziale); Andrea Pietro administration for the treatment of cancer-associated Sponghini (Az. Osp. Maggiore della Carità, anemia. JAMA 299: 914–992. Novara); Giorgio Bonciarelli (Azienda ULSS 17 Bohlius, J., Weingart, O., Trelle, S. and Engert, A. – Monselice). (2006) Cancer-related anemia and recombinant human erythropoietin: an updated overview. Nat Clin Funding Pract 3: 152–164. The author(s) disclosed receipt of the following Bokemeyer, C., Aapro, M., Courdi, A., Foubert, financial support for the research, authorship, J., Osterborg, A., Repetto, L. et al. (2007) EORTC and/or publication of this article: This study was guidelines for the use of erythropoietic proteins in sponsored by Sandoz S.p.A., Italy. anaemic patients with cancer: 2006 update. Eur J Cancer 43: 258–270. Conflict of interest statement The author(s) declared no potential conflicts of Bokemeyer, C. and Foubert, J. (2004) Anemia impact and management: focus on patients needs interest with respect to the research, authorship, and the use of erythropoietic agents. Sem Oncol 31: and/or publication of this article. 4–11. Cella, D., Kallich, J., McDermott, A. and Xu, X. (2004) The longitudinal relationship of hemoglobin, References fatigue and quality of life in anemic cancer patients: Aapro, M. (2013) Biosimilars in oncology: current results from five randomized clinical trials. Ann Oncol and future perspectives. GaBI J 2: 91–94. 15: 979–986. Aapro, M., Abraham, I., Bokemeyer, C., Ludwig, Cornes, P. (2012) The economic pressures for H., Macdonald, K., Soubeyran, P. et al. (2008) The biosimilar drug use in cancer medicine. Target Oncol background and methodology of the Anaemia Cancer 7(Suppl. 1): S57–S67. http://tam.sagepub.com 31 Therapeutic Advances in Medical Oncology 9(1) Gafter-Gvili, A., Steensma, D. and Auerbach, M. Ludwig, H, Van Belle, S., Barrett-Lee, P., Birgegård, (2014) Should the ASCO/ASH guidelines for the use G., Bokemeyer, C., Gascón, P. et al. (2004) The of intravenous iron in cancer- and chemotherapy- European Cancer Anaemia Survey (ECAS): a induced anemia be updated? J Natl Compr Cancer large, multinational, prospective survey defining the Netw 12: 657–664. prevalence, incidence, and treatment of anaemia in cancer patients. Eur J Cancer 40: 2293–2306. Kerkhofs, L., Boschetti, G., Lugini, A., Stanculeanu, Rizzo, J, Lichtin, A, Woolf, S, Seidenfeld, J., D. and Palomo, A. (2012) Use of biosimilar epoetin Bennett, C, Cella, D. et al. (2002) Use of epoetin to increase hemoglobin levels in patients with in patients with cancer: evidence-based clinical chemotherapy-induced anemia: real-life clinical practice guidelines of the American Society of Clinical experience. Future Oncol 8: 751–6. doi:10.2217/ Oncology and the American Society of Hematology. fon.12.39. Epub 2012 Mar 23. Blood 100: 2303–2320. Littlewood, T. and Samol, J. (2003) The efficacy Rodriguez Garzotto, A., Cortijo Casacajares, S., of rHuEPO in cancer-related anemia: review. Br J Pernaut, C., Ruiz Ares, G., Otero Blas, I., Heine, Haematol 121: 3–11. O. et al. (2014) Erythropoiesis-stimulating agents Loney, M. and Chernecky, C. (2000) Anemia. Oncol for the treatment of chemotherapy-induced anemia: Nurs Forum 27: 951–962. comparisons from real-world clinical experience. J Blood Med 5: 43–48. Ludwig, H., Aapro, M., Bokemeyer, C., Glaspy, J., Hedenus, M., Littlewood, T. et al. (2014) A European Skillings, J., Rogers-Melamed, I., Nabholtz, J., patient record study on diagnosis and treatment of Sawka, C., Gwadry-Sridhar, F., Moquin, J. et al. chemotherapy-induced anaemia. Support Care Cancer (1995) An epidemiological review of anemia in 22: 2197–2206. cancer chemotherapy in Canada. Eur J Cancer 31A: S5. Ludwig, H., Aapro, M., Bokemeyer, C., MacDonald, K., Soubeyran, P., Turner, M. et al. (2009) Weigang-Köhler, K., Vetter, A. and Thyroff- Treatment patterns and outcomes in the management Friesinger, U. (2009) HX575, recombinant human Visit SAGE journals online of anaemia in cancer patients in Europe: findings from epoetin alfa, for the treatment of chemotherapy- http://tam.sagepub.com the Anaemia Cancer Treatment (ACT) study. Eur J associated symptomatic anaemia in patients with solid SAGE journals Cancer 45: 1603–1615. tumours. Onkologie 32: 168–174. 32 http://tam.sagepub.com http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Therapeutic Advances in Medical Oncology SAGE

Management of anaemia in oncohaematological patients treated with biosimilar epoetin alfa: results of an Italian observational, retrospective study:

