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Efficacy of biosimilar granulocyte colony-stimulating factor versus originator granulocyte colony-stimulating factor in peripheral blood stem cell mobilization in de novo multiple myeloma patients
Cytotherapy, 2015; 0: 1e9
Efficacy of biosimilar granulocyte colony-stimulating factor versus originator granulocyte colony-stimulating factor in peripheral blood stem cell mobilization in de novo multiple myeloma patients MASSIMO MARTINO1, ANNA GRAZIA RECCHIA2, TIZIANA MOSCATO1, ROBERTA FEDELE1, SANTO NERI3, MASSIMO GENTILE4, CATERINA ALATI5, IOLANDA DONATELLA VINCELLI5, EUGENIO PIRO6, GIUSEPPA PENNA7, CATERINA MUSOLINO7, FRANCESCA RONCO5, STEFANO MOLICA6 & FORTUNATO MORABITO2,4 1
Hematology and Stem Cell Transplant Unit, Azienda Ospedaliera BMM, Reggio Calabria, Italy, 2Biotechnology Research Unit, Azienda Sanitaria Provinciale di Cosenza, Aprigliano (CS), Italy, 3Hematology Unit, Azienda Ospedaliera Papardo, Messina, Italy, 4Haematology Unit, Azienda Ospedaliera Cosenza, Italy, 5Hematology Unit, Azienda Ospedaliera BMM, Reggio Calabria, Italy, 6Hematology Unit, Azienda Ospedaliera Pugliese Ciaccio, Catanzaro, Italy, and 7School and Division of Hematology, University Hospital “G. Martino”, Messina, Italy
Abstract Background aims. Filgrastim and lenograstim are the standard granulocyte colony-stimulating factor (G-CSF) agents for peripheral blood stem cell mobilization (PBSC) in patients who undergo autologous stem cell transplantation. Methods. To assess whether biosimilars are effective, we conducted a single-center, prospective study that included 40 consecutive de novo multiple myeloma patients who received cyclophosphamide 4 g/m2 per day plus biosimilar filgrastim G-CSF to mobilize PBSC. These patients were compared with a group of 37 patients matched for age, diagnosis, previous chemotherapy and mobilization who had been treated with originator G-CSF. The mean number of CD34þ cells/mL in the peripheral blood was 199.6 207.4 in the biosimilar and 192.8 154.7 in the originator group (P ¼ 0.87). The median number of CD34þ cells/kg recipient collected was 11.5 5.8 and 12.3 5.3 in the biosimilar and originator groups, respectively (P ¼ 0.51). The mobilization failure rate was 2.5% and 2.7% in the biosimilar filgrastim and originator filgrastim cohorts (P ¼ NS), respectively. Results. Twenty-nine patients in the biosimilar group and 28 patients in the originator group underwent autologous transplantation. There were no statistically significant differences between the biosimilar and originator G-CSF cohorts in terms of hematopoietic recovery parameters and transplant-related toxicities. Conclusions. The efficacy of biosimilar G-CSF appears to be equivalent to the reference G-CSF. Key Words: biosimilar G-CSF, engraftment, multiple myeloma, originator G-CSF, peripheral blood stem cell mobilization
Introduction Autologous stem cell transplantation (ASCT) is widely used for the treatment of hematological malignancies; the most common indication is multiple myeloma (MM) [1]. Recent data demonstrate that >80% to 90% of all ASCT worldwide are performed with the use of either colony-stimulating factor (CSF) or chemotherapy, followed by CSF-mobilized peripheral blood stem cells (PBSCs) [1]. Most mobilization regimens combine treatment with CSF after administration of a disease-specific chemotherapy
regimen to achieve higher CD34þ cell yields than treatment with CSF alone [2e4]. In MM, the most common stand-alone regimen includes high-dose cyclophosphamide (Cy) at different dose ranges (3e7 g/m2) plus CSF [5,6]. The first demonstration of a synergistic effect of Cy and CSF was reported by an Italian study [7]. Several retrospective and prospective, randomized studies have reported that granulocyte colony-stimulating factor (G-CSF) is as or more effective than granulocyte macrophage colony-stimulating factor (GM-CSF) in PBSC mobilization after chemotherapy [8e11].
Correspondence: Massimo Martino, MD, Hematology and Stem Cell Transplant Unit, Azienda Ospedaliera BMM, Via Melacrino n.1, 89100 Reggio Calabria, Italy. E-mail: [email protected] (Received 18 March 2015; accepted 14 May 2015) ISSN 1465-3249 Copyright Ó 2015, International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jcyt.2015.05.010
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The target CD34þ cell concentration to be collected as well as the number of aphereses performed varies widely. The minimum safe dose for ensuring rapid neutrophil and platelet recovery in MM patients is 2.0 106 CD34þ cells/kg [12e14], whereas the “optimal” number is 4 106 CD34þ cells/kg [15]. In MM patients, it has been suggested that a minimum target of 4 106 CD34þ cells/kg be collected, and, if feasible, up to an average of 8 106 CD34þ cells/kg. These targets would allow most patients with myeloma to undergo at least two autotransplants with an optimal CD34þ dose during the course of their disease [14]. Filgrastim and lenograstim, alone or in combination with chemotherapy, are the standard G-CSF agents used to mobilize PBSC. Biosimilars of filgrastim, on the basis of the originator product Neupogen, have been available since 2008 and are now in clinical use in Europe and elsewhere with the same indications as the originator G-CSF [16]. Biosimilars are similar but nonidentical versions of existing biological drugs for which patents have expired [17]. Despite the rigorous approval process for biosimilars, concerns have been expressed about the efficacy and safety of these products in clinical practice [18]. To assess whether biosimilars are effective, we conducted a single-center, prospective study with historic controls consisting of MM patients who received high-dose chemotherapy plus G-CSF for PBSC mobilization and subsequently, high-dose melphalan and ASCT plus biosimilar G-CSF until neutrophil recovery was achieved.
