- Email: [email protected]
ZOHé: A Prospective Study of the Use of Biosimilar Filgrastim Zarzio in Clinical Practice in Patients Treated With Chemotherapy for Lymphoid Malignancies
Accepted Manuscript ® ZOHé: A prospective study of the use of biosimilar filgrastim Zarzio in clinical practice in patients treated with chemotherapy for lymphoid malignancies Gandhi Laurent Damaj, Omar Benbrahim, Maya Hacini, Inna Voronina, Khaled Benabed, Ravaka-Fatoma Soumoudronga, Isabelle Gasnereau, Corinne Haioun, Philippe Solal-Céligny PII:
S2152-2650(17)30110-6
DOI:
10.1016/j.clml.2017.05.002
Reference:
CLML 918
To appear in:
Clinical Lymphoma, Myeloma and Leukemia
Received Date: 2 February 2017 Revised Date:
27 April 2017
Accepted Date: 4 May 2017
Please cite this article as: Damaj GL, Benbrahim O, Hacini M, Voronina I, Benabed K, Soumoudronga R-F, Gasnereau I, Haioun C, Solal-Céligny P, ZOHé: A prospective study of the use of biosimilar ® filgrastim Zarzio in clinical practice in patients treated with chemotherapy for lymphoid malignancies, Clinical Lymphoma, Myeloma and Leukemia (2017), doi: 10.1016/j.clml.2017.05.002. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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ZOHé: A prospective study of the use of biosimilar filgrastim Zarzio® in clinical practice in patients treated with chemotherapy for lymphoid malignancies
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Authors Gandhi Laurent Damaja, Omar Benbrahimb, Maya Hacinic, Inna Voroninad, Khaled Benabede, Ravaka-Fatoma Soumoudrongaf, Isabelle Gasnereauf, Corinne Haioung, Philippe Solal-
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Célignyh Affiliations
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a. Institut d’hématologie, Centre Hospitalier Universitaire de Caen and Faculté de Médecine, Université de Caen-Normandie, Caen, France, [email protected] b. Centre Hospitalier Régionale d’Orléans, Orléans, France, [email protected] c. Centre Hospitalier Métropole Savoie, Chambéry, France, [email protected]
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d. Centre Hospitalier Boulogne, Boulogne-sur-Mer, France, [email protected]
e. Centre Hospitalier Public du Cotentin, Cherbourg-en-Cotentin and Centre Hospitalier
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Universitaire Côte de Nacre, Caen, France, [email protected] Sandoz France, Levallois-Perret, France, ravaka-
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[email protected]; [email protected]
g. Unité Hémopathies Lymphoïdes, Hôpital Henri Mondor-Albert, Université Paris Est Créteil, France, [email protected]
h. Institut de Cancérologie de l’Ouest René Gauducheau, Saint Herblain, France, [email protected] Address for correspondence Dr Philippe SOLAL-CÉLIGNY Directeur Médical
ACCEPTED MANUSCRIPT Institut de Cancérologie de l’Ouest ICO René Gauducheau Bld Jacques Monod 44805 Saint Herblain Cedex
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France
Email: [email protected]; Tel: +33 2 40 67 99 62 Running head
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Patterns of real-world Zarzio® use for patients with haematological malignancies in France Word count
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Conflict of interest All authors received funding from Sandoz for the conduct of the study in their institutions. Additionally, GLD has acted on advisory boards for Mundipharma, Novartis and Keocyt. CH
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has acted on advisory boards for Sandoz, Roche, Celgene, Janssen and Gilead. PSC has received research support from Roche, acted as a consultant for Sandoz and on advisory boards for Roche and Bayer, and is a shareholder in Roche. OB and MH have no further
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conflicts of interest to declare. RFS and IG are employed by Sandoz. Author contributions
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All authors had full access to the data and final responsibility for the decision to submit the
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manuscript. All authors read and approved the final draft of the manuscript.
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MicroAbstract The ZOHé study showed that Zarzio® is readily used for prophylaxis of chemotherapyinduced neutropenia in France, and clinicians’ assessment of febrile neutropenia risk is
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driven by patient factors more than the EORTC risk category of the chemotherapy regimen. Maintenance of dose intensity was high, especially in non-Hodgkin lymphoma patients at high risk of neutropenia. Zarzio® safety profile was confirmed.
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Abstract
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Background
The ZOHé study was a prospective, observational, multicentre study in France to assess use of biosimilar filgrastim Zarzio® in routine clinical practice in patients undergoing neutropeniainducing chemotherapy (CT).
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Patients and methods
Patients ≥18 years undergoing CT for a malignant disease and with a first prescription for Zarzio® were enrolled in two cohorts: solid tumour (1174 patients) or haematological
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malignancy (633 patients); the latter is reported here. Analyses primarily described the prescription and use of Zarzio® in current practice, and included identification of factors linked
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to prescription for primary prophylaxis, comparison of use in relation to European Organisation for the Research and Treatment of Cancer (EORTC) guidelines, and estimation of CT dose intensity maintenance in patients given Zarzio®. Results Use of Zarzio® in clinical practice was relatively standardised and followed label indication in 96.7% of the analysis population (633 patients). The majority of patients had ≥2 EORTC patient-related risk factors for febrile neutropenia (FN). CT dose intensity was maintained in 85.2% of evaluable patients and 89.6% of patients with non-Hodgkin lymphoma receiving R-
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ACCEPTED MANUSCRIPT CHOP (rituximab-cyclophosphamide/doxorubicin/vincristine/prednisone). The safety profile of Zarzio® was confirmed. Conclusions
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In routine clinical practice in France, Zarzio® is mostly used as primary prophylaxis for CTinduced neutropenia in patients with haematological malignancies. Patient-related risk
factors appear to have more weight in clinicians’ decisions to give Zarzio® than the FN risk
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category of the CT regimen alone in real-world practice.
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Keywords
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G-CSF, febrile neutropenia, prophylaxis, real-world practice, EP2006
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Introduction Patients treated with cytotoxic chemotherapy (CT) for haematological malignancies (HM) are at risk of developing CT-induced neutropenia and febrile neutropenia (FN), which are
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potentially life-threatening. Administration of granulocyte colony-stimulating factors (G-CSF) has been shown to reduce the incidence of CT-induced neutropenia, the duration of
hospitalisation, neutropenia, fever recovery time and/or antibiotic use in patients receiving standard and intensive doses of CT.1–4 G-CSF is also used for maintenance of CT dose
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intensity, which has been associated with improved survival and reduced mortality in HM,5,6 especially non-Hodgkin lymphoma (NHL).7
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Recommendations for G-CSF use were defined in guidelines set up by the European Society for Medical Oncology (ESMO), the European Organisation for the Research and Treatment of Cancer (EORTC), the American Society of Clinical Oncology (ASCO), and the National Comprehensive Cancer Network (NCCN). The most recent updates were issued in 2010 for
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ESMO8 and EORTC,9 2015 for ASCO10 and 2016 for NCCN.10,11 The guidelines all recommend G-CSF prophylaxis where a risk of FN due to the CT protocol is ≥20%, and for patients with intermediate risk (10–20%) who have additional risk factors (mainly age ≥65
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years, advanced stage of the disease, previous episode(s) of FN, low performance status and comorbidities). Since the most recent EORTC update, numerous anticancer agents and
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new CT combinations have been developed and brought into routine clinical practice, especially in haematology, and the FN risk of these agents is not always known. Filgrastim was the first recombinant human G-CSF used in clinical practice and since 2008 biosimilar versions have been available in Europe. Zarzio® (Sandoz GmbH) is a filgrastim biosimilar with demonstrated equivalence in clinical safety and efficacy in Phase 1 and Phase 3 studies to the reference product (Neupogen®).12–16 Extensive long-term data on its safety and efficacy in clinical practice have been collected.17–19 The ZOHé study evaluated the use
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ACCEPTED MANUSCRIPT of Zarzio® by oncologists and haematologists to manage the neutropenic risk of CT in routine practice in France. This paper reports the results for the cohort of patients with HM.
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Patients and methods Study design
ZOHé was a prospective, non-interventional, longitudinal, national, multicentre study,
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describing biosimilar filgrastim (Zarzio®, Sandoz, Holzkirchen, Austria) use by oncologists and haematologists in routine practice for patients receiving chemotherapy for solid tumours
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or HM. Ethical approval and data protection approval of the ZOHé study was authorised by the Comité Consultatif sur le Traitement d’Information en matière de Recherche dans le domaine de la Santé (CCTIRS) and the Commission Nationale de l’lnformatique et des Libertés (CNIL). Informed patient consent was obtained prior to study participation. This study was conducted according to the current revision of the 1964 Helsinki declaration.
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A total of 1816 patients (637 with HM were recruited consecutively across 125 sites in France between June 2013 and April 2014. Baseline patient characteristics and data regarding Zarzio® prescription were collected at Visit 1, on the first day of the CT cycle in which Zario
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was initiated. Data on the use of Zarzio®, patient clinical status, occurrence of neutropenia and adverse events (AEs) were collected at Visit 2, 3 months after inclusion or on
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discontinuation of CT or Zarzio® if this occurred earlier. A supplemental questionnaire on the administration of CT was also completed at Visit 2 to estimate maintenance of dose intensity. Data were collected using an electronic case report form and monitored centrally for quality control; AEs were coded using version 17.0 of the Medical Dictionary for Regulatory Activities (MedDRA). Obligatory fields, drop-down lists and consistency controls verified immediately on data entry were set up to limit missing or incoherent data.
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ACCEPTED MANUSCRIPT Patients Patients 18 years or older undergoing cytotoxic CT for solid tumours or HM who had a first prescription for biosimilar filgrastim Zarzio® and who consented to take part in the study were
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included. This paper presents results from the HM cohort of ZOHé. Primary and secondary objectives
The primary objective was to describe indications and use of biosimilar filgrastim Zarzio® in
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routine clinical practice in patients receiving CT for HM. The study also aimed to describe the characteristics of patients treated with Zarzio®, and estimate the proportion of patients whose
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CT dose intensity was maintained over the course of their regimen. Statistical methodology
To have a precision of 5% with a confidence interval of 95% for the descriptive study objectives, the number of patients required was calculated to be approximately 1830, for a
account.