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Giovanni Rosti, MD Background: Many patients with solid tumours or nonmyeloid haematopoietic tumours Oncologia, Policlinico San Matteo IRCCS, Pavia, Via develop symptomatic anaemia, which has a major impact on quality of life (QoL). The efficacy Scarpa 1, 31100 Treviso, Italy of erythropoiesis-stimulating agents (ESAs) in improving QoL and reducing blood transfusions rosti.giovanni@gmail.com has been widely demonstrated. Binocrit (biosimilar epoetin alfa) is an ESA indicated in the Mario Petrini, MD Azienda Ospedaliera European Union for treating chemotherapy-induced anaemia. The aim of this study was to Universitaria Pisana, Pisa, investigate the effect of Binocrit on haemoglobin (Hb) levels in anaemic cancer patients in Italy Italian clinical practice. Alberto Bosi, MD Department of Methods: The ANEMONE study was a national, longitudinal, retrospective, multicentre Hematology, Careggi Hospital and University of observational study. Patients had to be 18 years or older, with a solid tumour or non-Hodgkin’s Florence, Firenze, Italy lymphoma, Hodgkin’s disease or multiple myeloma, receiving chemotherapy, and treated Piero Galieni, MD Ospedale C. e G. Mazzoni, with Binocrit to manage chemotherapy-induced anaemia. The primary outcomes were Ascoli Piceno, Italy the proportion of patients with a Hb increase ⩾1 g/dl during the first 4 weeks and with a Hb Daniele Bernardi, MD increase ⩾2 g/dl during the first 12 weeks. ULSS 10 ‘Veneto Orientale’, San Donà di Results: A total of 245 patients were enrolled and 215 patients were evaluable for statistical Piave, Italy analysis. In the first 4 weeks, 49.3% of patients showed an increase in Hb of ⩾1 g/dl: 45.5% in Gianfranco Giglio, MD Ospedale Cardarelli, patients with solid tumours and 52.1% in patients with haematological malignancies. In the Campobasso, Italy first 12 weeks, 51.6% of patients showed an increase in Hb of ⩾2 g/dl (48.4% solid tumours, Laura Dorotea, MD ® Ospedale Riuniti Padova 54.2% haematological diseases). Treatment with Binocrit was well tolerated. Sud, Monselice, Italy Conclusions: These results confirm the effectiveness and safety of Binocrit for Brunangelo Falini, MD Ospedale Santa Maria chemotherapy-induced anaemia in routine practice in patients with solid tumours, lymphoma della Misericordia, and myeloma. Perugia, Italy Elvira Scelzi, MD Ospedale di Castelfranco Veneto (ULSS), Keywords: biosimilar, chemotherapy-induced anaemia, epoetin alfa, erythropoiesis- Castelfranco Veneto, Italy stimulating agents, erythropoietin Enzo Veltri, MD Ospedale S. Maria Goretti, Latina, Italy Roberto Castelli, MD Fondazione Cà Granda Introduction 1995]. About two-thirds of cancer patients under- Ospedale Maggiore About 50% of patients with solid tumours or non- going chemotherapy developed anaemia during Policlinico, Milano, Italy myeloid haematopoietic tumours develop symp- treatment in the European Cancer Anaemia Chiara Longagnani, MD MediNeos surl, Modena, tomatic anaemia during the course of their disease Survey (ECAS) [Ludwig et al. 2004]. Italy [Bokemeyer et al. 2004]. In cancer patients, anae- Tommaso Raggi, MSc mia may have multiple causes; it can result from Anaemia has a substantial impact on patients’ Sandoz S.p.A., Origgio, Italy cancer itself, concomitant diseases, older age, quality of life (QoL), and is largely responsible for Federico Simonetti, MD inflammation, malnutrition, low iron levels and the fatigue reported by many cancer patients. An Versilia Azienda ULSS 12, treatment with chemotherapy [Skillings et  al. increase in haemoglobin (Hb) level can produce a Lido di Camaiore, Italy 22 http://tam.sagepub.com G Rosti, M Petrini et al. meaningful improvement in fatigue, with related The Anaemia Cancer Treatment (ACT) study improvement in physical, functional, emotional assessed ESA treatment response rates in anae- and overall well-being [Cella et al. 2004]. In cases mic patients (Hb ⩽ 11 g/dl). It demonstrated that of severe anaemia, red blood cell (RBC) transfu- 65% of patients showed an increase in Hb of ⩾1 sions may be needed [Ludwig et al. 2004]. These g/dl over 8–10 weeks after initiation, while a rise are effective, but inconvenient, in short supply of Hb ⩾2 g/dl was observed in 34% of patients and not without associated risks and cost [Ludwig et  al. 2009]. This study confirmed the [Abraham and Sun, 2012]. Furthermore, low importance of anaemia in real-life clinical practice levels of Hb before or during chemotherapy and suggested that that the treatment response cycles may require dose reductions or delays in rates were lower than reported in randomized administration, resulting in a decrease in the controlled trials. Observational studies are there- overall treatment intensity. fore important to assess the real-world effective- ness of these agents in the context of a rapidly Anaemia is defined as a Hb level <10 or 11 g/dl, evolving disease management framework. with severe anaemia defined as a Hb level <8 g/dl [Bokemeyer et  al. 2007]. Although considerable Binocrit (biosimilar epoetin alfa) is an ESA indi- progress has been made in preventing or alleviat- cated for the treatment of anaemia as a result of ing many of the common toxicities associated chronic kidney disease or chemotherapy-induced with cancer and its therapy, anaemia continues anaemia [Binocrit® Summary of Product to be relatively undertreated [Loney et al. 2000]. Characteristics (available at http://www.ema. The efficacy of erythropoiesis-stimulating agents europa.eu/docs/en_GB/document_library/ (ESAs) in correcting anaemia in cancer patients EPAR_-_Product_Information/human/000725/ has been widely demonstrated [Littlewood et al. WC500053680.pdf)]. However, data on the use 2003; Bohlius et  al. 2006]. These substances of Binocrit for the treatment of chemotherapy- improve QoL and reduce the need for transfu- induced anaemia in clinical practice are limited sion. The administration of ESAs in cancer [Weigang-Köhler et  al. 2009; Kerkhofs et  al. patients has been reported to be associated with 2012; Rodriguez Garzotto et al. 2014]. an increased risk of thromboembolic events, reduced survival and reduced time to disease The aim of this retrospective study was to investi- progression [Bennett et  al. 2008]. However, in gate the effect of Binocrit on Hb levels in anae- many studies ESAs had been used with target Hb mic cancer patients in Italian clinical practice. levels significantly higher than those currently Secondary aims were to describe: (i) the charac- recommended by guidelines. According to cur- teristics of the treated population; (ii) all adverse rent guidelines, ESAs should be used only in events (AEs) over the 12-week observational patients with chemotherapy-induced anemia, period; (iii) factors related to improvement of and treatment should be discontinued once the anaemia; and (iv) key factors considered by clini- chemotherapy course is completed, and these cians in the management of anaemia. agents should not be used when the aim of treat- ment is cure. Materials and methods Recently, the UK National Institute for Health and Care Excellence (NICE) found ESA usage Study design in cancer-induced anaemia to be cost-effective, The ANEMONE (Anaemia management in largely due to the availability of lower cost bio- oNcohaEMatological patients treated with similar ESAs. Treatment guidelines and recom- binOcrit: an italiaN retrospective obsErvational mendations have been published regarding the study) study was designed as a national, longitudi- safe use of ESAs [Bokemeyer et  al. 2007; Rizzo nal, retrospective, multicentre observational study. et al. 2002]. Although the evidence for specifying It involved 23 Italian oncology or haematology cen- the optimal strategy of monitoring iron and insti- tres. The study was approved by the Institutional tuting iron repletion is not optimal, the majority Review Boards of all participating centres. Patients of these guidelines also suggest the importance included in the study were those who started treat- of using intravenous (IV) iron in combination ment with Binocrit according to normal clinical with ESAs to ensure patients are iron replete practice before site activation, in order to manage [Bokemeyer et al. 2007; Rizzo et al. 2002]. chemotherapy-induced anaemia. http://tam.sagepub.com 23 Therapeutic Advances in Medical Oncology 9(1) For each patient included, the decision to pre- (e.g. other ESAs or transfusion) in the 28 days ® ® scribe treatment with Binocrit was taken by their preceding the start of treatment with Binocrit . doctor regardless of enrolment in the ANEMONE study. Data were retrospectively collected from clinical medical records over a 12-week observa- Study aims and sample size tional period (± 1 week) after starting Binocrit The primary aim of the study was to describe the administration. Alive and reachable patients were trend of Hb levels in a 12-week observational consecutively enrolled at their normal scheduled period in patients receiving chemotherapy for a visits, during which they signed the informed con- solid tumour, lymphoma or myeloma and treated sent to the study and to retrospective data collec- with Binocrit . tion from existing clinical medical records. During the second half of the enrolment period, deceased/ In detail, the two primary outcomes considered unreachable patients were also consecutively for the evaluation of the primary objective were: included in descending order of Binocrit start date according to the list of all potentially eligible 1. the proportion of patients who, during the patients generated by each site at the time of acti- first 4 weeks after the start of treatment vation. This study was retrospective and observa- with Binocrit , showed an increase in Hb of tional, and did not affect the relationship between ⩾1 g/dl; clinicians and patients or standard patient follow- 2. the proportion of patients who, during the up patterns. Clinicians in the study remained free first 12 weeks after the start of treatment to decide on the treatment of their patients. The with Binocrit , showed an increase in Hb of enrolment period lasted 10 months. Data were ⩾2 g/dl. collected using an electronic data collection sheet, which automatically checked for possible data Secondary objectives of the study were to describe entry errors and inconsistencies. Site monitoring the treated population, to assess AEs