Methods Study design A total of 40 consecutive de novo MM patients with sensitive disease (at least partial remission) [19] after a bortezomib-based induction therapy (in association with corticosteroids with/without thalidomide) and scheduled to receive a biosimilar G-CSF (Zarzio, Sandoz Industrial Products) (biosimilar group) after chemotherapy for autologous PBSC mobilization were prospectively included between June 2013 and December 2014. Patients were recruited from four hematological centers in the South of Italy (Calabria Region) and one from Northern Sicily (City of Messina) after induction therapy; all patients were referred to Bone Marrow Transplant Unit of the Azienda Ospedaliera BMM, Reggio Calabria (Italy) for PBSC harvesting and transplantation. These patients were compared with a historic control group of 37 patients matched for age, diagnosis, previous chemotherapy and mobilization who had been treated with originator G-CSF (Neupogen) (originator group) at the same Bone Marrow Transplant Unit of the Azienda
Ospedaliera BMM, Reggio Calabria (Italy) between January 2012 and May 2013. The study was approved by the local Institutional Review Boards and was conducted according to the Declaration of Helsinki and the International Conference on Harmonization Guidelines for Good Clinical Practice. All patients provided written informed consent. Mobilization In both groups, Cy was administered as a 2-h intravenous infusion at a dose of 2 g/m2 per day on days 1 and 2, along with 2-mercaptoethane sulfonate Na (MESNA). All patients received anti-emetic prophylaxis with intravenous palonosetron 0.25 mg, 30 min before chemotherapy on day 1 and hydration with 1000 mL of normal saline before chemotherapy. Biosimilar G-CSF or originator G-CSF (5 mg/kg per day subcutaneously) was started on day þ3 and continued until the completion of apheresis. All patients in both treatment arms received prophylaxis for bacterial and viral infection with oral antimicrobial agents (levofloxacin and acyclovir). Apheresis CD34þ cell monitoring began during hematologic recovery after chemotherapy, when the white blood cell (WBC) count exceeded 1 109/L. CD34þ cell measurements in peripheral blood were performed during mobilization according to the International Society of Hematotherapy and Graft Engineering (ISHAGE) single-platform method in all patients [20,21]. Monitoring of CD34þ cells in peripheral blood continued until the day of last leukapheresis. The first PBSC collection was performed in patients showing a CD34þ count of at least 20 cells/mL in peripheral blood, until reaching the prescribed target cell dose. The optimal target PBSC dose to be collected was 8 106 CD34þ cells/kg recipient body weight, whereas a minimal cell dose of 2 106 CD34þ cells/ kg was considered acceptable. Apheresis was carried out with continuous-flow apheresis equipment (COM.TEC cell separators, AS 104/AS 204 and COM.TEC in, Fresenius Hemo-Care GmbH). Monitoring of adverse events Physical examination and subjective and objective findings were recorded before chemo-mobilization, 1 week after chemo-mobilization, daily when the WBC count exceeded 1 109/L and until the completion of the apheresis collection, and 1 month after chemomobilization. The severity of adverse events was recorded according to the National Cancer InstituteCommon Toxicity Criteria. For the treatment of bone
Biosimilar G-CSF and stem cell mobilization
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Table I. Baseline patient characteristics. Variables
Biosimilar G-CSF
Originator G-CSF
No. of patients, n (%) Age, ya Sex, n (%) Male Female Durie-Salmon classification, n (%) Stage I Stage II Stage III A B ISS, n (%) Stage I Stage II Stage III Monoclonal protein type, n (%) IgG IgA Light chain only First-line therapy, n (%) Velcade-based Response after primary therapy, n (%) Complete response Very good partial response Partial response Body weight, kga Height, cma WBC, 109/La Platelets, 109/La Hemoglobin, g/dL
40 (100) 54.1 (40.0e69.0)
37 (100) 59.0 (44.0e67.6)
20 (50.0) 20 (50.0)
20 (54.1) 17 (45.9)
1 4 35 33 7
3 1 33 35 2
P value 0.12 0.82
0.25 (2.5) (10.0) (87.5) (82.5) (17.5)
(8.1) (2.7) (89.2) (94.6) (5.5) 0.85
24 (60.0) 12 (30.0) 4 (10.0)
24 (64.9) 9 (24.3) 4 (10.8)
26 (65.0) 10 (25.0) 4 (10.0)
27 (73.0) 9 (24.3) 1 (2.7)
40 (100)
37 (100)
0.41
1 0.74 9 24 7 72 163 5.8 196 12.1
(22.5) (60.0) (17.5) (50e102) (150e180) (3.1e10.6) (123e469) (10.1e14.9)
7 21 9 66 167 5.6 189 12.0
(18.9) (56.8) (24.3) (49e100) (145e188) (3.0e11.0) (121e337) (9.8e14.0)
0.14 0.59 0.92 0.14 0.26
ISS, International Staging System Classification. a Values are expressed as median and range.
pain caused by G-CSF, oral paracetamol at a dose of 500 mg, with at least a 6-h interval, was prescribed. Short-term adverse events were defined as any death within 30 days from chemo-mobilization; any mild adverse event within 30 days; or any severe adverse event requiring hospitalization within 30 days. Transplantation details After 4 to 6 weeks from administration of Cy, patients in both groups received high-dose melphalan, 200 mg/m2 (MEL-200), given as a single dose intravenously (day e1) followed by PBSC infusion (2 106 CD4þ cells/kg) 24 h later (day 0). G-CSF (originator filgrastim or biosimilar filgrastim) at 5 mg/kg per day was started at day 5 until neutrophil recovery was achieved. All patients received either originator or biosimilar filgrastim for both mobilization and posttransplant neutrophil recovery. During the aplastic phase, all patients received oral prophylaxis with levofloxacin from day 0 until neutrophil recovery and acyclovir from day þ3 after transplantation until approximately day þ90. Red blood cell and platelet transfusions were given to
maintain hemoglobin levels >8 mg/dL and platelet counts >10 109/L or in the case of symptomatic anemia and/or minimal muco-cutaneous hemorrhagic syndrome. Neutropenic fever was defined as an axillary temperature exceeding >38.2 C on at least two consecutive occasions or a persistent temperature of 38 C for at least 1 h. Neutropenia was defined as an absolute neutrophil count <0.5 109/L or absolute neutrophil count of 1 and a predicted decline to <0.5 over the next 48 h. When neutropenic fever was observed, blood and catheter cultures were set up and empiric antibiotic therapy with intravenous ceftriaxone was promptly started. Efficacy end points The primary end points of the present study were to evaluate the peak CD34þ cell count in peripheral blood during mobilization with G-CSF and the total number of CD34þ cells per recipient body weight collected. Secondary end points were percentage of patients achieving 2 106, 4 106 and 8 106 CD34þ cells/kg recipient; percentage of those
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Figure 1. Box plots show the peak number of mobilized CD34þ cells/mL in peripheral blood after mobilization with originator (192.8 154.7) or biosimilar (199.6 207.4) G-CSF.
achieving the same targets with a single apheresis; and mobilization failure rate. Mobilization failure was defined as a collection of <2 106/kg CD34þ recipient. As an efficacy evaluation, we analyzed neutrophil and platelet engraftment after ASCT and early transplantation-related mortality (TRM). Neutrophil and platelet recoveries were defined as the first of 3 consecutive days of an absolute neutrophil count 0.5 109/L and the first of 3 days of a platelet count 20 109/L without transfusion support for 7 consecutive days. Early TRM was defined as mortality from any cause other than disease progression within 100 days from transplantation.
As the primary end points, the mean number of CD34þ cells/mL in the peripheral blood according to G-CSF type was 199.6 207.4 in the biosimilar group and 192.8 154.7 in the originator group, respectively (P ¼ 0.87) (Figure 1). The total median number of CD34þ cell/kg recipient collected was 11.5 5.8 and 12.3 5.3 in the biosimilar group and originator group, respectively (P ¼ 0.51, Figure 2). Patients with biosimilar filgrastim had comparable WBC, platelet and hematocrit counts as well as blood volume processed compared with patients with originator filgrastim (Table II). The mobilization failure rate was 2.5% (1/40) and 2.7% (1/37) for biosimilar filgrastim and originator filgrastim, respectively (P ¼ NS). No differences were observed in the percentage of patients who obtained the target dose 4 and 8 106/kg of CD34þ cells (Table II). The median number of apheresis sessions was 2 in both groups. The number of apheresis sessions performed in relation to the type of G-CSF is summarized in Table II and Figure 3. The biosimilar G-CSF group was subjected to a higher number of apheresis sessions, at the limit of statistical significance, to reach the target of CD34þ8 106/kg (P ¼ 0.046). A comparison of side effects between the groups of patients was performed, but no significant difference was observed. The most common side effects were bone pain, headache and muscle cramps. Some patients had nausea and fatigue, but none of the patients required interruption of the treatment procedure. Transplantation data
Statistical analysis Continuous data are presented as mean and standard deviation or as median and range and categorical data as absolute values and percentages. Data comparisons between two groups were performed by c2 test for categorical variables and by independent t-test for continuous variables. A box-and-whisker plot was also used to summarize and compare data distribution between two groups. A value of P < 0.05 was considered statistically significant. Data analysis was performed with the use of SPSS for Windows (version 20.0.0, IBM).