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fixed alpha risk of 5% and a reference proportion of 50%, and taking incomplete files into
Descriptive statistics, and univariate and multivariate comparative analyses were carried out
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using the SAS package (version 9.4, SAS Institute, Cary, NC, USA). The threshold of significance of comparative analyses was fixed at 5%. For univariate analyses, the
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association between qualitative variables was tested using Pearson’s chi-squared test and, for theoretical frequencies <5, values were regrouped or Fisher’s exact test performed. Mean values of quantitative variables were compared between groups using Student’s t-test. Imputation of missing data was not carried out for the analyses. The average relative dose intensity (ARDI) was calculated at each cycle as the total dose of CT administered during a cycle divided by the total dose scheduled for the same cycle.20 The CT dose administered was calculated during each cycle as mg/m2/unit of time using data from the follow-up questionnaire. Dose intensity was considered maintained for ratios ≥85%.
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Results Study population
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Of the 1807 patients included in the ZOHé analysis population, 633 (35%) received CT for HM (Supplementary Figure 1). Patients who withdrew before the 3-month follow-up are
detailed in Supplementary Data, Table 1; most (72.8%, n = 59) were due to completion or discontinuation of CT or Zarzio®. Maintenance of CT dose intensity was estimated in 420
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patients (66.4% of the analysis population) who had evaluable data from the supplementary
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questionnaire. Patient demographics and clinical characteristics
Baseline patient characteristics are shown in Table 1. Two-thirds of patients in the HM cohort had NHL (64.6%, n = 409). A complete list of HM is given in Supplementary Data, Table 2.
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The mean age of the overall HM cohort was 64.2±16.1 years, although the Hodgkin lymphoma (HL) patients were younger, with a mean age of 45.5±18.2 years. At inclusion, 10.7% (n = 68) of the HM cohort had a prior episode of severe neutropenia (Grade 3 or 4;
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Table 1).
CT planned at inclusion (Table 1) was first line in 82.9% of patients; of those who were
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receiving salvage therapy following relapse, most (82.6%) were on at least their second line of salvage CT. Planned CT regimens are shown grouped by regimen type and malignancy type in Table 1. The majority of patients in each malignancy group were prescribed a CT regimen classed as high (>20%) or intermediate (10–20%) risk for FN in EORTC guidelines.9 Zarzio® administration and treatment patterns Zarzio® use is detailed by subgroup of HM in Table 2. Its use was predominantly in accordance with the label indication for established cytotoxic CT.12 The median day of
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ACCEPTED MANUSCRIPT administration was Day 6 of the current CT cycle for the NHL and HL groups, and Day 7 for ‘other HM’ group. The median duration of planned Zarzio® treatment was 5 days per cycle for patients with HL and other HM, and 6 days for patients with NHL; 66.5% of patients who were followed up (n
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= 409/615) received Zarzio® for 4.5–6.5 days, and 24.9% received Zarzio® for >6.5 days including three (0.5%) treated for >14 days. The majority of patients who were followed up
with 20.5% receiving a mean dose of 48 MIU per cycle.
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received a mean dose of 30 MIU per cycle (78.7%) throughout the course of their treatment,
In ZOHé, prophylaxis with G-CSF was considered primary if it occurred during Cycle 1 of the
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current course of CT at study inclusion, regardless of the intended protocol and day of Zarzio® initiation. Zarzio® was prescribed as primary prophylaxis in 67.6% of all HM patients (n = 427), and with curative intent or as secondary prophylaxis in the remainder (32.5%, n = 206). This treatment pattern was consistent across the subgroups: 69.4% of 409 NHL
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patients, 72.4% of 87 HL patients and 58.4% of 137 patients with ‘other HM’ were given Zarzio® as primary prophylaxis.
Zarzio® was administered for a median of four cycles of CT across the cohort. Treatment
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stayed constant for subsequent cycles in most patients (89.6%); in the 64 patients who had their treatment modified this was mostly a change to the treatment duration (82.8%, n = 53).
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Overall, 28.6% (n = 176) of patients stopped Zarzio® treatment before the end of the study, mostly due to cessation of CT. Eight patients stopped Zarzio® treatment as a result of AEs linked to Zarzio® (Table 2).
Estimated maintenance of CT dose intensity Dose intensity was estimated by comparing the actual doses received with doses planned by the investigator before start of treatment, and was considered to have been maintained (total
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ACCEPTED MANUSCRIPT ARDI ≥85%) in 85.2% of the evaluable HM patients. Maintenance of dose intensity was similar in all subgroups: 86.5%, 85.7% and 81.6% of patients with NHL, HL and other HM, respectively. ARDI was high in the overall cohort (mean±standard deviation total ARDI 93.9±24.4) and across the subgroups of NHL, HL and ‘other HM’ (mean total ARDI 94.1, 95.8
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and 92.4, respectively). Use of Zarzio® in relation to guidelines
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The FN risk of patients was assessed in terms of guidelines for FN risk according to the risk of their CT regimen and patient-related risk factors from EORTC recommendations,9 and is
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shown in Table 3. Where the EORTC recommendations did not provide a risk category for a particular regimen, ASCO 201510 and NCCN 201611 guidelines were checked for this analysis. No patients receiving Zarzio® had a CT regimen in the low risk (<10%) category, in line with recommendations. Many patients received CT regimens whose FN risk was ‘unknown’ i.e. not specified in the guidelines, particularly in the ‘other HM’ subgroup. Almost
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all patients overall (99.4%, n = 618/622), and all of those with a CT regimen of unknown FN risk (100%, n = 350), had at least one of the additional patient-related FN risk factors listed in the EORTC recommendations. The prevalence of the risk factors is listed in Table 3, and was
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similar across the disease subgroups.
Clinicians’ reasons for giving Zarzio® and their assessment of the FN risk of the CT regimen
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planned for the patient are shown in Table 4. While the majority of clinicians’ assessments were aligned to the guideline risk categories given for the CT regimens, there were some differences. Two-thirds of patients were classed as having a high risk of FN due to their planned CT regimen (67.0%) compared with 12.8% according to EORTC guidelines (Table 3). The reasons clinicians gave for G-CSF prescription (Table 4) were mostly in alignment with risk factors for FN in the EORTC guidelines (Table 3). Toxicity or intensity of CT (including maintenance of dose intensity) were given as reasons (in the ‘other reasons’ category) for prescribing Zarzio® in 57 patients (9.0%) overall.
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ACCEPTED MANUSCRIPT Incidence of neutropenia Severe (Grade 3–4) neutropenia presented in 16.7% (n = 103) of patients followed up during the study and FN in 4.9% (n = 30). Most patients who had an episode of FN were in Cycle 1 of their CT regimen (86.7%, n = 26) and, by definition, receiving primary prophylaxis. The
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characteristics of the severe neutropenia episodes are described in Figure 1. Most of the patients who had at least one episode of FN had NHL (n = 21); 42.9% of these were receiving R-CHOP or CHOP-like CT.
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Safety
During the study, a total of 53 AEs reported as associated with Zarzio® occurred in 4.9% (n =
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30) of all patients, none of which were considered serious (detailed in Supplementary Data, Table 3). Most AEs were mild (47.6%, n = 20/42) or moderate (40.5%, n = 17/42). Musculoskeletal and connective tissue disorders was the most commonly reported class of AE (50.9%, n = 27), followed by administration site conditions and general disorders (13.2%,
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n = 7), gastrointestinal disorders (9.4%, n = 5) and nervous system disorders (7.5%, n = 4).
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Discussion The strength of the ZOHé prospective study was the large sample size (1816 patients in 125 centres across France), enabling successful analysis of all planned endpoints. In this study, prescription and use of Zarzio® in routine clinical practice were predominantly compliant with
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the label indication, and treatment modifications were rarely used. Zarzio® was largely used for primary prophylaxis in the first cycle of chemotherapy (67.5% of patients with HM).
Patients being treated for HM who are given Zarzio® tend to be older (mean age 64.2 years;
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42.2% ≥70 years old), except for patients with HL (mean age 45.5 years), and to have
advanced metastatic disease (61.6% Stage III or IV) but a good performance status (95.6%
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Eastern Cooperative Oncology Group [ECOG] PS 0–2). Other EORTC risk factors for FN that were common in these patients included low haemoglobin (<12 g/dL, 51.3%) and no previous G-CSF use (81.8%).
Few AEs related to Zarzio® were reported during the study, the most frequent being muscular
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and/or bone pain, confirming the safety profile of this biosimilar filgrastim. No unexpected AEs were seen in patients included in the analysis. Numerous CT protocols were recorded for the patients included in the study, which reflects
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the diversity of HM, disease stage, aims of the CT course, and the practices of the participating centres. The majority of patients received a CT protocol for which G-CSF
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support is recommended to reduce neutropenia and maintain dose intensity.9 The majority of patients in ZOHé were able to maintain the dose intensity of their CT regimen during the follow-up period, allowing them to gain the full benefit of their CT with potential improvements in mortality.5,6,21,22 Patients with NHL receiving R-CHOP/CHOP-like CT, who were at high risk of FN both from their disease23 and the CT protocol, maintained a high ARDI, despite having factors known to reduce ARDI, i.e. older age and advanced disease,24 similar to that described elsewhere for real-world use of Zarzio®.18 Maintenance of dose intensity is critical in those patients who are receiving CT with curative intent.