occurring visits were performed at six participating centres, during the 12-week observational period, the where all data were validated with source data. evaluation of demographic and clinical factors potentially related to improvement of anaemia, and the description of the key factors considered Eligibility criteria by clinicians in the management of anaemia. To be eligible for inclusion, patients (both males and females) had to be 18 years or older at initia- According to feasibility considerations based on tion of Binocrit , presenting with a solid tumour, clinicians’ opinions, a total of 300 patients were non-Hodgkin’s lymphoma, Hodgkin’s disease or expected. Sample size was not based on the power multiple myeloma. They were to be receiving to investigate a formal statistical hypothesis but chemotherapy (alone or in combination with the achievable estimate precision was evaluated other treatments). Treatment to manage chemo- based on literature data. In the ACT study therapy-induced anaemia with Binocrit had to [Ludwig et  al. 2009], the proportion of patients have been started before site activation and data who showed an increased level of Hb ⩾ 1 g/dl was in medical records had to be available for the 65.0%, with a median time to response of 4.7 period from the start of treatment with Binocrit weeks, while the proportion of patients who for the following 12 weeks. showed an increased level of Hb ⩾ 2 g/dl was 33.7%, with a median time to response of 6 Patients were not eligible if they received treat- weeks. Starting from these results, we assumed ments for their cancer or anaemia in the context that the two proportions of interest at 4 and 12 of a clinical trial during the retrospective observa- weeks would be 32.5% and 33.7%, respectively. tional period, if they were in treatment only with Thus, considering 32.5% as the expected value of radiotherapy or molecular targeted therapy, if the primary outcome, with a sample size of 300 they presented with acute leukaemia or a chronic patients (corresponding to 270 evaluable patients, myeloproliferative syndrome, if they presented assuming 10% of patients as not evaluable due to with uncorrected haemolytic anaemia or anaemia screening failures, missing data, etc.), the 95% due to a deficiency not related to cancer (e.g. confidence interval (CI) for the expected propor- deficiency of iron, vitamin B12 or folic acid), or if tion would be 32.5% ± 5.6%. A smaller sample they received any other treatment for anaemia size would mean lower estimated precision, but 24 http://tam.sagepub.com G Rosti, M Petrini et al. the precision was acceptable (relative error ⩽ factors of interest (age, gender, Karnofsky perfor- 20%), even for 200 evaluable patients. mance status, baseline Hb level, tumour type). For the description of key factors considered by Statistical analysis clinicians in the management of anaemia, clini- Quantitative variables were described in terms of cians were asked to report the key criteria they th th mean, standard deviation, median, 25 and 75 take into account in management of anaemia and percentile [interquartile range (IQR)], minimum in initiating treatment with Binocrit (for exam- and maximum. Qualitative variables were described ple maintenance of QoL, reduction of transfu- in terms of absolute and relative frequency, with sions, expected improvement of Hb level and bilateral 95% CI (where relevant). patient request). These were described in terms of frequency. For both primary outcomes, the last available value in the month preceding the first administra- All the analyses were performed using SAS for tion of Binocrit was considered as the Hb level at Windows, release 9.2 (SAS Institute Inc., US). the start of treatment. The first outcome was calculated as the number Results of patients who, during the first 4 (+1) weeks From June 2013 to March 2014, 245 patients after the start of treatment, showed at least one were enrolled in the study. Of these, 30 were Hb level which exceeded the level at the start of excluded due to violations of the eligibility criteria treatment by ⩾1 g/dl in absence of blood trans- or unavailability of at least one Hb value during fusion or other ESA treatment during the 28 the Binocrit monitoring period. Thus, 215 days preceding that value, divided by the num- patients were evaluable for statistical analysis. ber of evaluable patients with at least one Hb value in that period. If an increased level of Hb The main demographic and clinical characteristics ⩾ 1 g/dl in the first 4 weeks occurred when the of the patients are shown in Table 1. Median age patient had undergone blood transfusion or was 68 years in females, and 71.5 years in males. other ESA treatment within 28 days before that Half of patients presented with at least one relevant increased value, the patient was still considered comorbidity. Overall, 95 (44.2%) patients pre- in the analysis but as a patient who did not show sented with a primary solid tumour, while 