Twenty-nine patients in the biosimilar group and 28 patients in the originator group received MEL-200
Results Mobilization Patient characteristics were similar in both the biosimilar and originator G-CSF treatment groups, and no statistical differences were detected among them (Table I).
Figure 2. Box plots show the number of CD34þ cells/kg body weight collected by originator (12.3 5.3) and biosimilar (11.5 5.8) G-CSF.
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Table II. Stem cell collection data. Variable No. of patients (%) No. of apheresis sessionsa Blood volume processed during the first apheresisa, liters Blood volume processed during the second apheresisa, liters Pre-leukapheresis hematocrit count (first apheresis)a, % Pre-leukapheresis platelet count (first apheresis)a, 109/L Pre-leukapheresis WBC count (first apheresis)a, 109/L Pre-leukapheresis hematocrit count (second apheresis)a, % Pre-leukapheresis platelet count (second apheresis)a, 109/L Pre-leukapheresis WBC count (second apheresis)a, 109/L Mobilization failureb, n (%) No. patients (%) who failed to collect CD34þ 4 106/kg No. patients (%) who failed to collect CD34þ >8 106/kg No. of apheresis procedures to achieve the target CD34þ cell dose 2 106/kg 1 procedure 2 procedures No. of apheresis procedures to achieve the target CD34þ cell dose 4 106/kg 1 procedure 2 procedures 3 procedures No. of apheresis procedures to achieve the target CD34þ cell dose 8 106/kg 1 procedure 2 procedures 3 procedures 4 procedures a
Biosimilar G-CSF
Originator G-CSF
P value
40 (100) 2 (0e4) 9.3 (4.2e14.6)
37 (100) 2 (1e4) 8.5 (4.2e14.0)
0.33 0.1
11.4 (3.1e11.3)
9.8 (5.8e13.9)
0.23
32 (24e40)
32 (25e40)
0.87
87 (30e219)
100 (23e228)
0.47
19 (4e55)
23 (1.5e62)
0.22
32 (22e39)
31 (25e40)
0.68
86 (49e185)
88 (34e259)
0.80
26 (7e56)
34 (7e56)
0.44
1 (2.5) 2 (5.0)
1 (2.7) 2 (5.4)
1 0.66
4 (10.0)
5 (13.5)
0.73 0.10
36 patients 3 patients
28 patients 8 patients 0.27
30 patients 6 patients 2 patients
22 patients 6 patients 6 patients 0.046
18 patients 5 patients 3 patients 6 patients
15 patients 17 patients 2 patients 2 patients
Values are expressed as median and range. Mobilization failure was defined as a collection of CD34þ <2 106/kg recipient.
b
and ASCT. There were no statistically significant differences between the biosimilar and originator G-CSF group in terms of the number of stem cells infused and hematopoietic recovery parameters (Table III). Although the incidence of fever was higher in the originator group (64.2% versus 44.8%), the difference was not significant (P ¼ 0.095). The median duration of hospitalization was similar (18 days; range, 15 to 30 in the biosimilar versus 18 days; range, 14 to 27, in the originator group, P ¼ 0.7). No TRM was observed in either group.
Discussion Mobilization of PBSCs by G-CSF has largely replaced bone marrow collection for ASCT due to ease of collection, avoidance of general anesthesia and more
rapid recovery of blood counts [22]. Consensus is lacking on the use of CSF in the post-transplant setting. G-CSF administration after high-dose chemotherapy and ASCT has been shown to expedite neutrophil recovery in randomized trials and results are mixed on the impact of G-CSF on duration of hospital stay, infections and survival [23e25]. The use of biosimilar G-CSF for PBSC mobilization and neutrophil recovery after ASCT has stimulated an ongoing debate regarding their efficacy and safety. Although there are few published data regarding their use in these contexts, biosimilars of G-CSF were approved by the European Medicines Agency for all the registered indications of the originator G-CSF including mobilization of stem cells. Nevertheless, most scientific societies still recommend not applying biosimilar G-CSF in the autologous setting before adequate scientific validation (Consensus Conference
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Figure 3. Number of apheresis sessions in biosimilar G-CSF and originator G-CSF groups.
on Biosimilar Growth Factors of the Italian Society of Hematology and Gruppo Italiano trapianto Midollo Osseo) [26]. The published studies are heterogeneous and low-powered [27e31], and, in this context, our study contributes to the growing body of evidence in support of efficacy of G-CSF biosimilars. To our knowledge, this study represents one of the largest and homogeneous undertaken so far on this issue. The study sample is extremely homogeneous for MM diagnosis and therapy of mobilization (Cy 4 gr/ m2). Moreover, it should be emphasized that MM is the condition in which ASCT is most used worldwide and therefore where therapy with growth factors find widespread use, both as a mobilization agent and in post-transplant therapy. Its sequential, although not randomized, nature should minimize the bias related to the use of historic controls. Our data suggest that biosimilar and originator filgrastim are similarly effective for the mobilization and collection of CD34þ progenitor cells when used with the same schedules and doses. CD34þ stem/ progenitor cell collection correlates with the absolute number of circulating CD34þ cells before apheresis, and the aim of an optimal apheresis procedure is to achieve the target CD34þ cell dose with the lowest number of procedures. In this regard, the median peak peripheral blood count for CD34þ cells before leukapheresis and the median total CD34þ/kg yield collected were similar between the study group and the control group. The proportion of PBSC mobilization failures and the median number of apheresis procedures were also comparable between groups.
The number of leukapheresis sessions required to reach the target of CD34þ8 106/kg was superior with the biosimilar compared with the originator GCSF, although at the limit of statistical significance. The frequency and the severity of side effects such as headache and/or bone pain observed in the biosimilar group were comparable to the originator group and to other published studies of G-CSF at 5 and 10 mg/kg per day doses [32]. Sivgin et al. [28] retrospectively analyzed data of 96 patients who underwent ASCT diagnosed with MM, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma and others. The authors showed that the biosimilar filgrastim administered after chemotherapy was equivalent to originator for mobilization and PBSC collection when used with the same schedules and doses. Lefrere et al. [27], in a prospective study, compared filgrastim with biosimilar filgrastim in autologous PBSC mobilization and showed that no significant differences were observed between groups in terms of the median number of CD34þ cells mobilized and collected, nor in the number of G-CSF injections and leukaphereses required to obtain the minimal CD34þ cell count. Moreover, the study showed that biosimilar G-CSF could provide a more cost-effective strategy. In a recent published study [29], after administration of mobilizing regimens [primarily high-dose etoposide, high-dose Cy, intermediate-dose cytosine arabinoside (Ara-C) or ESHAP regimens], patients with MM, non-Hodgkin’s lymphoma, Hodgkin’s lymphoma or other diagnosis were randomly assigned to a standard daily 10 mg/kg dose of biosimilar G-CSF
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Table III. Outcome and hematopoietic recovery in multiple myeloma patients receiving biosimilar or originator G-CSF after autologous transplantation. Variable No. patients (%) CD34þ cells (10E6/kg) infuseda No. of erythrocyte transfusions (units)a No. of platelet transfusions (units)a Engraftment (days after transplant)a Days to reach neutrophils >0.5 109/L Days to reach platelets >20 109/L Fever 38.2 C, No. (%) No Yes Fever origin, No. (%) FUO CVC-related Clinically documented Microbiologically documented infection No. of days of fever 38.2 Ca No. of days antibiotic on therapya Mucositis Grade 0e2, No. (%) Grade 3e4, No. (%) Hospitalization duration, days, median (range) a
Biosimilar G-CSF 29 4.9 0 1
(100) (2.3e9.0) (0e3) (0e3)
Originator G-CSF 28 5.0 0 0.5
(100) (2.3e7.0) (0e3) (0e4)
11 (9e12) 13 (10e16)
11 (9e15) 13 (10e19)
16 (55.2) 13 (44.8)
10 (35.8) 18 (64.2)
P value 0.37 0.93 0.27 0.57 0.69 0.095
0.1 11/13 1/13 1/13 0/13 1 1
(84.6) (7.7) (7.7) (0) (0e5) (0e8)
27 (93.1) 2 (6.9) 18 (15e30)
14/18 0/18 1/18 3/18 1.5 5
(77.8) (0) (5.6) (16.6) (0e9) (0e12)
27 (96.4) 1 (3.6) 18 (14e27)
0.13 0.07 0.06
0.7
Values are expressed as median and range.