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ACCEPTED MANUSCRIPT The ZOHé study suggests that, in real-world practice, clinicians predominantly give Zarzio® to patients they consider to be at high risk of neutropenia, either due to their CT regimen and/or a combination of risk factors due to patient characteristics.9,10 However, many of the CT regimens used in clinical practice do not have a FN risk category in the guidelines. With
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these patients, clinicians must rely on the patient-related risk factors to guide their decision to prescribe G-CSF support. The majority of patients in the HM cohort of ZOHé (76.0%, n = 473/622) had 2–3 patient-based risk factors for increased incidence of FN, which, along with
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the ≥10% FN risk intrinsic to HM,23 most likely underlies the clinicians’ decision to prescribe primary prophylaxis. The need for G-CSF support to maintain dose intensity in patients with
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HM who are given CT with curative intent could also underlie clinicians’ use of Zarzio®. In the MONITOR-GCSF study of real-world Zarzio® treatment patterns and FN incidence across 12 countries, including France, 26% of patients were given Zarzio® as primary prophylaxis despite being below the risk threshold for such treatment according to EORTC
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guidelines,19 suggesting that G-CSF prophylaxis in routine practice is much more readily used than the EORTC guidelines envisage. While earlier studies found that G-CSF prophylaxis for CT-induced neutropenia was under-used in European real-world practice,25,26 more recent studies suggest that the widespread availability and reduced cost of biosimilar
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G-CSFs is leading to increased use in clinical practice.17,27,28
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Limitations of the current study include selection bias, recall bias and the need to pool data. Selection bias is inherent to the voluntary participation in this observational study, and was addressed by recruiting physicians such that the sample of investigators recruited reflected the practices of physicians throughout France, by including patients sequentially and limiting the number of patients to 35 for each site. The need to group CT protocols by category and treatment stage in order to assess the results limited the overall interpretations of the individual clinical situations. The assessment of maintenance of dose intensity is limited by being based on self-assessed data completed for all cycles at the final visit, which was potentially subject to recall bias on the part of the investigators.
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Conclusions The ZOHé study was a large observational study of Zarzio® use in routine clinical practice in France in patients undergoing CT for HM. Zarzio® use is relatively standardised, regardless of malignancy and variations in patient characteristics, and compliant with the label
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indication. In patients with HM, Zarzio® was most commonly used as primary prophylaxis. Incidences of FN and AEs were low and in keeping with previous studies of Zarzio®.
Maintenance of dose intensity was high, particularly in patients with NHL receiving R-
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CHOP/CHOP-like CT regimens, and in line with other real-world studies, such as MONITORGCSF.19 Patient-based risk factors for neutropenia appear to have more weight in clinicians’
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decisions to use Zarzio® in real-world practice than the guideline risk category of the CT
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Clinical Practice Points •
Guidelines for G-CSF in support of chemotherapy recommend its use based on assessment of febrile neutropenia risk factors developed from clinical trial data, but large-scale data on the use of G-CSF in routine clinical practice, given the many new
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chemotherapy regimens and targeted drugs coming into use, and widespread availability of biosimilars, are lacking. •
For clinicians in France, patient risk factors appear to be the main driver of the
decision to prescribe Zarzio®, rather than the risk category of the chemotherapy regimen.
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Use of Zarzio® in routine clinical practice enabled a high proportion (90%) of patients with non-Hodgkin lymphoma receiving R-CHOP or CHOP-like regimens to maintain
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the dose intensity necessary for chemotherapy with curative intent.
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•
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Acknowledgements The authors gratefully acknowledge the patients and clinical investigators who participated in this trial. This study was sponsored by Sandoz. Medical writing support, including drafting of
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the article in English, was provided by Dr Lucy Smithers of ApotheCom. Statistical analyses
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were performed by Kappa Santé.
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22. Kwak LW, Halpern J, Olshen RA, Horning SJ. Prognostic significance of actual dose intensity in diffuse large-cell lymphoma: results of a tree-structured survival analysis. J Clin Oncol. 1990;8:963-977.
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23. Flowers CR, Seidenfeld J, Bow EJ, et al. Antimicrobial prophylaxis and outpatient management of fever and neutropenia in adults treated for malignancy: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2013;31:794-810. 24. Lyman GH, Dale DC, Friedberg J, Crawford J, Fisher RI. Incidence and predictors of low chemotherapy dose-intensity in aggressive non-Hodgkin’s lymphoma: a nationwide study. J Clin Oncol. 2004;22:4302-4311. 25. Almenar D, Mayans J, Juan O, et al. Pegfilgrastim and daily granulocyte colonystimulating factor: patterns of use and neutropenia-related outcomes in cancer patients in Spain - results of the LEARN Study. Eur J Cancer Care. 2009;18(3):280-286. 26. Falandry C, Campone M, Cartron G, Guerin D, Freyer G. Trends in G-CSF use in 990 patients after EORTC and ASCO guidelines. Eur J Cancer. 2010;46:2389-2398.
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ACCEPTED MANUSCRIPT 27. Aapro M, Cornes P, Abraham I. Comparative cost-efficiency across the European G5 countries of various regimens of filgrastim, biosimilar filgrastim, and pegfilgrastim to reduce the incidence of chemotherapy-induced febrile neutropenia. J Oncol Pharm Pract. 2012;18:171-179.
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28. Verpoort K, Mohler TM. A non-interventional study of biosimilar granulocyte colonystimulating factor as prophylaxis for chemotherapy-induced neutropenia in a community oncology centre. Ther Adv Med Oncol. 2012;4:289-293.
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ACCEPTED MANUSCRIPT
Tables Table 1. Patient characteristics of the HM cohort at inclusion (N = 633)*
≥70 years, n (%) Male, n (%) ECOG performance score, n (%)* Grade 0–1 Comorbidities and pathologies with
Other HM
Total
(n = 409)
(n = 87)
(n = 137)
(N = 633)
66.7±14.1
45.5±18.2
68.7±11.9
64.2±16.1
184 (45.0)
11 (12.6)
72 (52.6)
267 (42.2)
244 (59.7)
57 (65.5)
91 (66.4)
392 (61.9)
n = 397
n = 84
n = 133
n = 614
307 (77.3)
77 (91.7)
93 (69.9)
477 (77.7)
97 (23.7)
11 (12.6)
36 (26.3)
144 (22.7)
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risk factor, n (%)
HL
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Age, mean±SD (years)
NHL
SC
Characteristic
n = 409
n = 85
330 (80.7)
56 (65.9)
NA
386 (61.6)
Prior G-CSF, n (%)
97 (23.7)
20 (23.0)
33 (24.1)
150 (23.7)
Prior CT, n (%)
106 (25.9)
23 (26.4)
60 (43.8)
189 (29.9)
35 (8.6)
13 (14.9)
20 (14.6)
68 (10.7)
349 (85.3)
76 (87.4)
100 (73.0)
525 (82.9)
49 (12.0)
11 (12.6)
32 (23.4)
92 (14.5)
224 (54.8)
5 (5.7)
5 (3.6)
234 (37.0)
-
18 (20.7)
-
18 (2.8)
185 (45.2)
64 (73.6)
132 (96.4)
381 (60.2)
Stage of malignancy, n (%)* III/IV
Planned CT regimen, n (%) First line
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Prior Grade 3–4 neutropenia, n (%)
Protocols
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Salvage treatment (after relapse)
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R-CHOP/CHOP-like BEACOPP Others
n = 627
*Some patients had missing data. BEACOPP, bleomycin/etoposide/doxorubicin/cyclophosphamide/vincristine/procarbazine/prednisone; CT, chemotherapy; CHOP, cyclophosphamide/doxorubicin/vincristine/prednisone; ECOG, Eastern Cooperative Oncology Group; G-CSF, granulocyte colony-stimulating factor; HL, Hodgkin lymphoma; HM, haematological malignancies; NA, not applicable; NHL, non-Hodgkin lymphoma; R-CHOP, rituximab-CHOP; SD, standard deviation.