120 that increase. (55.8%) had lymphoma or myeloma. Among patients with primary solid tumours, the most fre- The second outcome was calculated as the num- quent sites were lung, prostate and breast, and ber of patients who, during the first 12 (+1) 26.3% of patients had received prior radiotherapy weeks after the start of treatment, showed at least while 44.2% had received previous chemotherapy. one Hb level which exceeded the level at the start of treatment by at least 2 g/dl, with the same cave- Among patients with haematological malignan- ats as above. Moreover, the mean and standard cies, non-Hodgkin’s lymphoma was most com- deviation of Hb level at each time point was pro- mon. A total of 5% of haematological patients vided and tested by repeated-measure analysis of had received previous radiotherapy and 30.8% of variance (ANOVA). patients had received previous chemotherapy. All AEs (serious related or unrelated, non-serious Among all patients, the median Hb level at related or unrelated) arising during the 12-week Binocrit treatment initiation was 9.6 g/dl (IQR observational period were described. Incidence of 8.9, 10.1 g/dl). During the 12-week observation AEs was calculated for all events overall and by period, 42 patients (19.5%) received iron supple- event type. mentation: 21 (9.8%) received IV iron, and 27 (12.6%) received oral supplementation. Figure 1 The association between demographic and clini- shows iron administration at each time point. cal factors and the improvement of anaemia was studied by means of univariate logistic regression models. The dependent variable of these models Treatment with Binocrit was anaemia improvement (present versus absent), Mean [± standard deviation (SD)] starting dose while the independent variables were each of the of Binocrit was 35,673 ± 8449 IU/injection, and http://tam.sagepub.com 25 Therapeutic Advances in Medical Oncology 9(1) Table 1. Baseline characteristics of evaluable patients. Age Median (range) 70 22–89 Gender, n (%) Male 102 47.4 Female 113 52.6 Weight, kg, median (IQR) 68 60–78 Karnofsky score, median (IQR) 90 80–90 Main relevant comorbidities, n (%) Any relevant comorbidity 108 50.2 Arterial hypertension 64 29.8 Cardiovascular/cardiac 15 7.0 Diabetes 14 6.5 Myocardial infarction 13 6.0 Type of neoplastic disease Primary solid tumour, n (%) 95 44.2 Lung 15 15.8 Prostate 14 14.7 Breast 13 13.7 Colorectal 11 11.6 Ovary 8 8.4 Head and neck 3 3.2 Other 31 32.6 Haematological malignancies, n (%) 120 55.8 Non-Hodgkin’s lymphoma 77 64.2 Multiple myeloma 22 18.3 Hodgkin’s disease 19 15.8 Non-Hodgkin’s lymphoma type B-cell-chronic 2 1.7 lymphocytic leukaemia Hb level at Binocrit® treatment initiation: 9.6 8.9–10.1 median (25–75 percentiles), g/dl Relevant comorbidities with frequency >5% are reported. Percentages are computed out of the number of evaluable pa- tients (N = 215). For primary solid tumour site and type of haematological malignancy, percentages are computed out of the number of evaluable patients with solid tumour (N = 95) and with haematological malignancy (N = 120), respectively. Hb, haemoglobin; IQR, interquartile range. almost all patients (95.2%) started treatment with (range 1–13 weeks). No AEs leading to adjust- one injection per week (N = 104 patients with ment of dosage of Binocrit or temporary suspen- data available for the three time points). Almost sion of treatment with the drug were reported. half of patients (103, 47.9%) discontinued Initial Binocrit dosage was increased during Binocrit within 12 weeks; in 14.6% of these treatment in two patients, who continued the cases treatment was discontinued because chem- increased dosage until the end of the observation otherapy was discontinued and in 75.7% because period. targeted values were attained (i.e. anaemia improvement was reached). In particular mean (SD) Hb values at treatment start were 9.34 Primary outcomes (1.02) versus 9.83 (0.94) in patients who did not Of 205 patients with at least one Hb value in the versus did discontinue because anaemia was first 4 (+1) weeks after Binocrit start (88 with improved (Student’s t-test p value = 0.0187). solid tumours and 117 with haematological malig- nancies), 101 (49.3%) showed a ⩾1 g/dl increase Binocrit was administered to half of the patients in Hb in the first 4 weeks of treatment: 45.5% in for at least 10 weeks during the observation period patients with solid tumours, 52.1% in patients 26 http://tam.sagepub.com G Rosti, M Petrini et al. Figure 1. Iron administration during the observation period. The proportion of patients who received iron at each time point is shown. Percentages are computed out of the number of evaluable patients (N = 215). OS, by mouth. Figure 2. Increase of haemoglobin level during the observation period. The proportion of patients who showed at least one ⩾1 increased Hb value during the first 4 (+1) weeks/at least one ⩾2 increased Hb value during the first 12 (+1) weeks/ at least one ⩾1 increased Hb value during the first 12 (+1) weeks. 