or originator G-CSF. Both groups had a median of one apheresis with a median time until first apheresis of 11 days. There were no statistically significant differences between groups in the mean number of mobilized CD34þ cells/mL in peripheral blood or the number of CD34þ cells/kg body weight. Recently, Schmitt et al. [30] summarized the currently available data through the use of biosimilar G-CSF for stem cell mobilization. A total of 904 patients mostly with hematological malignancies as well as healthy donors underwent successful autologous or allogeneic stem cell mobilization, respectively, with the use of a biosimilar G-CSF (520 with Ratiograstim/ Tevagrastim, 384 with Zarzio). The indication for stem cell mobilization in hematology patients included 326 patients with MM, 273 with non-Hodgkin’s lymphoma, 79 with Hodgkin’s lymphoma and other diseases. A total of 156 sibling or volunteer unrelated donors were mobilized with the use of biosimilar GCSF. Mobilization resulted in good mobilization of CD34þ stem cells with side effects similar to originator G-CSF. Post-transplantation engraftment did not significantly differ from results previously documented with the originator G-CSF. The side effects experienced by the patients or donors mobilized by biosimilar G-CSF were minimal and were comparable to those of originator G-CSF. In terms of neutrophil recovery, several studies showed the non-inferiority of biosimilar filgrastim in febrile neutropenia prophylaxis and hematological recovery after ASCT when compared with the other non-pegylated G-CSF formulations [31,33e37].
Gascon et al. [17] conducted a pooled analysis of five post-approval studies of biosimilar G-CSF that included 1302 adult patients who received at least one cycle of chemotherapy with G-CSF support for the prevention of neutropenia to assess whether biosimilars are effective in the real-world clinical practice setting. Overall, 36% of patients had a febrile neutropenia risk of >20%, whereas 39.6% had a risk of 10% to 20%, based on the chemotherapy regimen used. The occurrence of severe or febrile neutropenia was within the range of that observed in previous studies of originator G-CSF. In addition, the safety profile of biosimilar G-CSF was consistent with that reported for originator G-CSF and the known safety profile of G-CSF. In our study, we did not observe any differences in terms of engraftment and toxicity after transplantation. However, the two cohorts were relatively small, and this could limit the utility of these data. In conclusion, the efficacy of biosimilar GCSFs, in terms of PBSC yield and their relative toxicity profiles, appears to be equivalent to the reference G-CSF. However, until results from multicenter randomized, clinical trials that directly compare biosimilar G-CSFs with the originator G-CSF are reported, it is important to collect and summarize all of the available clinical experience with these agents to allow the transplant community to make informed decisions regarding the choice of G-CSF. More importantly, overall these data contribute to reduce initial unfounded concerns on the use of biosimilar G-CSF, allowing the reduction
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of healthcare costs, and ultimately improving patient access to biological treatments.
[14]
Disclosure of interests: The authors have no commercial, proprietary, or financial interest in the products or companies described in this article. [15]
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multiple myeloma: identification of favourable variables for engraftment in 225 patients. Blood 1995;85:588e96. Giralt S, Stadtmauer EA, Harousseau JL, Palumbo A, Bensinger W, Comenzo RL, et al. International myeloma working group (IMWG) consensus statement and guidelines regarding the current status of stem cell collection and highdose therapy for multiple myeloma and the role of plerixafor (AMD 3100). Leukemia 2009;23:1904e12. Siena S, Schiavo R, Pedrazzoli P, Carlo-Stella C. Therapeutic relevance of CD34 cell dose in blood cell transplantation for cancer therapy. J Clin Oncol 2000;18: 1360e77. Gascon P, Fuhr U, Sörgel F, Kinzig-Schippers M, Makhson A, Balser S, et al. Development of a new G-CSF product based on biosimilarity assessment. Ann Oncol 2010; 21:1419e29. Gascon P, Tesch H, Verpoort K, Rosati MS, Salesi N, Agrawal S, et al. Clinical experience with ZarzioÒ in Europe: what have we learned? Support Care Cancer 2013;21: 2925e32. Pierelli L, Perseghin P, Marchetti M, Accorsi P, Fanin R, Messina C, et al. Best practice for peripheral blood progenitor cell mobilization and collection in adults and children: results of a Società Italiana Di Emaferesi e Manipolazione Cellulare (SIDEM) and Gruppo Italiano Trapianto Midollo Osseo (GITMO) consensus process. Transfusion 2012;52: 893e905. Rajkumar SV, Harousseau JL, Durie B, Anderson KC, Dimopoulos M, Kyle R, et al. Consensus recommendations for the uniform reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1. Blood 2011;117:4691e5. Brando B, Barnett D, Janossy G, Mandy F, Autran B, Rothe G, et al. Cytofluorometric methods for assessing absolute numbers of cell subsets in blood. European Working Group on Clinical Cell Analysis. Cytometry 2000;42: 327e46. Keeney M, Brown W, Gratama J, Papa S, Lanza F, Sutherland DR, et al. Single platform enumeration of viable CD34 pos cells. J Biol Regul Homeost Agents 2003;17: 247e53. Hosing C. Hematopoietic stem cell mobilization with GCSF. Methods Mol Biol 2012;904:37e47. Spitzer G, Adkins DR, Spencer V, Dunphy FR, Petruska PJ, Velasquez WS, et al. Randomized study of growth factors post-peripheral-blood stem-cell transplant: neutrophil recovery is improved with modest clinical benefit. J Clin Oncol 1994;12:661e70. Klumpp TR, Mangan KF, Goldberg SL, Pearlman ES, Macdonald JS. Granulocyte colony-stimulating factor accelerates neutrophil engraftment following peripheral-blood stem-cell transplantation: a prospective, randomized trial. J Clin Oncol 1995;13:1323e7. Linch DC, Milligan DW, Winfield DA, Kelsey SM, Johnson SA, Littlewood TJ, et al. G G-CSF after peripheral blood stem cell transplantation in lymphoma patients significantly accelerated neutrophil recovery and shortened time in hospital: results of a randomized BNLI trial. Br J Haematol 1997;99:933e8. Barosi G, Bosi A, Abbracchio MP, Danesi R, Genazzani A, Corradini P, et al. Key concepts and critical issues on epoetin and filgrastim biosimilars. A position paper from the Italian Society of Hematology, Italian Society of Experimental Hematology and Italian Group for Bone Marrow Transplantation. Haematologica 2011;96:937e42. Lefrere F, Brignier AC, Elie C, Ribeil JA, Bernimoulin M, Aoun C, et al. First experience of autologous peripheral