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ACCEPTED MANUSCRIPT Table 2. Characteristics of treatment with Zarzio® during the study in patients with follow-up in the HM cohort (n = 615) NHL
HL
Other HM
Total
(n = 395)
(n = 84)
(n = 136)
(N = 615)
4±1.3
3.8±1.4
3.3±1.3
3.8±1.3
Mean±SD
6.5±2
6.4±2.7
Day 1*, n (%)
3 (0.8)
2 (2.4)
Day 2–5, n (%)
77 (19.5)
25 (29.8)
Day >5, n (%)
315 (79.7) 5.8±1.4
®
Number of cycles on Zarzio , mean±SD ®
First day of Zarzio administration per CT cycle
†
cycle , mean±SD days ®
Zarzio stopped before study end, n (%) ®‡
Reason for stopping Zarzio , n (%)
Planned CT cessation Toxicity of CT Disease progression ®
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Zarzio -related adverse event Other reason
8 (5.9)
13 (2.1)
25 (18.4)
127 (20.7)
57 (67.9)
103 (75.7)
475 (77.2)
5.6±2.1
6.1±2.1
5.9±1.7
110 (27.8)
32 (38.1)
34 (25.0)
176 (28.6)
81 (73.6)
24 (75.0)
19 (55.9)
124 (70.5)
68 (61.8)
19 (59.4)
16 (47.1)
103 (58.5)
5 (4.5)
2 (6.3)
1 (2.9)
8 (4.5)
9 (8.2)
3 (9.4)
2 (5.9)
14 (8.0)
5 (4.5)
2 (6.3)
1 (2.9)
8 (4.5)
28 (25.5)
6 (18.8)
14 (41.2)
48 (27.3)
†
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6.5±2.2
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CT cessation
6.6±2.4
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®
Duration of Zarzio administration per CT
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Characteristic
®
‡
*Some patients had missing data. Zarzio begun the same day as the CT cycle. Multiple reasons could be given. Note: 18 patients from the analysis population of 633 patients did not have follow-up data recorded (See Figure 1). CT, chemotherapy; HL, Hodgkin lymphoma; HM, haematological malignancies; NHL, non-Hodgkin lymphoma; SD, standard deviation
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ACCEPTED MANUSCRIPT Table 3. FN risk of CT regimen and additional risk factors according to EORTC guidelines in patients in the HM cohort (N = 633) NHL
HL
Other HM
Total
(n = 409)
(n = 87)
(n = 137)
(N = 633)
Intermediate risk (10–20%) High risk (≥20%) Unknown risk
0 (0)
0 (0)
187 (45.7)
3 (3.4)
23 (5.6)
58 (66.7)
199 (48.7)
26 (29.7)
Patients with additional EORTC risk factor, n (%)*
0 (0)
0 (0)
1 (0.7)
191 (30.2)
0 (0)
81 (12.8)
136 (99.3)
361 (57.0)
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Low risk (<10%)
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Patients with CT regimen in EORTC FN risk category, n (%)
241 (58.9)
15 (17.2)
90 (65.7)
346 (54.7)
Female gender
165 (40.3)
30 (34.5)
46 (33.6)
241 (38.1)
330 (81.5)
56 (65.9)
NA
386 (61.6)
90 (22.7)
7 (8.3)
40 (30.1%)
137 (22.3)
183 (46.8)
45 (52.9)
84 (63.6)
312 (51.3)
16 (3.9)
4 (4.6)
13 (9.5)
33 (5.2)
31 (7.6)
3 (3.4)
13 (9.5)
47 (7.4)
340 (83.1)
73 (83.9)
105 (76.6)
518 (81.8)
‡
Advanced tumour: Stage III or IV ‡
ECOG PS ≥2
‡
Prior episode of FN Concomitant pathologies at increased risk of FN
†
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Haemoglobin level <12 g/dL
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Age >65 years
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No G-CSF use before inclusion
‡
†
*Patients could have multiple risk factors. Some patients had missing data. Liver, renal or
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cardiovascular disease, according to EORTC definition. CT, chemotherapy; ECOG PS, Eastern Cooperative Oncology Group Performance Status; EORTC, European Organisation for Research and Treatment of Cancer; FN, febrile neutropenia; G-CSF, granulocyte colony-stimulating factor; HL, Hodgkin lymphoma; HM, haematological malignancies; NA, not applicable; NHL, non-Hodgkin lymphoma
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ACCEPTED MANUSCRIPT Table 4. Reasons for treatment with Zarzio® (analysis population, N = 633) NHL
HL
Other HM
Total
(n = 409)
(n = 87)
(n = 137)
(N = 633)
≥20%
279 (68.2)
56 (64.4)
89 (65.0)
424 (67.0)
10–20% (with risk factors)
122 (29.8)
28 (32.2)
8 (2.0)
3 (3.4)
Elderly patient
190 (46.5)
Concomitant pathologies Low leukocyte levels
<10%
44 (32.1)
194 (30.6)
4 (2.9)
15 (2.4)
11 (12.6)
73 (53.3)
274 (43.3)
101 (24.7)
17 (19.5)
34 (24.8)
152 (24.0)
79 (19.3)
12 (13.8)
54 (39.4)
145 (22.9)
78 (19.1)
12 (13.8)
25 (18.2)
115 (18.2)
46 (11.2)
9 (10.3)
32 (23.4)
87 (13.7)
35 (8.6)
9 (10.3)
16 (11.7)
60 (9.5)
41 (10.0)
7 (8.0)
35 (25.5)
83 (13.1)
13 (3.2)
4 (4.7)
3 (2.2)
20 (3.2)
124 (30.3)
45 (51.7)
34 (24.8)
203 (32.1)
†
Prior FN
FN in previous CT cycle Other reason †
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Prophylactic antibiotic
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Low haemoglobin levels
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Reason for G-CSF prescription
Poor functional or nutritional status
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FN risk of CT, according to clinician, n (%)
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Multiple reasons could be given.
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CT, chemotherapy; FN, febrile neutropenia; G-CSF, granulocyte colony-stimulating factor; HL, Hodgkin lymphoma; HM, haematological malignancies; NHL, non-Hodgkin lymphoma
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Figure Figure 1. Description of severe neutropenia episodes during study follow-up, by subgroup (n = 175)
100
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80 70 60.6
60 50 40 30
53.3
SC
51.0
49.0
46.7
39.4 34.0 29.8
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Severe neutropenia episodes (%)
90
17.6
20
13.7
10 0
Grade 4
HL (n=51) Febrile
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NHL (n=94) Grade 3
13.3 10.0
Other HM (n=30) Hospitalisation
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HL, Hodgkin lymphoma; HM, haematological malignancies; NHL, non-Hodgkin lymphoma
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ACCEPTED MANUSCRIPT Supplementary Table 1. Reasons for premature withdrawal N
%
Total
81
100.0
Completion or withdrawal of the chemotherapy before 3-month follow-up
35
43.2
Completion or withdrawal of Zarzio® before 3-month follow-up
24
29.6
12
14.8
8
9.9
1
1.2
11
13.6
1
9.1
1
9.1
2
18.2
1
9.1
4
36.4
Left just before the end of the study
1
9.1
Respiratory decompensation
1
9.1
Death Patient lost to follow-up
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Decision of the patient Other reason*
Change of therapeutic strategy Hyperleukocytosis
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Incomplete records
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Autograft given in another institution Cardiogenic shock
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Reasons
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*Reasons listed below are given as % of ‘other reason’ group (n = 22)
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ACCEPTED MANUSCRIPT Supplementary Table 2. Malignancy types of evaluable patients in the HM cohort Malignancy
Patients, n (%) N = 633 409 (64.6) 233 (57.0)
Follicular lymphoma
75 (18.3)
T cell lymphoma
34 (8.3)
Mantle cell lymphoma
26 (6.4)
Marginal zone B cell lymphoma
14 (3.4)
Lymphocytic lymphoma
12 (2.9)
MALT lymphoma
6 (1.5)
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Burkitt lymphoma
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Diffuse large B cell lymphoma
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Non-Hodgkin lymphoma
3 (0.7)
Unknown
6 (1.5)
Hodgkin lymphoma
87 (13.7)
Other lymphoid malignancies
137 (21.6) 68 (49.6)
Multiple myeloma
47 (34.3)
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Chronic lymphocytic leukaemia
Waldenström macroglobulinaemia
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Acute lymphoblastic leukaemia
14 (10.2) 4 (2.9) 3 (2.2)
Unclassifiable lymphoma
1 (0.7)
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Hairy cell leukaemia
HM, haematological malignancies; MALT, mucosa-associated lymphoid tissue
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ACCEPTED MANUSCRIPT Supplementary Table 3. Summary of adverse events (n = 53) experienced by HM patients during the study 9 (17.0)
Back pain
8 (15.1)
Headache
3 (5.7)
Myalgia
3 (5.7)
Nausea
3 (5.7)
Pelvic pain
3 (5.7)
Chest pain
2 (3.8)
Neck pain
2 (3.8)
Neutropenia
2 (3.8)
Pain
1 (1.9)
Abdominal pain
1 (1.9)
Arthralgia
1 (1.9)
Asthenia
1 (1.9)
Diarrhoea
1 (1.9)
Drug intolerance
1 (1.9)
Dysgeusia
1 (1.9)
General physical condition abnormal
1 (1.9)
Injection site pain Muscular weakness Musculoskeletal chest pain
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Rash
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Musculoskeletal stiffness
Pyrexia
1 (1.9)
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Hypersensitivity
Pain in jaw
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Bone pain
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AEs, n (%)
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Adverse events (MedDRA term)
1 (1.9) 1 (1.9) 1 (1.9) 1 (1.9) 1 (1.9) 1 (1.9) 1 (1.9)
Urticaria
1 (1.9)
Vertigo
1 (1.9)
AE, adverse event; HM, haematological malignancies; MedDRA, Medical Dictionary for Regulatory Activities
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ACCEPTED MANUSCRIPT Supplementary Figure 1. Study population for the HM cohort
Analysed n = 633
Followed up‡ n = 615
No follow-up† n = 18
Completed questionnaire n = 462
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Questionnaire not completed n = 153
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Not analysed* n=4
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Inclusion n = 637
Dose intensity evaluable n = 420
†
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*Four patients were excluded from the analysis: two due to deviation from the eligibility criteria and two were duplicated patient records.
‡
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The 18 patients who left the study prematurely and were not followed up were comparable to the followed-up patients in terms of age, sex, comorbidities concomitant with neutropenia risk, and number of CT cycles planned. There were more patients with prior episodes of neutropenia (p = 0.04) and patients had a lower performance score (p<0.01) at inclusion compared with the followed-up patients.
63 of these patients left the study before the 3-month follow-up visit but were reviewed for data collection.
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HM, haematological malignancies
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ACCEPTED MANUSCRIPT
S2152-2650(17)30110-6
DOI:
10.1016/j.clml.2017.05.002
Reference:
CLML 918
To appear in:
Clinical Lymphoma, Myeloma and Leukemia
Received Date: 2 February 2017 Revised Date:
27 April 2017
Accepted Date: 4 May 2017
Please cite this article as: Damaj GL, Benbrahim O, Hacini M, Voronina I, Benabed K, Soumoudronga R-F, Gasnereau I, Haioun C, Solal-Céligny P, ZOHé: A prospective study of the use of biosimilar ® filgrastim Zarzio in clinical practice in patients treated with chemotherapy for lymphoid malignancies, Clinical Lymphoma, Myeloma and Leukemia (2017), doi: 10.1016/j.clml.2017.05.002. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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ZOHé: A prospective study of the use of biosimilar filgrastim Zarzio® in clinical practice in patients treated with chemotherapy for lymphoid malignancies
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Authors Gandhi Laurent Damaja, Omar Benbrahimb, Maya Hacinic, Inna Voroninad, Khaled Benabede, Ravaka-Fatoma Soumoudrongaf, Isabelle Gasnereauf, Corinne Haioung, Philippe Solal-
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Célignyh Affiliations
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a. Institut d’hématologie, Centre Hospitalier Universitaire de Caen and Faculté de Médecine, Université de Caen-Normandie, Caen, France, [email protected] b. Centre Hospitalier Régionale d’Orléans, Orléans, France, [email protected] c. Centre Hospitalier Métropole Savoie, Chambéry, France, [email protected]
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d. Centre Hospitalier Boulogne, Boulogne-sur-Mer, France, [email protected]
e. Centre Hospitalier Public du Cotentin, Cherbourg-en-Cotentin and Centre Hospitalier
f.