95% CI of the proportion is shown with error bars. CI, confidence interval; Hb, haemoglobin. with haematological malignancies (Figure 2). g/dl increase in Hb level (62.5% in patients with Considering all evaluable patients (N = 215) in solid tumours, 68.8% in patients with haemato- the first 12 weeks after treatment initiation, 72.6% logical malignancies), while 46.4% showed a of patients showed a ⩾1 g/dl increase in Hb ⩾2 g/dl increase in Hb level (39.6% in patients (69.5% in patients with solid tumours, 75.0% in with solid tumours, 51.6% in patients with hae- patients with lymphoma/myeloma) and 51.6% of matological malignancies). Considering only patients showed a ⩾2 g/dl increase in Hb level patients who did not discontinue Binocrit or (48.4% in patients with solid tumours, 54.2% in who discontinued it after the first 5 weeks (N = patients with haematological malignancies). 150), 72.0% of patients showed a ⩾1 g/dl increase in Hb (66.7% in patients with solid Considering the first 12 weeks after treatment tumours, 75.6% in patients with haematological initiation and only patients who did not discon- malignancies), and 51.3% showed a ⩾2 g/dl tinue Binocrit (N = 112), 66.1% showed a ⩾1 increase in Hb (45.0% in patients with solid http://tam.sagepub.com 27 Therapeutic Advances in Medical Oncology 9(1) Figure 3. Haemoglobin level during the observation period. Hb mean (± SD) level (g/dl) at each time point is shown. Only patients with all available values at each time point were considered (N = 48 for solid tumours and N = 75 for haematological malignancies). p value refers to repeated measures ANOVA. ANOVA, analysis of variance; Hb, haemoglobin; SD, standard deviation. Table 2. Univariate logistic regression models for improvement of anaemia. Independent variable Odds ratio (point Wald 95% CI estimate) Age Continuous variable 1.015 0.994–1.037 Gender Female versus male 1.330 0.767–2.307 Hb level before starting Continuous variable 0.572 0.423–0.773 Binocrit Karnofsky performance Continuous variable 1.005 0.985–1.026 status Tumour type Malignant blood dyscrasia 1.114 0.805–1.541 versus primary solid tumour Note: The dependent variable was anaemia improvement (present versus absent), defined as either ⩾1 g/dl increased Hb ® ® level after 4 (+1) weeks from Binocrit treatment start or ⩾2 g/dl increased Hb level after 12 (+1) weeks from Binocrit treatment start. CI, confidence interval; Hb, haemoglobin. tumours, 55.6% in patients with haematological of obtaining an improvement (odds ratio 0.572, malignancies). 95% CI 0.423–0.773). Among patients with available Hb values at each Among 21 patients who received IV iron adminis- time point, a statistically significant increase in tration, 16 (76.2%) experienced anaemia improve- Hb levels in both patients with solid tumours and ment; among the 194 patients who did not receive in patients with haematological malignancies was IV iron administration, 116 (59.8%) experienced observed (Figure 3). anaemia improvement (not statistically signifi- cant). A total of 38 patients received RBC transfu- In univariate logistic regression models, improve- sions during the observation period: 23 (10.7%) ment in Hb level was not significantly associated by 4 weeks, and 25 (11.6%) by 12 weeks. with age, gender or Karnofsky performance sta- tus, tumour type (Table 2). The only variable that was significantly associated with improve- Adverse events ment in Hb level was baseline Hb level: patients Overall, 29 (13.5%) patients experienced one or with higher baseline Hb level had a lower chance more AEs during the observation period, for a 28 http://tam.sagepub.com G Rosti, M Petrini et al. Table 3. Key factors in the management of anaemia as reported by clinicians. First key factor Second key factor Third key factor Maintenance of quality 155 (72.1%) Maintenance of 80 (37.2%) International 78 (36.3%) of life chemotherapy dosages recommendations Maintenance of 36 (16.7%) Reduction of 66 (30.7%) Maintenance of 40 (18.6%) chemotherapy dosages transfusions chemotherapy dosages Reduction of 14 (6.5%) Maintenance of quality 40 (18.6%) Expected efficacy 30 (14.0%) transfusions of life Expected efficacy 5 (2.3%) Expected efficacy 17 (7.9%) Reduction of 18 (8.4%) transfusions Other factor 5 (2.3%) Other factor 8 (3.7%) Other factor 28 (13.0%) No other key factor – No other key factor 4 (1.9%) No other key factor 21 (9.8%) Percentages are computed out of the number of evaluable patients (N = 215). total of 63 AEs. The most commonly observed patients undergoing chemotherapy for solid AEs were asthenia (nine events) and dyspnoea tumours or lymphoma and myeloma was associ- (six events), followed by oedema, diarrhoea, nau- ated with a clinically relevant increase in Hb level sea and anorexia (three events each). Out of 63 (⩾1 g/dl) in the first 4 weeks after treatment initia- events, 40 (63.5%) were mild, 15 (23.8%) were tion in nearly half (49%) of patients. This propor- moderate