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blood stem cell mobilization with biosimilar granulocyte colony-stimulating factor. Adv Ther 2011;28:304e10. Sivgin S, Karakus E, Kaynar L, Kurnaz F, Pala C, Keklik M, et al. The comparison of Filgrastim (Neupogen), biosimilar filgrastim (Leucostim) and Lenograstim (Granocyte) as a first line peripheral blood stem cell mobilization strategy in autologous hematopoietic stem cell transplantation: a single center experience from Turkey. Transfus Apher Sci 2013;48: 315e20. Manko J, Walter-Croneck A, Jawniak D, Grzasko N, GorskaKosicka M, Cioch M, et al. A clinical comparison of the efficacy and safety of biosimilar G-CSF and originator GCSF in hematopoietic stem cell mobilization. Pharmacol Rep 2014;66:239e42. Schmitt M, Publicover A, Orchard KH, Görlach M, Wang L, Schmitt A, et al. Biosimilar G-CSF based mobilization of peripheral blood hematopoietic stem cells for autologous and allogeneic stem cell transplantation. Theranostics 2014;4:280e9. Remenyi P, Gopcsa L, Marton I, Reti M, Mikala G, Pet} o M, et al. Peripheral blood stem cell mobilization and engraftment after autologous stem cell transplantation with biosimilar rh G-CSF. Adv Ther 2014;31:451e60. Engelhardt M, Bertz H, Afting M, Waller CF, Finke J. Highversus standard-dose filgrastim (rhG-CSF) for mobilization of peripheral-blood progenitor cells from allogeneic donors
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and CD34(þ) immunoselection. J Clin Oncol 1999;17: 2160e72. Ferro HH, Juni M, Bello R, Vidal A, Diez RA, Pavlovsky S, et al. Utilization study of filgrastim (Neutromax) during autologous hematopoietic precursor transplantation for myeloma and lymphoma patients. Transfus Apher Sci 2009; 41:87e93. Niederwieser D, Schmitz S. Biosimilar agents in oncology/ haematology: from approval to practice. Eur J Haematol 2011;86:277e88. Ianotto JC, Tempescul A, Yan X, Delepine P, Le Calloch R, Hardy E, et al. Experience (1 year) of G-CSF biosimilars in PBSCT for lymphoma and myeloma patients. Bone Marrow Transplant 2012;47:874e6. Cioch M, Jawniak D, Kotwica K, Wach M, Ma nko J, Goracy A, et al. Biosimilar granulocyte colony-stimulating Î is effective in reducing the duration of neutropenia factor after autologous peripheral blood stem cell transplantation. Transplant Proc 2014;46:2882e4. Marchesi F, Cerchiara E, Dessanti ML, Gumenyuk S, Franceschini L, Palombi F, et al. Comparison between biosimilar filgrastim vs other granulocyte-colony stimulating factor formulations (originator filgrastim, peg-filgrastim and lenograstim) after autologous stem cell transplantation: a retrospective survey from the Rome Transplant Network. Br J Haematol 2014;169:293e6.
Efficacy of biosimilar granulocyte colony-stimulating factor versus originator granulocyte colony-stimulating factor in peripheral blood stem cell mobilization in de novo multiple myeloma patients MASSIMO MARTINO1, ANNA GRAZIA RECCHIA2, TIZIANA MOSCATO1, ROBERTA FEDELE1, SANTO NERI3, MASSIMO GENTILE4, CATERINA ALATI5, IOLANDA DONATELLA VINCELLI5, EUGENIO PIRO6, GIUSEPPA PENNA7, CATERINA MUSOLINO7, FRANCESCA RONCO5, STEFANO MOLICA6 & FORTUNATO MORABITO2,4 1
Hematology and Stem Cell Transplant Unit, Azienda Ospedaliera BMM, Reggio Calabria, Italy, 2Biotechnology Research Unit, Azienda Sanitaria Provinciale di Cosenza, Aprigliano (CS), Italy, 3Hematology Unit, Azienda Ospedaliera Papardo, Messina, Italy, 4Haematology Unit, Azienda Ospedaliera Cosenza, Italy, 5Hematology Unit, Azienda Ospedaliera BMM, Reggio Calabria, Italy, 6Hematology Unit, Azienda Ospedaliera Pugliese Ciaccio, Catanzaro, Italy, and 7School and Division of Hematology, University Hospital “G. Martino”, Messina, Italy
Abstract Background aims. Filgrastim and lenograstim are the standard granulocyte colony-stimulating factor (G-CSF) agents for peripheral blood stem cell mobilization (PBSC) in patients who undergo autologous stem cell transplantation. Methods. To assess whether biosimilars are effective, we conducted a single-center, prospective study that included 40 consecutive de novo multiple myeloma patients who received cyclophosphamide 4 g/m2 per day plus biosimilar filgrastim G-CSF to mobilize PBSC. These patients were compared with a group of 37 patients matched for age, diagnosis, previous chemotherapy and mobilization who had been treated with originator G-CSF. The mean number of CD34þ cells/mL in the peripheral blood was 199.6 207.4 in the biosimilar and 192.8 154.7 in the originator group (P ¼ 0.87). The median number of CD34þ cells/kg recipient collected was 11.5 5.8 and 12.3 5.3 in the biosimilar and originator groups, respectively (P ¼ 0.51). The mobilization failure rate was 2.5% and 2.7% in the biosimilar filgrastim and originator filgrastim cohorts (P ¼ NS), respectively. Results. Twenty-nine patients in the biosimilar group and 28 patients in the originator group underwent autologous transplantation. There were no statistically significant differences between the biosimilar and originator G-CSF cohorts in terms of hematopoietic recovery parameters and transplant-related toxicities. Conclusions. The efficacy of biosimilar G-CSF appears to be equivalent to the reference G-CSF. Key Words: biosimilar G-CSF, engraftment, multiple myeloma, originator G-CSF, peripheral blood stem cell mobilization
Introduction Autologous stem cell transplantation (ASCT) is widely used for the treatment of hematological malignancies; the most common indication is multiple myeloma (MM) [1]. Recent data demonstrate that >80% to 90% of all ASCT worldwide are performed with the use of either colony-stimulating factor (CSF) or chemotherapy, followed by CSF-mobilized peripheral blood stem cells (PBSCs) [1]. Most mobilization regimens combine treatment with CSF after administration of a disease-specific chemotherapy
regimen to achieve higher CD34þ cell yields than treatment with CSF alone [2e4]. In MM, the most common stand-alone regimen includes high-dose cyclophosphamide (Cy) at different dose ranges (3e7 g/m2) plus CSF [5,6]. The first demonstration of a synergistic effect of Cy and CSF was reported by an Italian study [7]. Several retrospective and prospective, randomized studies have reported that granulocyte colony-stimulating factor (G-CSF) is as or more effective than granulocyte macrophage colony-stimulating factor (GM-CSF) in PBSC mobilization after chemotherapy [8e11].