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Universitaire Côte de Nacre, Caen, France, [email protected] Sandoz France, Levallois-Perret, France, ravaka-
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[email protected]; [email protected]
g. Unité Hémopathies Lymphoïdes, Hôpital Henri Mondor-Albert, Université Paris Est Créteil, France, [email protected]
h. Institut de Cancérologie de l’Ouest René Gauducheau, Saint Herblain, France, [email protected] Address for correspondence Dr Philippe SOLAL-CÉLIGNY Directeur Médical
ACCEPTED MANUSCRIPT Institut de Cancérologie de l’Ouest ICO René Gauducheau Bld Jacques Monod 44805 Saint Herblain Cedex
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France
Email: [email protected]; Tel: +33 2 40 67 99 62 Running head
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Patterns of real-world Zarzio® use for patients with haematological malignancies in France Word count
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2861
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ACCEPTED MANUSCRIPT
Conflict of interest All authors received funding from Sandoz for the conduct of the study in their institutions. Additionally, GLD has acted on advisory boards for Mundipharma, Novartis and Keocyt. CH
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has acted on advisory boards for Sandoz, Roche, Celgene, Janssen and Gilead. PSC has received research support from Roche, acted as a consultant for Sandoz and on advisory boards for Roche and Bayer, and is a shareholder in Roche. OB and MH have no further
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conflicts of interest to declare. RFS and IG are employed by Sandoz. Author contributions
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All authors had full access to the data and final responsibility for the decision to submit the
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manuscript. All authors read and approved the final draft of the manuscript.
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MicroAbstract The ZOHé study showed that Zarzio® is readily used for prophylaxis of chemotherapyinduced neutropenia in France, and clinicians’ assessment of febrile neutropenia risk is
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driven by patient factors more than the EORTC risk category of the chemotherapy regimen. Maintenance of dose intensity was high, especially in non-Hodgkin lymphoma patients at high risk of neutropenia. Zarzio® safety profile was confirmed.
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Abstract
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Background
The ZOHé study was a prospective, observational, multicentre study in France to assess use of biosimilar filgrastim Zarzio® in routine clinical practice in patients undergoing neutropeniainducing chemotherapy (CT).
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Patients and methods
Patients ≥18 years undergoing CT for a malignant disease and with a first prescription for Zarzio® were enrolled in two cohorts: solid tumour (1174 patients) or haematological
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malignancy (633 patients); the latter is reported here. Analyses primarily described the prescription and use of Zarzio® in current practice, and included identification of factors linked
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to prescription for primary prophylaxis, comparison of use in relation to European Organisation for the Research and Treatment of Cancer (EORTC) guidelines, and estimation of CT dose intensity maintenance in patients given Zarzio®. Results Use of Zarzio® in clinical practice was relatively standardised and followed label indication in 96.7% of the analysis population (633 patients). The majority of patients had ≥2 EORTC patient-related risk factors for febrile neutropenia (FN). CT dose intensity was maintained in 85.2% of evaluable patients and 89.6% of patients with non-Hodgkin lymphoma receiving R-
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ACCEPTED MANUSCRIPT CHOP (rituximab-cyclophosphamide/doxorubicin/vincristine/prednisone). The safety profile of Zarzio® was confirmed. Conclusions
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In routine clinical practice in France, Zarzio® is mostly used as primary prophylaxis for CTinduced neutropenia in patients with haematological malignancies. Patient-related risk
factors appear to have more weight in clinicians’ decisions to give Zarzio® than the FN risk
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category of the CT regimen alone in real-world practice.
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Keywords
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G-CSF, febrile neutropenia, prophylaxis, real-world practice, EP2006
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Introduction Patients treated with cytotoxic chemotherapy (CT) for haematological malignancies (HM) are at risk of developing CT-induced neutropenia and febrile neutropenia (FN), which are
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potentially life-threatening. Administration of granulocyte colony-stimulating factors (G-CSF) has been shown to reduce the incidence of CT-induced neutropenia, the duration of
hospitalisation, neutropenia, fever recovery time and/or antibiotic use in patients receiving standard and intensive doses of CT.1–4 G-CSF is also used for maintenance of CT dose
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intensity, which has been associated with improved survival and reduced mortality in HM,5,6 especially non-Hodgkin lymphoma (NHL).7
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Recommendations for G-CSF use were defined in guidelines set up by the European Society for Medical Oncology (ESMO), the European Organisation for the Research and Treatment of Cancer (EORTC), the American Society of Clinical Oncology (ASCO), and the National Comprehensive Cancer Network (NCCN). The most recent updates were issued in 2010 for
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ESMO8 and EORTC,9 2015 for ASCO10 and 2016 for NCCN.10,11 The guidelines all recommend G-CSF prophylaxis where a risk of FN due to the CT protocol is ≥20%, and for patients with intermediate risk (10–20%) who have additional risk factors (mainly age ≥65
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years, advanced stage of the disease, previous episode(s) of FN, low performance status and comorbidities). Since the most recent EORTC update, numerous anticancer agents and
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new CT combinations have been developed and brought into routine clinical practice, especially in haematology, and the FN risk of these agents is not always known. Filgrastim was the first recombinant human G-CSF used in clinical practice and since 2008 biosimilar versions have been available in Europe. Zarzio® (Sandoz GmbH) is a filgrastim biosimilar with demonstrated equivalence in clinical safety and efficacy in Phase 1 and Phase 3 studies to the reference product (Neupogen®).12–16 Extensive long-term data on its safety and efficacy in clinical practice have been collected.17–19 The ZOHé study evaluated the use
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ACCEPTED MANUSCRIPT of Zarzio® by oncologists and haematologists to manage the neutropenic risk of CT in routine practice in France. This paper reports the results for the cohort of patients with HM.
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Patients and methods Study design
ZOHé was a prospective, non-interventional, longitudinal, national, multicentre study,
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describing biosimilar filgrastim (Zarzio®, Sandoz, Holzkirchen, Austria) use by oncologists and haematologists in routine practice for patients receiving chemotherapy for solid tumours
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or HM. Ethical approval and data protection approval of the ZOHé study was authorised by the Comité Consultatif sur le Traitement d’Information en matière de Recherche dans le domaine de la Santé (CCTIRS) and the Commission Nationale de l’lnformatique et des Libertés (CNIL). Informed patient consent was obtained prior to study participation. This study was conducted according to the current revision of the 1964 Helsinki declaration.
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A total of 1816 patients (637 with HM were recruited consecutively across 125 sites in France between June 2013 and April 2014. Baseline patient characteristics and data regarding Zarzio® prescription were collected at Visit 1, on the first day of the CT cycle in which Zario
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was initiated. Data on the use of Zarzio®, patient clinical status, occurrence of neutropenia and adverse events (AEs) were collected at Visit 2, 3 months after inclusion or on
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discontinuation of CT or Zarzio® if this occurred earlier. A supplemental questionnaire on the administration of CT was also completed at Visit 2 to estimate maintenance of dose intensity. Data were collected using an electronic case report form and monitored centrally for quality control; AEs were coded using version 17.0 of the Medical Dictionary for Regulatory Activities (MedDRA). Obligatory fields, drop-down lists and consistency controls verified immediately on data entry were set up to limit missing or incoherent data.
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ACCEPTED MANUSCRIPT Patients Patients 18 years or older undergoing cytotoxic CT for solid tumours or HM who had a first prescription for biosimilar filgrastim Zarzio® and who consented to take part in the study were
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included. This paper presents results from the HM cohort of ZOHé. Primary and secondary objectives
The primary objective was to describe indications and use of biosimilar filgrastim Zarzio® in
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routine clinical practice in patients receiving CT for HM. The study also aimed to describe the characteristics of patients treated with Zarzio®, and estimate the proportion of patients whose
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CT dose intensity was maintained over the course of their regimen. Statistical methodology
To have a precision of 5% with a confidence interval of 95% for the descriptive study objectives, the number of patients required was calculated to be approximately 1830, for a
account.
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fixed alpha risk of 5% and a reference proportion of 50%, and taking incomplete files into
Descriptive statistics, and univariate and multivariate comparative analyses were carried out
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using the SAS package (version 9.4, SAS Institute, Cary, NC, USA). The threshold of significance of comparative analyses was fixed at 5%. For univariate analyses, the
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association between qualitative variables was tested using Pearson’s chi-squared test and, for theoretical frequencies <5, values were regrouped or Fisher’s exact test performed. Mean values of quantitative variables were compared between groups using Student’s t-test. Imputation of missing data was not carried out for the analyses. The average relative dose intensity (ARDI) was calculated at each cycle as the total dose of CT administered during a cycle divided by the total dose scheduled for the same cycle.20 The CT dose administered was calculated during each cycle as mg/m2/unit of time using data from the follow-up questionnaire. Dose intensity was considered maintained for ratios ≥85%.
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Results Study population
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Of the 1807 patients included in the ZOHé analysis population, 633 (35%) received CT for HM (Supplementary Figure 1). Patients who withdrew before the 3-month follow-up are
detailed in Supplementary Data, Table 1; most (72.8%, n = 59) were due to completion or discontinuation of CT or Zarzio®. Maintenance of CT dose intensity was estimated in 420
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patients (66.4% of the analysis population) who had evaluable data from the supplementary
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questionnaire. Patient demographics and clinical characteristics
Baseline patient characteristics are shown in Table 1. Two-thirds of patients in the HM cohort had NHL (64.6%, n = 409). A complete list of HM is given in Supplementary Data, Table 2.
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The mean age of the overall HM cohort was 64.2±16.1 years, although the Hodgkin lymphoma (HL) patients were younger, with a mean age of 45.5±18.2 years. At inclusion, 10.7% (n = 68) of the HM cohort had a prior episode of severe neutropenia (Grade 3 or 4;
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Table 1).
CT planned at inclusion (Table 1) was first line in 82.9% of patients; of those who were
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receiving salvage therapy following relapse, most (82.6%) were on at least their second line of salvage CT. Planned CT regimens are shown grouped by regimen type and malignancy type in Table 1. The majority of patients in each malignancy group were prescribed a CT regimen classed as high (>20%) or intermediate (10–20%) risk for FN in EORTC guidelines.9 Zarzio® administration and treatment patterns Zarzio® use is detailed by subgroup of HM in Table 2. Its use was predominantly in accordance with the label indication for established cytotoxic CT.12 The median day of
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ACCEPTED MANUSCRIPT administration was Day 6 of the current CT cycle for the NHL and HL groups, and Day 7 for ‘other HM’ group. The median duration of planned Zarzio® treatment was 5 days per cycle for patients with HL and other HM, and 6 days for patients with NHL; 66.5% of patients who were followed up (n
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= 409/615) received Zarzio® for 4.5–6.5 days, and 24.9% received Zarzio® for >6.5 days including three (0.5%) treated for >14 days. The majority of patients who were followed up
with 20.5% receiving a mean dose of 48 MIU per cycle.