and 8 (12.7%) were severe. Overall, tion was similar in the two groups: 45% in patients four patients experienced one or more serious with primary solid tumours and 52% in patients AEs (a total of six serious AEs): all these events with haematological disorders. Furthermore, in the were judged unrelated to Binocrit . There were first 12 weeks after treatment initiation, 73% of two patients that experienced adverse drug reac- patients achieved a Hb increase of ⩾1 g/dl and 52% tions: one superficial venous thrombosis and one achieved an increase of ⩾2 g/dl. These proportions deep venous thrombosis, both considered possi- were also similar in patients with solid tumours and bly related to Binocrit administration. Antibody haematological malignancies. formation to biosimilar epoetin alpha was not specifically evaluated, in any case no patients These results are largely consistent with literature developed pure red cell aplasia (PRCA) during about the activity of ESAs. In the ACT study, an this study. Hb increase of >1 g/dl was obtained in 65% of patients [Ludwig et  al. 2009]. The ACT study was run before the 2008 ESA-class label change Key factors taken into account by clinicians in and United States Food and Drug Administration the management of anaemia (FDA) black box warning, so one could postulate Key considerations reported by clinicians in that treatment habits in Italy are likely to be more the management of anaemia are summarized in conservative during the period of our later study Table 3. The main reason taken into account by (i.e. less aggressive ESA treatment); this hypoth- clinicians to treat chemotherapy-induced anaemia esis requires further evaluation. Our secondary was maintenance of patients’ QoL (72.1%), fol- analysis of potential association between demo- lowed by maintenance of chemotherapy dose graphic and clinical variables and successful treat- (16.7%) and reduction of transfusions (6.5%). ment in terms of Hb increase did not show a Key factors reported by clinicians in the decision to significant impact of sex, performance status and start Binocrit included (i) the existence of hospital age. The only variable showing a statistically sig- instructions (ESAS available in pharmacy) (38.1%) nificant association with the chance of success in and (ii) maintenance of QoL (27.9%) and (iii) Hb increase was baseline Hb level, with a signifi- expected efficacy of the chosen treatment (15.8%). cantly greater chance of benefit from Binocrit treatment in patients starting treatment with lower Hb values. This finding suggests that, even Discussion in a population of patients with a relatively low In this retrospective, observational study, treatment Hb value, with a high risk of QoL deterioration with biosimilar epoetin alfa (Binocrit ) in a series of due to anaemia and a high risk of transfusion, http://tam.sagepub.com 29 Therapeutic Advances in Medical Oncology 9(1) treatment with Binocrit is able to deliver a clini- [Abraham et  al. 2014]. The simulation showed cally meaningful benefit. that, under fixed dosing, the savings from 100% conversion were €110,592,159, translating into an Our results show a relatively low use of iron sup- additional 9770 rituximab, 3912 bevacizumab, or plementation in clinical practice, and this could 3713 trastuzumab treatments. have had a detrimental effect on the increase in Hb level obtained with Binocrit . However, this is not Another recent study evaluated the comparative the first report showing under-treatment of iron cost efficiency of different ESAs in the manage- deficiency in patients with cancer and chemother- ment of chemotherapy-induced anaemia [Aapro apy-induced anaemia. In a recent survey asking et  al. 2015]. The administration of biosimilar oncologists and haematologists from nine epoetin alfa was shown to be consistently cost- European countries about their last five patients efficient with respect to treatment with originator treated for chemotherapy-induced anaemia, iron epoetin alfa, epoetin beta and darbepoetin alfa status was measured (by serum ferritin) in less (both once weekly and once every 3 weeks), under than half (48%) of patients [Ludwig et  al. 2014]. different dosing scenarios. Despite the demonstration of iron deficiency in 42% of evaluated patients, iron supplementation Along with the increasing adoption of biosimilar was only used in 31% of the cases, with oral admin- drugs in clinical practice, patient exposure to istration in the majority of cases. While there is lit- these products continues to increase. As of tle evidence that oral iron supplements increase February 2014, the estimated exposure to response to ESAs, there is consistent evidence of a Binocrit was over 300,000 patient-years, with better response to ESAs when iron is adminis- >5000 patients studied in clinical trials [Aapro, tered IV in patients with absolute or functional 2013]. No relevant differences in safety profiles iron deficiency [Aapro et  al. 2008; Gafter-Gvili