Correspondence: Massimo Martino, MD, Hematology and Stem Cell Transplant Unit, Azienda Ospedaliera BMM, Via Melacrino n.1, 89100 Reggio Calabria, Italy. E-mail: [email protected] (Received 18 March 2015; accepted 14 May 2015) ISSN 1465-3249 Copyright Ó 2015, International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jcyt.2015.05.010
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The target CD34þ cell concentration to be collected as well as the number of aphereses performed varies widely. The minimum safe dose for ensuring rapid neutrophil and platelet recovery in MM patients is 2.0 106 CD34þ cells/kg [12e14], whereas the “optimal” number is 4 106 CD34þ cells/kg [15]. In MM patients, it has been suggested that a minimum target of 4 106 CD34þ cells/kg be collected, and, if feasible, up to an average of 8 106 CD34þ cells/kg. These targets would allow most patients with myeloma to undergo at least two autotransplants with an optimal CD34þ dose during the course of their disease [14]. Filgrastim and lenograstim, alone or in combination with chemotherapy, are the standard G-CSF agents used to mobilize PBSC. Biosimilars of filgrastim, on the basis of the originator product Neupogen, have been available since 2008 and are now in clinical use in Europe and elsewhere with the same indications as the originator G-CSF [16]. Biosimilars are similar but nonidentical versions of existing biological drugs for which patents have expired [17]. Despite the rigorous approval process for biosimilars, concerns have been expressed about the efficacy and safety of these products in clinical practice [18]. To assess whether biosimilars are effective, we conducted a single-center, prospective study with historic controls consisting of MM patients who received high-dose chemotherapy plus G-CSF for PBSC mobilization and subsequently, high-dose melphalan and ASCT plus biosimilar G-CSF until neutrophil recovery was achieved.
Methods Study design A total of 40 consecutive de novo MM patients with sensitive disease (at least partial remission) [19] after a bortezomib-based induction therapy (in association with corticosteroids with/without thalidomide) and scheduled to receive a biosimilar G-CSF (Zarzio, Sandoz Industrial Products) (biosimilar group) after chemotherapy for autologous PBSC mobilization were prospectively included between June 2013 and December 2014. Patients were recruited from four hematological centers in the South of Italy (Calabria Region) and one from Northern Sicily (City of Messina) after induction therapy; all patients were referred to Bone Marrow Transplant Unit of the Azienda Ospedaliera BMM, Reggio Calabria (Italy) for PBSC harvesting and transplantation. These patients were compared with a historic control group of 37 patients matched for age, diagnosis, previous chemotherapy and mobilization who had been treated with originator G-CSF (Neupogen) (originator group) at the same Bone Marrow Transplant Unit of the Azienda
Ospedaliera BMM, Reggio Calabria (Italy) between January 2012 and May 2013. The study was approved by the local Institutional Review Boards and was conducted according to the Declaration of Helsinki and the International Conference on Harmonization Guidelines for Good Clinical Practice. All patients provided written informed consent. Mobilization In both groups, Cy was administered as a 2-h intravenous infusion at a dose of 2 g/m2 per day on days 1 and 2, along with 2-mercaptoethane sulfonate Na (MESNA). All patients received anti-emetic prophylaxis with intravenous palonosetron 0.25 mg, 30 min before chemotherapy on day 1 and hydration with 1000 mL of normal saline before chemotherapy. Biosimilar G-CSF or originator G-CSF (5 mg/kg per day subcutaneously) was started on day þ3 and continued until the completion of apheresis. All patients in both treatment arms received prophylaxis for bacterial and viral infection with oral antimicrobial agents (levofloxacin and acyclovir). Apheresis CD34þ cell monitoring began during hematologic recovery after chemotherapy, when the white blood cell (WBC) count exceeded 1 109/L. CD34þ cell measurements in peripheral blood were performed during mobilization according to the International Society of Hematotherapy and Graft Engineering (ISHAGE) single-platform method in all patients [20,21]. Monitoring of CD34þ cells in peripheral blood continued until the day of last leukapheresis. The first PBSC collection was performed in patients showing a CD34þ count of at least 20 cells/mL in peripheral blood, until reaching the prescribed target cell dose. The optimal target PBSC dose to be collected was 8 106 CD34þ cells/kg recipient body weight, whereas a minimal cell dose of 2 106 CD34þ cells/ kg was considered acceptable. Apheresis was carried out with continuous-flow apheresis equipment (COM.TEC cell separators, AS 104/AS 204 and COM.TEC in, Fresenius Hemo-Care GmbH). Monitoring of adverse events Physical examination and subjective and objective findings were recorded before chemo-mobilization, 1 week after chemo-mobilization, daily when the WBC count exceeded 1 109/L and until the completion of the apheresis collection, and 1 month after chemomobilization. The severity of adverse events was recorded according to the National Cancer InstituteCommon Toxicity Criteria. For the treatment of bone
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Table I. Baseline patient characteristics. Variables
Biosimilar G-CSF
Originator G-CSF
No. of patients, n (%) Age, ya Sex, n (%) Male Female Durie-Salmon classification, n (%) Stage I Stage II Stage III A B ISS, n (%) Stage I Stage II Stage III Monoclonal protein type, n (%) IgG IgA Light chain only First-line therapy, n (%) Velcade-based Response after primary therapy, n (%) Complete response Very good partial response Partial response Body weight, kga Height, cma WBC, 109/La Platelets, 109/La Hemoglobin, g/dL
40 (100) 54.1 (40.0e69.0)
37 (100) 59.0 (44.0e67.6)
20 (50.0) 20 (50.0)
20 (54.1) 17 (45.9)
1 4 35 33 7
3 1 33 35 2
P value 0.12 0.82
0.25 (2.5) (10.0) (87.5) (82.5) (17.5)
(8.1) (2.7) (89.2) (94.6) (5.5) 0.85
24 (60.0) 12 (30.0) 4 (10.0)
24 (64.9) 9 (24.3) 4 (10.8)
26 (65.0) 10 (25.0) 4 (10.0)
27 (73.0) 9 (24.3) 1 (2.7)
40 (100)
37 (100)
0.41
1 0.74 9 24 7 72 163 5.8 196 12.1
(22.5) (60.0) (17.5) (50e102) (150e180) (3.1e10.6) (123e469) (10.1e14.9)
7 21 9 66 167 5.6 189 12.0
(18.9) (56.8) (24.3) (49e100) (145e188) (3.0e11.0) (121e337) (9.8e14.0)
0.14 0.59 0.92 0.14 0.26
ISS, International Staging System Classification. a Values are expressed as median and range.
pain caused by G-CSF, oral paracetamol at a dose of 500 mg, with at least a 6-h interval, was prescribed. Short-term adverse events were defined as any death within 30 days from chemo-mobilization; any mild adverse event within 30 days; or any severe adverse event requiring hospitalization within 30 days. Transplantation details After 4 to 6 weeks from administration of Cy, patients in both groups received high-dose melphalan, 200 mg/m2 (MEL-200), given as a single dose intravenously (day e1) followed by PBSC infusion (2 106 CD4þ cells/kg) 24 h later (day 0). G-CSF (originator filgrastim or biosimilar filgrastim) at 5 mg/kg per day was started at day 5 until neutrophil recovery was achieved. All patients received either originator or biosimilar filgrastim for both mobilization and posttransplant neutrophil recovery. During the aplastic phase, all patients received oral prophylaxis with levofloxacin from day 0 until neutrophil recovery and acyclovir from day þ3 after transplantation until approximately day þ90. Red blood cell and platelet transfusions were given to
maintain hemoglobin levels >8 mg/dL and platelet counts >10 109/L or in the case of symptomatic anemia and/or minimal muco-cutaneous hemorrhagic syndrome. Neutropenic fever was defined as an axillary temperature exceeding >38.2 C on at least two consecutive occasions or a persistent temperature of 38 C for at least 1 h. Neutropenia was defined as an absolute neutrophil count <0.5 109/L or absolute neutrophil count of 1 and a predicted decline to <0.5 over the next 48 h. When neutropenic fever was observed, blood and catheter cultures were set up and empiric antibiotic therapy with intravenous ceftriaxone was promptly started. Efficacy end points The primary end points of the present study were to evaluate the peak CD34þ cell count in peripheral blood during mobilization with G-CSF and the total number of CD34þ cells per recipient body weight collected. Secondary end points were percentage of patients achieving 2 106, 4 106 and 8 106 CD34þ cells/kg recipient; percentage of those
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Figure 1. Box plots show the peak number of mobilized CD34þ cells/mL in peripheral blood after mobilization with originator (192.8 154.7) or biosimilar (199.6 207.4) G-CSF.
achieving the same targets with a single apheresis; and mobilization failure rate. Mobilization failure was defined as a collection of <2 106/kg CD34þ recipient. As an efficacy evaluation, we analyzed neutrophil and platelet engraftment after ASCT and early transplantation-related mortality (TRM). Neutrophil and platelet recoveries were defined as the first of 3 consecutive days of an absolute neutrophil count 0.5 109/L and the first of 3 days of a platelet count 20 109/L without transfusion support for 7 consecutive days. Early TRM was defined as mortality from any cause other than disease progression within 100 days from transplantation.
As the primary end points, the mean number of CD34þ cells/mL in the peripheral blood according to G-CSF type was 199.6 207.4 in the biosimilar group and 192.8 154.7 in the originator group, respectively (P ¼ 0.87) (Figure 1). The total median number of CD34þ cell/kg recipient collected was 11.5 5.8 and 12.3 5.3 in the biosimilar group and originator group, respectively (P ¼ 0.51, Figure 2). Patients with biosimilar filgrastim had comparable WBC, platelet and hematocrit counts as well as blood volume processed compared with patients with originator filgrastim (Table II). The mobilization failure rate was 2.5% (1/40) and 2.7% (1/37) for biosimilar filgrastim and originator filgrastim, respectively (P ¼ NS). No differences were observed in the percentage of patients who obtained the target dose 4 and 8 106/kg of CD34þ cells (Table II). The median number of apheresis sessions was 2 in both groups. The number of apheresis sessions performed in relation to the type of G-CSF is summarized in Table II and Figure 3. The biosimilar G-CSF group was subjected to a higher number of apheresis sessions, at the limit of statistical significance, to reach the target of CD34þ8 106/kg (P ¼ 0.046). A comparison of side effects between the groups of patients was performed, but no significant difference was observed. The most common side effects were bone pain, headache and muscle cramps. Some patients had nausea and fatigue, but none of the patients required interruption of the treatment procedure. Transplantation data
Statistical analysis Continuous data are presented as mean and standard deviation or as median and range and categorical data as absolute values and percentages. Data comparisons between two groups were performed by c2 test for categorical variables and by independent t-test for continuous variables. A box-and-whisker plot was also used to summarize and compare data distribution between two groups. A value of P < 0.05 was considered statistically significant. Data analysis was performed with the use of SPSS for Windows (version 20.0.0, IBM).
Twenty-nine patients in the biosimilar group and 28 patients in the originator group received MEL-200
Results Mobilization Patient characteristics were similar in both the biosimilar and originator G-CSF treatment groups, and no statistical differences were detected among them (Table I).
Figure 2. Box plots show the number of CD34þ cells/kg body weight collected by originator (12.3 5.3) and biosimilar (11.5 5.8) G-CSF.
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Table II. Stem cell collection data. Variable No. of patients (%) No. of apheresis sessionsa Blood volume processed during the first apheresisa, liters Blood volume processed during the second apheresisa, liters Pre-leukapheresis hematocrit count (first apheresis)a, % Pre-leukapheresis platelet count (first apheresis)a, 109/L Pre-leukapheresis WBC count (first apheresis)a, 109/L Pre-leukapheresis hematocrit count (second apheresis)a, % Pre-leukapheresis platelet count (second apheresis)a, 109/L Pre-leukapheresis WBC count (second apheresis)a, 109/L Mobilization failureb, n (%) No. patients (%) who failed to collect CD34þ 4 106/kg No. patients (%) who failed to collect CD34þ >8 106/kg No. of apheresis procedures to achieve the target CD34þ cell dose 2 106/kg 1 procedure 2 procedures No. of apheresis procedures to achieve the target CD34þ cell dose 4 106/kg 1 procedure 2 procedures 3 procedures No. of apheresis procedures to achieve the target CD34þ cell dose 8 106/kg 1 procedure 2 procedures 3 procedures 4 procedures a
Biosimilar G-CSF
Originator G-CSF
P value
40 (100) 2 (0e4) 9.3 (4.2e14.6)
37 (100) 2 (1e4) 8.5 (4.2e14.0)
0.33 0.1
11.4 (3.1e11.3)
9.8 (5.8e13.9)
0.23
32 (24e40)
32 (25e40)
0.87
87 (30e219)
100 (23e228)
0.47
19 (4e55)
23 (1.5e62)
0.22
32 (22e39)
31 (25e40)
0.68
86 (49e185)
88 (34e259)
0.80
26 (7e56)
34 (7e56)
0.44
1 (2.5) 2 (5.0)
1 (2.7) 2 (5.4)
1 0.66
4 (10.0)
5 (13.5)
0.73 0.10
36 patients 3 patients
28 patients 8 patients 0.27
30 patients 6 patients 2 patients
22 patients 6 patients 6 patients 0.046
18 patients 5 patients 3 patients 6 patients
15 patients 17 patients 2 patients 2 patients
Values are expressed as median and range. Mobilization failure was defined as a collection of CD34þ <2 106/kg recipient.
b
and ASCT. There were no statistically significant differences between the biosimilar and originator G-CSF group in terms of the number of stem cells infused and hematopoietic recovery parameters (Table III). Although the incidence of fever was higher in the originator group (64.2% versus 44.8%), the difference was not significant (P ¼ 0.095). The median duration of hospitalization was similar (18 days; range, 15 to 30 in the biosimilar versus 18 days; range, 14 to 27, in the originator group, P ¼ 0.7). No TRM was observed in either group.
Discussion Mobilization of PBSCs by G-CSF has largely replaced bone marrow collection for ASCT due to ease of collection, avoidance of general anesthesia and more
rapid recovery of blood counts [22]. Consensus is lacking on the use of CSF in the post-transplant setting. G-CSF administration after high-dose chemotherapy and ASCT has been shown to expedite neutrophil recovery in randomized trials and results are mixed on the impact of G-CSF on duration of hospital stay, infections and survival [23e25]. The use of biosimilar G-CSF for PBSC mobilization and neutrophil recovery after ASCT has stimulated an ongoing debate regarding their efficacy and safety. Although there are few published data regarding their use in these contexts, biosimilars of G-CSF were approved by the European Medicines Agency for all the registered indications of the originator G-CSF including mobilization of stem cells. Nevertheless, most scientific societies still recommend not applying biosimilar G-CSF in the autologous setting before adequate scientific validation (Consensus Conference
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M. Martino et al.