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received a mean dose of 30 MIU per cycle (78.7%) throughout the course of their treatment,
In ZOHé, prophylaxis with G-CSF was considered primary if it occurred during Cycle 1 of the
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current course of CT at study inclusion, regardless of the intended protocol and day of Zarzio® initiation. Zarzio® was prescribed as primary prophylaxis in 67.6% of all HM patients (n = 427), and with curative intent or as secondary prophylaxis in the remainder (32.5%, n = 206). This treatment pattern was consistent across the subgroups: 69.4% of 409 NHL
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patients, 72.4% of 87 HL patients and 58.4% of 137 patients with ‘other HM’ were given Zarzio® as primary prophylaxis.
Zarzio® was administered for a median of four cycles of CT across the cohort. Treatment
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stayed constant for subsequent cycles in most patients (89.6%); in the 64 patients who had their treatment modified this was mostly a change to the treatment duration (82.8%, n = 53).
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Overall, 28.6% (n = 176) of patients stopped Zarzio® treatment before the end of the study, mostly due to cessation of CT. Eight patients stopped Zarzio® treatment as a result of AEs linked to Zarzio® (Table 2).
Estimated maintenance of CT dose intensity Dose intensity was estimated by comparing the actual doses received with doses planned by the investigator before start of treatment, and was considered to have been maintained (total
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ACCEPTED MANUSCRIPT ARDI ≥85%) in 85.2% of the evaluable HM patients. Maintenance of dose intensity was similar in all subgroups: 86.5%, 85.7% and 81.6% of patients with NHL, HL and other HM, respectively. ARDI was high in the overall cohort (mean±standard deviation total ARDI 93.9±24.4) and across the subgroups of NHL, HL and ‘other HM’ (mean total ARDI 94.1, 95.8
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and 92.4, respectively). Use of Zarzio® in relation to guidelines
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The FN risk of patients was assessed in terms of guidelines for FN risk according to the risk of their CT regimen and patient-related risk factors from EORTC recommendations,9 and is
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shown in Table 3. Where the EORTC recommendations did not provide a risk category for a particular regimen, ASCO 201510 and NCCN 201611 guidelines were checked for this analysis. No patients receiving Zarzio® had a CT regimen in the low risk (<10%) category, in line with recommendations. Many patients received CT regimens whose FN risk was ‘unknown’ i.e. not specified in the guidelines, particularly in the ‘other HM’ subgroup. Almost
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all patients overall (99.4%, n = 618/622), and all of those with a CT regimen of unknown FN risk (100%, n = 350), had at least one of the additional patient-related FN risk factors listed in the EORTC recommendations. The prevalence of the risk factors is listed in Table 3, and was
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similar across the disease subgroups.
Clinicians’ reasons for giving Zarzio® and their assessment of the FN risk of the CT regimen
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planned for the patient are shown in Table 4. While the majority of clinicians’ assessments were aligned to the guideline risk categories given for the CT regimens, there were some differences. Two-thirds of patients were classed as having a high risk of FN due to their planned CT regimen (67.0%) compared with 12.8% according to EORTC guidelines (Table 3). The reasons clinicians gave for G-CSF prescription (Table 4) were mostly in alignment with risk factors for FN in the EORTC guidelines (Table 3). Toxicity or intensity of CT (including maintenance of dose intensity) were given as reasons (in the ‘other reasons’ category) for prescribing Zarzio® in 57 patients (9.0%) overall.
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ACCEPTED MANUSCRIPT Incidence of neutropenia Severe (Grade 3–4) neutropenia presented in 16.7% (n = 103) of patients followed up during the study and FN in 4.9% (n = 30). Most patients who had an episode of FN were in Cycle 1 of their CT regimen (86.7%, n = 26) and, by definition, receiving primary prophylaxis. The
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characteristics of the severe neutropenia episodes are described in Figure 1. Most of the patients who had at least one episode of FN had NHL (n = 21); 42.9% of these were receiving R-CHOP or CHOP-like CT.
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Safety
During the study, a total of 53 AEs reported as associated with Zarzio® occurred in 4.9% (n =
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30) of all patients, none of which were considered serious (detailed in Supplementary Data, Table 3). Most AEs were mild (47.6%, n = 20/42) or moderate (40.5%, n = 17/42). Musculoskeletal and connective tissue disorders was the most commonly reported class of AE (50.9%, n = 27), followed by administration site conditions and general disorders (13.2%,
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n = 7), gastrointestinal disorders (9.4%, n = 5) and nervous system disorders (7.5%, n = 4).
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Discussion The strength of the ZOHé prospective study was the large sample size (1816 patients in 125 centres across France), enabling successful analysis of all planned endpoints. In this study, prescription and use of Zarzio® in routine clinical practice were predominantly compliant with
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the label indication, and treatment modifications were rarely used. Zarzio® was largely used for primary prophylaxis in the first cycle of chemotherapy (67.5% of patients with HM).
Patients being treated for HM who are given Zarzio® tend to be older (mean age 64.2 years;
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42.2% ≥70 years old), except for patients with HL (mean age 45.5 years), and to have
advanced metastatic disease (61.6% Stage III or IV) but a good performance status (95.6%
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Eastern Cooperative Oncology Group [ECOG] PS 0–2). Other EORTC risk factors for FN that were common in these patients included low haemoglobin (<12 g/dL, 51.3%) and no previous G-CSF use (81.8%).
Few AEs related to Zarzio® were reported during the study, the most frequent being muscular
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and/or bone pain, confirming the safety profile of this biosimilar filgrastim. No unexpected AEs were seen in patients included in the analysis. Numerous CT protocols were recorded for the patients included in the study, which reflects
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the diversity of HM, disease stage, aims of the CT course, and the practices of the participating centres. The majority of patients received a CT protocol for which G-CSF
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support is recommended to reduce neutropenia and maintain dose intensity.9 The majority of patients in ZOHé were able to maintain the dose intensity of their CT regimen during the follow-up period, allowing them to gain the full benefit of their CT with potential improvements in mortality.5,6,21,22 Patients with NHL receiving R-CHOP/CHOP-like CT, who were at high risk of FN both from their disease23 and the CT protocol, maintained a high ARDI, despite having factors known to reduce ARDI, i.e. older age and advanced disease,24 similar to that described elsewhere for real-world use of Zarzio®.18 Maintenance of dose intensity is critical in those patients who are receiving CT with curative intent.
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ACCEPTED MANUSCRIPT The ZOHé study suggests that, in real-world practice, clinicians predominantly give Zarzio® to patients they consider to be at high risk of neutropenia, either due to their CT regimen and/or a combination of risk factors due to patient characteristics.9,10 However, many of the CT regimens used in clinical practice do not have a FN risk category in the guidelines. With
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these patients, clinicians must rely on the patient-related risk factors to guide their decision to prescribe G-CSF support. The majority of patients in the HM cohort of ZOHé (76.0%, n = 473/622) had 2–3 patient-based risk factors for increased incidence of FN, which, along with
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the ≥10% FN risk intrinsic to HM,23 most likely underlies the clinicians’ decision to prescribe primary prophylaxis. The need for G-CSF support to maintain dose intensity in patients with
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HM who are given CT with curative intent could also underlie clinicians’ use of Zarzio®. In the MONITOR-GCSF study of real-world Zarzio® treatment patterns and FN incidence across 12 countries, including France, 26% of patients were given Zarzio® as primary prophylaxis despite being below the risk threshold for such treatment according to EORTC
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guidelines,19 suggesting that G-CSF prophylaxis in routine practice is much more readily used than the EORTC guidelines envisage. While earlier studies found that G-CSF prophylaxis for CT-induced neutropenia was under-used in European real-world practice,25,26 more recent studies suggest that the widespread availability and reduced cost of biosimilar
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G-CSFs is leading to increased use in clinical practice.17,27,28
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Limitations of the current study include selection bias, recall bias and the need to pool data. Selection bias is inherent to the voluntary participation in this observational study, and was addressed by recruiting physicians such that the sample of investigators recruited reflected the practices of physicians throughout France, by including patients sequentially and limiting the number of patients to 35 for each site. The need to group CT protocols by category and treatment stage in order to assess the results limited the overall interpretations of the individual clinical situations. The assessment of maintenance of dose intensity is limited by being based on self-assessed data completed for all cycles at the final visit, which was potentially subject to recall bias on the part of the investigators.
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Conclusions The ZOHé study was a large observational study of Zarzio® use in routine clinical practice in France in patients undergoing CT for HM. Zarzio® use is relatively standardised, regardless of malignancy and variations in patient characteristics, and compliant with the label
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indication. In patients with HM, Zarzio® was most commonly used as primary prophylaxis. Incidences of FN and AEs were low and in keeping with previous studies of Zarzio®.
Maintenance of dose intensity was high, particularly in patients with NHL receiving R-
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CHOP/CHOP-like CT regimens, and in line with other real-world studies, such as MONITORGCSF.19 Patient-based risk factors for neutropenia appear to have more weight in clinicians’
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decisions to use Zarzio® in real-world practice than the guideline risk category of the CT
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regimen.
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Clinical Practice Points •
Guidelines for G-CSF in support of chemotherapy recommend its use based on assessment of febrile neutropenia risk factors developed from clinical trial data, but large-scale data on the use of G-CSF in routine clinical practice, given the many new
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chemotherapy regimens and targeted drugs coming into use, and widespread availability of biosimilars, are lacking. •
For clinicians in France, patient risk factors appear to be the main driver of the
decision to prescribe Zarzio®, rather than the risk category of the chemotherapy regimen.
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Use of Zarzio® in routine clinical practice enabled a high proportion (90%) of patients with non-Hodgkin lymphoma receiving R-CHOP or CHOP-like regimens to maintain
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the dose intensity necessary for chemotherapy with curative intent.