between biosimilar and reference products have et al. 2014]. Optimal treatment of chemotherapy- been demonstrated [Weigang-Köhler et al. 2009; induced anaemia should include an evaluation of Abraham and MacDonald, 2012]. From this iron status (transferrin saturation and ferritin) and point of view, our study confirmed the safety of optimal use of IV iron supplementation, when Binocrit , with a low incidence of AEs (13%) and needed, along with ESAs, in order to obtain an only two adverse reactions considered related to effective increase in Hb levels and avoid blood Binocrit administration. transfusions. A limitation of our study is that it was designed as In most countries, the sustainability of the health a retrospective, observational analysis, which can- system has been seriously challenged in recent not produce the high level of evidence associated years. Although the cost of drugs is not the only with randomized, controlled trials. On the other factor associated with this problem, it is considered hand, its observational nature allowed confirma- a leading driver of the phenomenon [Cornes, tion of the effectiveness and safety of Binocrit 2012]. A biosimilar drug is a successor to a biologi- outside the controlled and selected conditions of cal medicine that has lost patent protection or randomized trials. Furthermore, the retrospective exclusivity [Bennett et  al. 2014]. Biosimilars are design ensured there was no interaction between approved in highly-regulated markets around the study conduct and clinician’s behaviour. Thus, world, following very stringently-defined regula- the ANEMONE study offers an overview of the tory pathways, after they have demonstrated simi- use of Binocrit to manage chemotherapy- lar safety, efficacy and quality to the reference induced anaemia in a considerable sample of product. Increase in the use of biosimilar drugs has patients from Italian clinical practice. Although been proposed as one way of controlling the esca- participating sites did not represent a random lating costs of healthcare. Using biosimilar ESAs sample of all Italian ones, an effort was made to for supportive cancer care could produce substan- represent the north, centre and south of Italy. tial cost savings, potentially increasing accessibility The consecutive enrolment procedure and inclu- to primary anticancer treatment. A recent study sion of deceased patients were performed to simulated the budget impact of biosimilar ESAs reduce the risk of selection bias. in EU countries, and estimated the number of patients who could be treated with rituximab, bev- In conclusion, the results of this retrospective, acizumab or trastuzumab from the associated cost observational experience confirm the effectiveness savings in a hypothetical panel of 100,000 patients and safety of biosimilar epoetin alfa (Binocrit ) in 30 http://tam.sagepub.com G Rosti, M Petrini et al. Treatment (A.C.T.) study: a global retrospective the treatment of anaemia in cancer patients under- study of practice patterns and outcomes in the going chemotherapy in routine practice. Our management of anaemia in cancer patients and their results can be considered reassuring about the use congruence with evidence-based guidelines. Support of Binocrit in this setting. Care Cancer 16(2): 193–200. Acknowledgements Aapro, M., Moebus, V., Nitz, U., O’Shaughnessy, J., Pronzato, P., Untch, M. et al. (2015) Safety and This study was sponsored by Sandoz S.p.A., efficacy outcomes with erythropoiesis-stimulating Italy. Scientific and technical coordination, data agents in patients with breast cancer: a meta-analysis. management, and statistical support were pro- Ann Oncol 26: 688–695. vided by MediData. Abraham, I., Han, L., Sun, D., MacDonald, K. MediData study team: Christian Amici; and Aapro, M. (2014) Cost savings from anemia Daniela Longo; Gaia Vitali; Francesca Trevisan; management with biosimilar epoetin alfa and Saide Sala; Chiara Longagnani; Luca Zanoli; increased access to targeted antineoplastic treatment: Alice Malagutti; Alessandra Ori; Lucia Simoni; a simulation for the EU G5 countries. Future Oncol Simona Sgarbi. 10: 1599–1609. ANEMONE study group: Antonio Frassoldati Abraham, I. and MacDonald, K. (2012) (A. O. U. Arcispedale S. Anna, Cona di Ferrara); Clinical safety of biosimilar recombinant human erythropoietins. Expert Opin Drug Saf 11: 819–840. Teresa Gamucci (Ospedale S. S. Trinità, Sora); Roberto Maisano (Az. Osp. Bianchi Melacrino Abraham, I. and Sun, D. (2012) The cost of blood Morelli, Reggio Calabria); Claudia Minotto transfusion in Western Europe as estimated from six (Ospedale di Mirano ULSS 13, Mirano); studies. Transfusion 52: 1983–1988. 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Journal

Therapeutic Advances in Medical Oncology – SAGE

Published: Oct 21, 2016

Keywords: biosimilar; chemotherapy-induced anaemia; epoetin alfa; erythropoiesis-stimulating agents; erythropoietin

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