Figure 3. Number of apheresis sessions in biosimilar G-CSF and originator G-CSF groups.
on Biosimilar Growth Factors of the Italian Society of Hematology and Gruppo Italiano trapianto Midollo Osseo) [26]. The published studies are heterogeneous and low-powered [27e31], and, in this context, our study contributes to the growing body of evidence in support of efficacy of G-CSF biosimilars. To our knowledge, this study represents one of the largest and homogeneous undertaken so far on this issue. The study sample is extremely homogeneous for MM diagnosis and therapy of mobilization (Cy 4 gr/ m2). Moreover, it should be emphasized that MM is the condition in which ASCT is most used worldwide and therefore where therapy with growth factors find widespread use, both as a mobilization agent and in post-transplant therapy. Its sequential, although not randomized, nature should minimize the bias related to the use of historic controls. Our data suggest that biosimilar and originator filgrastim are similarly effective for the mobilization and collection of CD34þ progenitor cells when used with the same schedules and doses. CD34þ stem/ progenitor cell collection correlates with the absolute number of circulating CD34þ cells before apheresis, and the aim of an optimal apheresis procedure is to achieve the target CD34þ cell dose with the lowest number of procedures. In this regard, the median peak peripheral blood count for CD34þ cells before leukapheresis and the median total CD34þ/kg yield collected were similar between the study group and the control group. The proportion of PBSC mobilization failures and the median number of apheresis procedures were also comparable between groups.
The number of leukapheresis sessions required to reach the target of CD34þ8 106/kg was superior with the biosimilar compared with the originator GCSF, although at the limit of statistical significance. The frequency and the severity of side effects such as headache and/or bone pain observed in the biosimilar group were comparable to the originator group and to other published studies of G-CSF at 5 and 10 mg/kg per day doses [32]. Sivgin et al. [28] retrospectively analyzed data of 96 patients who underwent ASCT diagnosed with MM, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma and others. The authors showed that the biosimilar filgrastim administered after chemotherapy was equivalent to originator for mobilization and PBSC collection when used with the same schedules and doses. Lefrere et al. [27], in a prospective study, compared filgrastim with biosimilar filgrastim in autologous PBSC mobilization and showed that no significant differences were observed between groups in terms of the median number of CD34þ cells mobilized and collected, nor in the number of G-CSF injections and leukaphereses required to obtain the minimal CD34þ cell count. Moreover, the study showed that biosimilar G-CSF could provide a more cost-effective strategy. In a recent published study [29], after administration of mobilizing regimens [primarily high-dose etoposide, high-dose Cy, intermediate-dose cytosine arabinoside (Ara-C) or ESHAP regimens], patients with MM, non-Hodgkin’s lymphoma, Hodgkin’s lymphoma or other diagnosis were randomly assigned to a standard daily 10 mg/kg dose of biosimilar G-CSF
Biosimilar G-CSF and stem cell mobilization
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Table III. Outcome and hematopoietic recovery in multiple myeloma patients receiving biosimilar or originator G-CSF after autologous transplantation. Variable No. patients (%) CD34þ cells (10E6/kg) infuseda No. of erythrocyte transfusions (units)a No. of platelet transfusions (units)a Engraftment (days after transplant)a Days to reach neutrophils >0.5 109/L Days to reach platelets >20 109/L Fever 38.2 C, No. (%) No Yes Fever origin, No. (%) FUO CVC-related Clinically documented Microbiologically documented infection No. of days of fever 38.2 Ca No. of days antibiotic on therapya Mucositis Grade 0e2, No. (%) Grade 3e4, No. (%) Hospitalization duration, days, median (range) a
Biosimilar G-CSF 29 4.9 0 1
(100) (2.3e9.0) (0e3) (0e3)
Originator G-CSF 28 5.0 0 0.5
(100) (2.3e7.0) (0e3) (0e4)
11 (9e12) 13 (10e16)
11 (9e15) 13 (10e19)
16 (55.2) 13 (44.8)
10 (35.8) 18 (64.2)
P value 0.37 0.93 0.27 0.57 0.69 0.095
0.1 11/13 1/13 1/13 0/13 1 1
(84.6) (7.7) (7.7) (0) (0e5) (0e8)
27 (93.1) 2 (6.9) 18 (15e30)
14/18 0/18 1/18 3/18 1.5 5
(77.8) (0) (5.6) (16.6) (0e9) (0e12)
27 (96.4) 1 (3.6) 18 (14e27)
0.13 0.07 0.06
0.7
Values are expressed as median and range.
or originator G-CSF. Both groups had a median of one apheresis with a median time until first apheresis of 11 days. There were no statistically significant differences between groups in the mean number of mobilized CD34þ cells/mL in peripheral blood or the number of CD34þ cells/kg body weight. Recently, Schmitt et al. [30] summarized the currently available data through the use of biosimilar G-CSF for stem cell mobilization. A total of 904 patients mostly with hematological malignancies as well as healthy donors underwent successful autologous or allogeneic stem cell mobilization, respectively, with the use of a biosimilar G-CSF (520 with Ratiograstim/ Tevagrastim, 384 with Zarzio). The indication for stem cell mobilization in hematology patients included 326 patients with MM, 273 with non-Hodgkin’s lymphoma, 79 with Hodgkin’s lymphoma and other diseases. A total of 156 sibling or volunteer unrelated donors were mobilized with the use of biosimilar GCSF. Mobilization resulted in good mobilization of CD34þ stem cells with side effects similar to originator G-CSF. Post-transplantation engraftment did not significantly differ from results previously documented with the originator G-CSF. The side effects experienced by the patients or donors mobilized by biosimilar G-CSF were minimal and were comparable to those of originator G-CSF. In terms of neutrophil recovery, several studies showed the non-inferiority of biosimilar filgrastim in febrile neutropenia prophylaxis and hematological recovery after ASCT when compared with the other non-pegylated G-CSF formulations [31,33e37].
Gascon et al. [17] conducted a pooled analysis of five post-approval studies of biosimilar G-CSF that included 1302 adult patients who received at least one cycle of chemotherapy with G-CSF support for the prevention of neutropenia to assess whether biosimilars are effective in the real-world clinical practice setting. Overall, 36% of patients had a febrile neutropenia risk of >20%, whereas 39.6% had a risk of 10% to 20%, based on the chemotherapy regimen used. The occurrence of severe or febrile neutropenia was within the range of that observed in previous studies of originator G-CSF. In addition, the safety profile of biosimilar G-CSF was consistent with that reported for originator G-CSF and the known safety profile of G-CSF. In our study, we did not observe any differences in terms of engraftment and toxicity after transplantation. However, the two cohorts were relatively small, and this could limit the utility of these data. In conclusion, the efficacy of biosimilar GCSFs, in terms of PBSC yield and their relative toxicity profiles, appears to be equivalent to the reference G-CSF. However, until results from multicenter randomized, clinical trials that directly compare biosimilar G-CSFs with the originator G-CSF are reported, it is important to collect and summarize all of the available clinical experience with these agents to allow the transplant community to make informed decisions regarding the choice of G-CSF. More importantly, overall these data contribute to reduce initial unfounded concerns on the use of biosimilar G-CSF, allowing the reduction
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of healthcare costs, and ultimately improving patient access to biological treatments.
[14]
Disclosure of interests: The authors have no commercial, proprietary, or financial interest in the products or companies described in this article. [15]
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