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•
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Acknowledgements The authors gratefully acknowledge the patients and clinical investigators who participated in this trial. This study was sponsored by Sandoz. Medical writing support, including drafting of
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the article in English, was provided by Dr Lucy Smithers of ApotheCom. Statistical analyses
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were performed by Kappa Santé.
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References Lyman GH, Kuderer NM. Filgrastim in patients with neutropenia: potential effects on quality of life. Drugs. 2002;62 Suppl 1:65-78.
2.
Kuderer NM, Dale DC, Crawford J, Lyman GH. Impact of primary prophylaxis with granulocyte colony-stimulating factor on febrile neutropenia and mortality in adult cancer patients receiving chemotherapy: a systematic review. J Clin Oncol. 2007;25(21):3158-3167.
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Bohlius J, Herbst C, Reiser M, Schwarzer G, Engert A. Granulopoiesis-stimulating factors to prevent adverse effects in the treatment of malignant lymphoma. Cochrane Database Syst Rev. 2008:CD003189.
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Cooper KL, Madan J, Whyte S, Stevenson MD, Akehurst RL. Granulocyte colonystimulating factors for febrile neutropenia prophylaxis following chemotherapy: systematic review and meta-analysis. BMC Cancer. 2011;11:404.
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Bosly A, Bron D, Van HA, et al. Achievement of optimal average relative dose intensity and correlation with survival in diffuse large B-cell lymphoma patients treated with CHOP. Ann Hematol. 2008;87:277-283.
6.
Lyman GH, Dale DC, Culakova E, et al. The impact of the granulocyte colonystimulating factor on chemotherapy dose intensity and cancer survival: a systematic review and meta-analysis of randomized controlled trials. Ann Oncol. 2013;24:24752484.
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Wildiers H, Reiser M. Relative dose intensity of chemotherapy and its impact on outcomes in patients with early breast cancer or aggressive lymphoma. Crit Rev Oncol Hematol. 2011;77:221-240.
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Crawford J, Caserta C, Roila F, ESMO Guidelines Working Group. Hematopoietic growth factors: ESMO Clinical Practice Guidelines for the applications. Ann Oncol. 2010;21 Suppl 5:v248-251. doi:10.1093/annonc/mdq195.
9.
Aapro MS, Bohlius J, Cameron DA, et al. 2010 update of EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapyinduced febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumours. Eur J Cancer. 2011;47:8-32.
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10. Smith TJ, Bohlke K, Lyman GH, et al. Recommendations for the Use of WBC Growth Factors: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol. 2015;33:3199-3212. 11. Crawford J, Becker PS, Armitage JO, et al. NCCN Clinical Practice Guidelines in Oncology: Myeloid Growth Factors Version 1.2016. NCCN Guidelines: Myeloid Growth Factors v1.2016. https://www.nccn.org/professionals/physician_gls/pdf/myeloid_growth.pdf. Published March 15, 2016. Accessed May 11, 2016. 12. Zarzio® Summary of Product Characteristics. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Product_Information/human/000917/WC500046525.pdf. Accessed April 21, 2016.
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ACCEPTED MANUSCRIPT 13. Neupogen® (Filgrastim) Summary of Product Characteristics. 2006. 14. Sorgel F, Schwebig A, Holzmann J, Prasch S, Singh P, Kinzig M. Comparability of biosimilar filgrastim with originator filgrastim: protein characterization, pharmacodynamics, and pharmacokinetics. BioDrugs. 2015;29:123-131.
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15. Gascon P, Fuhr U, Sörgel F, et al. Development of a new G-CSF product based on biosimilarity assessment. Ann Oncol. 2010;21(7):1419-1429. 16. Blackwell K, Semiglazov V, Krasnozhon D, et al. Comparison of EP2006, a filgrastim biosimilar, to the reference: a phase III, randomized, double-blind clinical study in the prevention of severe neutropenia in patients with breast cancer receiving myelosuppressive chemotherapy. Ann Oncol. 2015;26(9):1948–53.
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17. Gascon P, Tesch H, Verpoort K, et al. Clinical experience with Zarzio(R) in Europe: what have we learned? Support Care Cancer. 2013;21:2925-2932.
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18. Nahon S, Rastkhah M, Ben AM, Soumoudronga RF, Gasnereau I, Labourey JL. Zarzio®, biosimilar of filgrastim, in prophylaxis of chemotherapy-induced neutropenia in routine practice: a French prospective multicentric study. Support Care Cancer. 2016;24:1991-1998. 19. Gascon P, Aapro M, Ludwig H, et al. Treatment patterns and outcomes in the prophylaxis of chemotherapy-induced (febrile) neutropenia with biosimilar filgrastim (the MONITOR-GCSF study). Support Care Cancer. 2016;24:911-925.
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20. Hryniuk W, Frei E, Wright FA. A single scale for comparing dose-intensity of all chemotherapy regimens in breast cancer: summation dose-intensity. J Clin Oncol. 1998;16(9):3137-3147. 21. Epelbaum R, Haim N, Ben-Shahar M, Ron Y, Cohen Y. Dose-intensity analysis for CHOP chemotherapy in diffuse aggressive large cell lymphoma. IsrJ Med Sci. 1988;24:533-538.
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22. Kwak LW, Halpern J, Olshen RA, Horning SJ. Prognostic significance of actual dose intensity in diffuse large-cell lymphoma: results of a tree-structured survival analysis. J Clin Oncol. 1990;8:963-977.
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23. Flowers CR, Seidenfeld J, Bow EJ, et al. Antimicrobial prophylaxis and outpatient management of fever and neutropenia in adults treated for malignancy: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2013;31:794-810. 24. Lyman GH, Dale DC, Friedberg J, Crawford J, Fisher RI. Incidence and predictors of low chemotherapy dose-intensity in aggressive non-Hodgkin’s lymphoma: a nationwide study. J Clin Oncol. 2004;22:4302-4311. 25. Almenar D, Mayans J, Juan O, et al. Pegfilgrastim and daily granulocyte colonystimulating factor: patterns of use and neutropenia-related outcomes in cancer patients in Spain - results of the LEARN Study. Eur J Cancer Care. 2009;18(3):280-286. 26. Falandry C, Campone M, Cartron G, Guerin D, Freyer G. Trends in G-CSF use in 990 patients after EORTC and ASCO guidelines. Eur J Cancer. 2010;46:2389-2398.
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ACCEPTED MANUSCRIPT 27. Aapro M, Cornes P, Abraham I. Comparative cost-efficiency across the European G5 countries of various regimens of filgrastim, biosimilar filgrastim, and pegfilgrastim to reduce the incidence of chemotherapy-induced febrile neutropenia. J Oncol Pharm Pract. 2012;18:171-179.
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28. Verpoort K, Mohler TM. A non-interventional study of biosimilar granulocyte colonystimulating factor as prophylaxis for chemotherapy-induced neutropenia in a community oncology centre. Ther Adv Med Oncol. 2012;4:289-293.
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Tables Table 1. Patient characteristics of the HM cohort at inclusion (N = 633)*
≥70 years, n (%) Male, n (%) ECOG performance score, n (%)* Grade 0–1 Comorbidities and pathologies with
Other HM
Total
(n = 409)
(n = 87)
(n = 137)
(N = 633)
66.7±14.1
45.5±18.2
68.7±11.9
64.2±16.1
184 (45.0)
11 (12.6)
72 (52.6)
267 (42.2)
244 (59.7)
57 (65.5)
91 (66.4)
392 (61.9)
n = 397
n = 84
n = 133
n = 614
307 (77.3)
77 (91.7)
93 (69.9)
477 (77.7)
97 (23.7)
11 (12.6)
36 (26.3)
144 (22.7)
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risk factor, n (%)
HL
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Age, mean±SD (years)
NHL
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Characteristic
n = 409
n = 85
330 (80.7)
56 (65.9)
NA
386 (61.6)
Prior G-CSF, n (%)
97 (23.7)
20 (23.0)
33 (24.1)
150 (23.7)
Prior CT, n (%)
106 (25.9)
23 (26.4)
60 (43.8)
189 (29.9)
35 (8.6)
13 (14.9)
20 (14.6)
68 (10.7)
349 (85.3)
76 (87.4)
100 (73.0)
525 (82.9)
49 (12.0)
11 (12.6)
32 (23.4)
92 (14.5)
224 (54.8)
5 (5.7)
5 (3.6)
234 (37.0)
-
18 (20.7)
-
18 (2.8)
185 (45.2)
64 (73.6)
132 (96.4)
381 (60.2)
Stage of malignancy, n (%)* III/IV
Planned CT regimen, n (%) First line
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Prior Grade 3–4 neutropenia, n (%)
Protocols
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Salvage treatment (after relapse)
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R-CHOP/CHOP-like BEACOPP Others
n = 627
*Some patients had missing data. BEACOPP, bleomycin/etoposide/doxorubicin/cyclophosphamide/vincristine/procarbazine/prednisone; CT, chemotherapy; CHOP, cyclophosphamide/doxorubicin/vincristine/prednisone; ECOG, Eastern Cooperative Oncology Group; G-CSF, granulocyte colony-stimulating factor; HL, Hodgkin lymphoma; HM, haematological malignancies; NA, not applicable; NHL, non-Hodgkin lymphoma; R-CHOP, rituximab-CHOP; SD, standard deviation.
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ACCEPTED MANUSCRIPT Table 2. Characteristics of treatment with Zarzio® during the study in patients with follow-up in the HM cohort (n = 615) NHL
HL
Other HM
Total
(n = 395)
(n = 84)
(n = 136)
(N = 615)
4±1.3
3.8±1.4
3.3±1.3
3.8±1.3
Mean±SD
6.5±2
6.4±2.7
Day 1*, n (%)
3 (0.8)
2 (2.4)
Day 2–5, n (%)
77 (19.5)
25 (29.8)
Day >5, n (%)
315 (79.7) 5.8±1.4
®
Number of cycles on Zarzio , mean±SD ®
First day of Zarzio administration per CT cycle
†
cycle , mean±SD days ®
Zarzio stopped before study end, n (%) ®‡
Reason for stopping Zarzio , n (%)
Planned CT cessation Toxicity of CT Disease progression ®
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EP
Zarzio -related adverse event Other reason
8 (5.9)
13 (2.1)
25 (18.4)
127 (20.7)
57 (67.9)
103 (75.7)
475 (77.2)
5.6±2.1
6.1±2.1
5.9±1.7
110 (27.8)
32 (38.1)
34 (25.0)
176 (28.6)
81 (73.6)
24 (75.0)
19 (55.9)
124 (70.5)
68 (61.8)
19 (59.4)
16 (47.1)
103 (58.5)
5 (4.5)
2 (6.3)
1 (2.9)
8 (4.5)
9 (8.2)
3 (9.4)
2 (5.9)
14 (8.0)
5 (4.5)
2 (6.3)
1 (2.9)
8 (4.5)
28 (25.5)
6 (18.8)
14 (41.2)
48 (27.3)
†
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6.5±2.2
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CT cessation
6.6±2.4
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®
Duration of Zarzio administration per CT
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Characteristic
®
‡
*Some patients had missing data. Zarzio begun the same day as the CT cycle. Multiple reasons could be given. Note: 18 patients from the analysis population of 633 patients did not have follow-up data recorded (See Figure 1). CT, chemotherapy; HL, Hodgkin lymphoma; HM, haematological malignancies; NHL, non-Hodgkin lymphoma; SD, standard deviation
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ACCEPTED MANUSCRIPT Table 3. FN risk of CT regimen and additional risk factors according to EORTC guidelines in patients in the HM cohort (N = 633) NHL
HL
Other HM
Total
(n = 409)
(n = 87)
(n = 137)
(N = 633)
Intermediate risk (10–20%) High risk (≥20%) Unknown risk
0 (0)
0 (0)
187 (45.7)
3 (3.4)
23 (5.6)
58 (66.7)
199 (48.7)
26 (29.7)
Patients with additional EORTC risk factor, n (%)*
0 (0)
0 (0)
1 (0.7)
191 (30.2)
0 (0)
81 (12.8)
136 (99.3)
361 (57.0)
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Low risk (<10%)
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Patients with CT regimen in EORTC FN risk category, n (%)
241 (58.9)
15 (17.2)
90 (65.7)
346 (54.7)
Female gender
165 (40.3)
30 (34.5)
46 (33.6)
241 (38.1)
330 (81.5)
56 (65.9)
NA
386 (61.6)
90 (22.7)
7 (8.3)
40 (30.1%)
137 (22.3)
183 (46.8)
45 (52.9)
84 (63.6)
312 (51.3)
16 (3.9)
4 (4.6)
13 (9.5)
33 (5.2)
31 (7.6)
3 (3.4)
13 (9.5)
47 (7.4)
340 (83.1)
73 (83.9)
105 (76.6)
518 (81.8)
‡
Advanced tumour: Stage III or IV ‡
ECOG PS ≥2
‡
Prior episode of FN Concomitant pathologies at increased risk of FN
†
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Haemoglobin level <12 g/dL
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Age >65 years
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No G-CSF use before inclusion
‡
†
*Patients could have multiple risk factors. Some patients had missing data. Liver, renal or
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cardiovascular disease, according to EORTC definition. CT, chemotherapy; ECOG PS, Eastern Cooperative Oncology Group Performance Status; EORTC, European Organisation for Research and Treatment of Cancer; FN, febrile neutropenia; G-CSF, granulocyte colony-stimulating factor; HL, Hodgkin lymphoma; HM, haematological malignancies; NA, not applicable; NHL, non-Hodgkin lymphoma
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ACCEPTED MANUSCRIPT Table 4. Reasons for treatment with Zarzio® (analysis population, N = 633) NHL
HL
Other HM
Total
(n = 409)
(n = 87)
(n = 137)
(N = 633)
≥20%
279 (68.2)
56 (64.4)
89 (65.0)
424 (67.0)
10–20% (with risk factors)
122 (29.8)
28 (32.2)
8 (2.0)
3 (3.4)
Elderly patient
190 (46.5)
Concomitant pathologies Low leukocyte levels
<10%
44 (32.1)
194 (30.6)
4 (2.9)
15 (2.4)
11 (12.6)
73 (53.3)
274 (43.3)
101 (24.7)
17 (19.5)
34 (24.8)
152 (24.0)
79 (19.3)
12 (13.8)
54 (39.4)
145 (22.9)
78 (19.1)
12 (13.8)
25 (18.2)
115 (18.2)
46 (11.2)
9 (10.3)
32 (23.4)
87 (13.7)
35 (8.6)
9 (10.3)
16 (11.7)
60 (9.5)
41 (10.0)
7 (8.0)
35 (25.5)
83 (13.1)
13 (3.2)
4 (4.7)
3 (2.2)
20 (3.2)
124 (30.3)
45 (51.7)
34 (24.8)
203 (32.1)
†
Prior FN
FN in previous CT cycle Other reason †
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Prophylactic antibiotic
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Low haemoglobin levels
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Reason for G-CSF prescription
Poor functional or nutritional status
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FN risk of CT, according to clinician, n (%)
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Multiple reasons could be given.
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CT, chemotherapy; FN, febrile neutropenia; G-CSF, granulocyte colony-stimulating factor; HL, Hodgkin lymphoma; HM, haematological malignancies; NHL, non-Hodgkin lymphoma
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Figure Figure 1. Description of severe neutropenia episodes during study follow-up, by subgroup (n = 175)
100
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80 70 60.6
60 50 40 30
53.3
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51.0
49.0
46.7
39.4 34.0 29.8
M AN U
Severe neutropenia episodes (%)
90
17.6
20
13.7
10 0
Grade 4
HL (n=51) Febrile
TE D
NHL (n=94) Grade 3
13.3 10.0
Other HM (n=30) Hospitalisation
AC C
EP
HL, Hodgkin lymphoma; HM, haematological malignancies; NHL, non-Hodgkin lymphoma
26/30
ACCEPTED MANUSCRIPT Supplementary Table 1. Reasons for premature withdrawal N
%
Total
81
100.0
Completion or withdrawal of the chemotherapy before 3-month follow-up
35
43.2
Completion or withdrawal of Zarzio® before 3-month follow-up
24
29.6
12
14.8
8
9.9
1
1.2
11
13.6
1
9.1
1
9.1
2
18.2
1
9.1
4
36.4
Left just before the end of the study
1
9.1
Respiratory decompensation
1
9.1
Death Patient lost to follow-up
SC
Decision of the patient Other reason*
Change of therapeutic strategy Hyperleukocytosis
TE D
Incomplete records
M AN U
Autograft given in another institution Cardiogenic shock
RI PT
Reasons
AC C
EP
*Reasons listed below are given as % of ‘other reason’ group (n = 22)
27/30
ACCEPTED MANUSCRIPT Supplementary Table 2. Malignancy types of evaluable patients in the HM cohort Malignancy
Patients, n (%) N = 633 409 (64.6) 233 (57.0)
Follicular lymphoma
75 (18.3)
T cell lymphoma
34 (8.3)
Mantle cell lymphoma
26 (6.4)
Marginal zone B cell lymphoma
14 (3.4)
Lymphocytic lymphoma
12 (2.9)
MALT lymphoma
6 (1.5)
M AN U
Burkitt lymphoma
SC
Diffuse large B cell lymphoma
RI PT
Non-Hodgkin lymphoma
3 (0.7)
Unknown
6 (1.5)
Hodgkin lymphoma
87 (13.7)
Other lymphoid malignancies
137 (21.6) 68 (49.6)
Multiple myeloma
47 (34.3)
TE D
Chronic lymphocytic leukaemia
Waldenström macroglobulinaemia
EP
Acute lymphoblastic leukaemia
14 (10.2) 4 (2.9) 3 (2.2)
Unclassifiable lymphoma
1 (0.7)
AC C
Hairy cell leukaemia
HM, haematological malignancies; MALT, mucosa-associated lymphoid tissue
28/30
ACCEPTED MANUSCRIPT Supplementary Table 3. Summary of adverse events (n = 53) experienced by HM patients during the study 9 (17.0)
Back pain
8 (15.1)
Headache
3 (5.7)
Myalgia
3 (5.7)
Nausea
3 (5.7)
Pelvic pain
3 (5.7)
Chest pain
2 (3.8)
Neck pain
2 (3.8)
Neutropenia
2 (3.8)
Pain
1 (1.9)
Abdominal pain
1 (1.9)
Arthralgia
1 (1.9)
Asthenia
1 (1.9)
Diarrhoea
1 (1.9)
Drug intolerance
1 (1.9)
Dysgeusia
1 (1.9)
General physical condition abnormal
1 (1.9)
Injection site pain Muscular weakness Musculoskeletal chest pain
AC C
Rash
EP
Musculoskeletal stiffness
Pyrexia
1 (1.9)
TE D
Hypersensitivity
Pain in jaw
M AN U
Bone pain
RI PT
AEs, n (%)
SC
Adverse events (MedDRA term)
1 (1.9) 1 (1.9) 1 (1.9) 1 (1.9) 1 (1.9) 1 (1.9) 1 (1.9)
Urticaria
1 (1.9)
Vertigo
1 (1.9)
AE, adverse event; HM, haematological malignancies; MedDRA, Medical Dictionary for Regulatory Activities
29/30
ACCEPTED MANUSCRIPT Supplementary Figure 1. Study population for the HM cohort
Analysed n = 633
Followed up‡ n = 615
No follow-up† n = 18
Completed questionnaire n = 462
M AN U
Questionnaire not completed n = 153
SC
Not analysed* n=4
RI PT
Inclusion n = 637
Dose intensity evaluable n = 420
†
TE D
*Four patients were excluded from the analysis: two due to deviation from the eligibility criteria and two were duplicated patient records.
‡
EP
The 18 patients who left the study prematurely and were not followed up were comparable to the followed-up patients in terms of age, sex, comorbidities concomitant with neutropenia risk, and number of CT cycles planned. There were more patients with prior episodes of neutropenia (p = 0.04) and patients had a lower performance score (p<0.01) at inclusion compared with the followed-up patients.
63 of these patients left the study before the 3-month follow-up visit but were reviewed for data collection.
AC C
HM, haematological malignancies
30/30
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT