Abstract
Background
In the Middle East, there is lack of data on peripheral blood CD34+stem cells mobilization by using biosimilar filgrastim. We have been using both Neupogen and a biosimilar G-CSF) Zarzio® (as a mobilizing agent since February 2014 for both allogenic and autologous stem cell transplantations.
Material/Methods
This was a single-center retrospective study. All patients and healthy donors who received either the biosimilar G-CSF (Zarzio®) or original G-CSF (Neupogen®) for mobilization of CD34+ stem cells were included in the study. The primary goal was to determine and compare the rate of successful harvest and amount of CD34+ stem cells collected in either adult cancer patients or healthy donors between Zarzio® and Neupogen® groups.
Results
A total of 114 patients, including 97 cancer patients and 17 healthy donors, underwent successful CD34+ stem cell mobilization using G-CSF with chemotherapy (35 with Zarzio® +chemotherapy, 39 with Neupogen® +chemotherapy) or G-CSF as monotherapy (14 with Zarzio®, 9 with Neupogen®) in autologous transplantation. In an allogeneic stem cell transplantation, successful harvest was achieved by using G-CSF monotherapy (8 with Zarzio®, 9 with Neupogen®). There was no difference between Zarzio® and Neupogen® in the amount of CD34+ stem cells collected at leukapheresis. There was no difference with regards to secondary outcomes between the 2 groups.
Conclusions
Our study showed that biosimilar G-CSF (Zarzio®) has comparable efficacy to the original G-CSF (Neupogen®) when used for mobilization in both autologous and allogenic stem cell transplantation and was associated with significant cost saving.
Keywords: Biosimilar Filgrastim, Zarzio, Neupogen, CD34+ Mobilization, Stem Cell Transplantation
Background
Hematopoietic stem cell transplantation (HSCT), either autologous or allogenic, provides a curative therapy for various hematological malignancies. The most widely used source for HSCT is peripheral blood stem cells (PBSCs). Autologous HSCT uses hematopoietic peripheral blood stem cells collected from patients and is widely used to treat many kinds of hematologic neoplasms. Allogenic HSCT uses hematopoietic PBSCs that are collected from healthy donors, not from patients. Mobilization of PBSCs (CD34+ stem cells) is successfully attained using a granulocyte-colony stimulating factor (G-CSF) alone or in combination with chemotherapy. The original G-CSF (Neupogen®) is widely used as a mobilizer of CD34+ stem cells among healthy donors in allogenic stem cell transplants or among cancer patients in autologous stem cell transplants as a standard of care [1]. Alternatively, biosimilar filgrastim (G-CSF) can be used instead of originator filgrastim. A biosimilar is highly similar to but not identical in quality, safety, and efficacy to the originator, which is already a licensed reference biotherapeutic product [2]. Biosimilars’ approval is attained based on comparable quality, safety, and efficacy data to the originator rather than on the basis of a positive risk-benefit assessment, which has already been done with the originator [2]. Various biosimilars of G-CSF have been widely used in Europe since 2009 after receiving approval from the European Medicines Agency (EMA) in 2008 and were recently approved by the US Food and Drug Administration (FDA) for the same indication as that of Neupogen®. They are intended to decrease the incidence of infection‚ as manifested by febrile neutropenia‚ in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a significant incidence of severe neutropenia with fever. They also reduce the time to neutrophil recovery and the duration of fever following induction or consolidation chemotherapy treatment for patients with acute myeloid leukemia (AML) and reduce the duration of neutropenia and neutropenia-related clinical sequelae (eg‚ febrile neutropenia) in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by blood marrow transplantation (BMT); to mobilize autologous hematopoietic peripheral blood stem cells into the peripheral blood for collection by leukapheresis; and to reduce the incidence and duration of sequelae of severe neutropenia (eg‚ fever‚ infection‚ oropharyngeal ulcers) in symptomatic patients with congenital neutropenia‚ cyclic neutropenia‚ or idiopathic neutropenia. Zarzio® was the first biosimilar, approved by the USFDA in 2015 [1,3]. Biosimilar Filgrastim (Zarzio®) has been used in the Princess Norah Oncology Centre since 2015 for peripheral blood progenitor cells mobilization for healthy donors and cancer patients, as well as mobilization for both types allogenic and autologous stem cell transplantation for many types of cancer.
Material and Methods
This was a single-center retrospective study conducted in Princess Nora Oncology Center, King Abdulaziz Medical City, Jeddah, Saudi Arabia. The study was approved by the IRB office of King Abdullah International Medical Research Center on April 16, 2019, with a study number RJ19/048/J received through a memo reference number IRBC/0544/19. All transplant-eligible patients at Princess Nourah Oncology Centre who attempted for PBSC collection from June 1, 2016 through December 31, 2018 were enrolled in the study. All patients older than 14 years who received either the biosimilar filgrastim (Zarzio®) or filgrastim (Neupogen®) were included in the study (n=97). In addition, all healthy donors older than 9 years who received either the biosimilar or originator filgrastim were included in the trial (n=17). Demographics, types of transplants (allogeneic or autologous), anthropometrics, concurrent chemotherapy, duration of G-CSF administration and rescue medication (plerixafor), and laboratory parameters (eg, CD34+ enumeration count and number of leukapheresis sessions) were collected for each patient enrolled in the study. We enrolled all patients or donors who received filgrastim either the Neupogen® or Zarzio® 10 mcg/kg/day as a monotherapy or 5 mcg/kg/day subcutaneous injection if used in combination with chemotherapy to enhance peripheral blood mobilization. In our institution filgrastim is administered for at least 4 days before the first leukapheresis and then continued until the last leukapheresis when filgrastim is used as monotherapy for mobilization of stem cells. The choice of combined mobilization regimen with chemotherapy depends on the type of cancer. For example, cyclophosphamide is used for multiple myeloma patients on day 1, then filgrastim is given from day 5 until collection. ESHAP or R-ESHAP is used for lymphoma from days 1–5, then filgrastim is given from day 6 until collection. The choice of which brand to be used in a mobilization regimen depends on the dose of the filgrastim. We use biosimilar G-CSF Zarzio® as a mobilization regimen if the dose is in the multiple of 300 mcg because the Zarzio® prefilled syringe is not calibrated. However, if the dose of G-CSF required for mobilization is below or above 300 mcg, then we use Neupogen® because the vial is calibrated. The goal of the collection for all patients and healthy donors was to obtain the minimum quantity of CD34+ that should be ≥2×106 cells/Kg body weight. We monitored peripheral blood CD34+ enumeration cell count and we used pre-emptive plerixafor if the peripheral CD34+ count was <10/μl at maximum stimulation after chemo-mobilization and <8/μl on day 4 of filgrastim mobilization. Between 10 and 15/μl suggests a “dynamic approach” with case-by-case decision-making. Calcium gluconate was given as infusion prophylactically to decrease the risk of citrate effects.
Outcomes
The primary outcome was to achieve successful harvest, defined as collection a minimum of 2×106/kg CD34+ cells. Secondary outcomes were time in days to achieve neutrophil and platelet engraftment. Neutrophil engraftment was considered complete when the absolute neutrophil count (ANC) was equal to or greater than 0.5×109/L for 3 consecutive days after infusion of PBSCs, whereas platelet engraftment was considered complete when the platelet count was 20×109/L or more for 7 consecutive days without platelet transfusion. We compared the safety of filgrastim (Zarzio®) versus Neupogen® in terms of allergic reaction and pain, number of leukapheresis sessions, and we compared the rescue use of plerixafor in both groups and the impact of biosimilar filgrastim (Zarzio®) in terms of cost savings.
Statistical Analysis
Descriptive analysis was done using SPSS software. The data are represented as median and percentage. All statistical analysis was completed using SPSS software version 23 and Excel 2019.
Results
Baseline Characteristics
A total of 114 patients, including 97 cancer patients, most of whom had Hodgkin lymphoma (n= 45), multiple myeloma (n=29), or other hematological leukemia (n=14), and 17 healthy donors, underwent mobilization from February 1, 2014 to December 31, 2018. In autologous transplantation, 49 patients received Zarzio® while 48 patients received Neupogen®. In the allogenic setting, 8 healthy donors received Zarzio® while 9 healthy donors received Neupogen®. Baseline characteristics were comparable in both groups (Table 1).
Table 1.
Patient characteristics.
| Overall | Zarzio® | Neupogen® | ||
|---|---|---|---|---|
| Autologous | Number of patients | 97 | 49 (51%) | 48 (49%) |
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| Male | 59 (61%) | 28 | 31 | |
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| Female | 38 (39%) | 21 | 17 | |
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| Age | 37 (16–65) | 37 (16–65) | 39 (21–63) | |
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| Diagnosis | ||||
| MM | 29 | 15 | 14 | |
| HL | 45 | 24 | 21 | |
| DLBCL | 11 | 7 | 4 | |
| Other | 12 | 4 | 8 | |
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| Chemotherapy + filgrastim | 74 | 35 | 39 | |
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| Monotherapy | 623 | 14 | 9 | |
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| Allogenic | Number of patients | 17 | Allogenic Stem cell transplant patients did not receive any G-CSF as G-CSF was received by healthy donors for mobilization of stem cells and their details are mentioned below in front of healthy donors | |
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| Male | 6 (35%) | |||
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| Female | 11 (65%) | |||
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| Age | 37 (16–59) | |||
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| Diagnosis | ||||
| ALL | 4 | 1 | 3 | |
| AML | 10 | 6 | 4 | |
| Other | 3 | 1 | 2 | |
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| Healthy donors | Number of donors | 17 | 8 | 9 |
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| Male | 10 (59%) | 2 | 8 | |
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| Female | 7 (41%) | 6 | 1 | |
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| Age | 33 (9–52) | 38 (18–47) | 27 (9–52) | |
Successful Mobilization
Ninety-seven cancer patients underwent successful CD34+ stem cell mobilization using G-CSF with chemotherapy (35 with Zarzio® +chemotherapy, 39 with Neupogen® +chemotherapy) or G-CSF as monotherapy (14 with Zarzio®, 9 with Neupogen®) in autologous transplantation. For allogeneic stem cell transplantation, successful harvest was achieved by using G-CSF monotherapy (8 with Zarzio®, 9 with Neupogen®). The mobilization success was similar across both groups, and the use of rescue plerixafor was similar across both groups in the autologous transplant setting. Plerixafor was used for 2 patients in the Zarzio® group and 2 patients in the Neupogen® group (Table 2).
Table 2.
Mobilization results.
| Parameters | Zarzio® | Neupogen® | P value | |
|---|---|---|---|---|
| Autologous | Time to successful harvest | |||
| Filgrastim + chemotherapy | 14 | 15 | 0.477 | |
| Filgrastim | 5 | 5 | 0.657 | |
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| CD34+ ×106/kg | ||||
| Filgrastim + chemotherapy | 5 | 5.5 | 0.641 | |
| Filgrastim | 3.76 | 4.44 | 0.214 | |
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| Allogeneic (healthy donors) | Time to successful harvest | 4 | 4 | 0.576 |
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| CD34+ ×106/kg | 6.445 | 6 | 0.347 | |
Harvest and Leukapheresis Results
There was no difference between Zarzio® and Neupogen® in the amount of CD34+ stem cells collected at leukapheresis. The total CD34+ stem cells collected with chemotherapy in autologous were 5×106/kg Zarzio® vs 5.5×106/kg Neupogen® (p=0.64); the total CD34+ stem cells collected using G-CSF as monotherapy in autologous stem cell transplants were 3.76×106/kg Zarzio® vs 4.44×106/kg Neupogen® (P=0.21) (Figure 1). In allogeneic stem cell transplant, the total CD34+ stem cells collected were 6.4×106/kg Zarzio® vs 6×106/kg Neupogen® (p=0.34) (Figure 2). Results of the successful harvest are shown in Table 2. In both groups, the median number of apheresis sessions was similar.
Figure 1.
Amount of CD34+ cells in autologous SCT. Created using SPSS software version 23.
Figure 2.
Amount of CD34+ cells in allogenic SCT. Created using SPSS software version 23.
Engraftment Results
There was no difference in median time to achieve neutrophil and platelet engraftment between the groups, as shown in Table 3.
Table 3.
engraftment results.
| Parameters | Zarzio® | Neupogen® | P value | |
|---|---|---|---|---|
| Autologous | Neutrophil engraftment | |||
| Filgrastim + chemotherapy | 10 | 11 | 0.83 | |
| Filgrastim | 10 | 10 | 0.657 | |
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| Platelet engraftment | ||||
| Filgrastim + chemotherapy | 12 | 13 | 0.239 | |
| Filgrastim | 12 | 12 | 0.657 | |
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| Allogeneic (patients) | Neutrophil engraftment | 13.5 | 14 | 0.62 |
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| Platelet engraftment | 13.5 | 14 | 0.62 | |
Safety and Cost Profile
There were no allergic reactions observed in either group. Two patients in the Neupogen® group and 1 patient in the Zarzio® group received analgesics for bone pain. Hence, safety issues regarding allergic reactions and bone pain were comparable in both groups. The total direct cost of Zarzio® was 3 times less than that of Neupogen®. The price of Neupogen® was 450 SAR/vial before the addition of Zarzio®, and then reduced to 225 SAR/vial after Zarzio® was added to the formulary in 2014. The price of Zarzio® was 96 SAR/vial when introduced to our formulary. We would have spent SAR 180 000 had we used Zarzio® in all 114 patients as mobilizing agent vs 600 000 SAR if only Neupogen® had been used in all 114 patients as the mobilizing agent. The use of biosimilar filgrastim reduces healthcare expenditure without affecting patient outcomes.
Discussion
Biosimilar products are generally approved based on the clinical trials in one indication and then extrapolation is used to include the other indications of the originator based on the totality of the evidence gained from one indication. Hence, there might be some concerns regarding the long-term evaluation of biosimilars, particularly the limited experience with these products in terms of efficacy, safety, and immunogenicity at the time of approval [4,5]. For instance, use of biosimilar filgrastim (Zarzio®) in mobilization of CD34+ve stem cells in both allogenic and autologous stem cell transplant patients is an extrapolated indication. Therefore, there is need to have more real-world evidence studies to confirm the biosimilarity of biosimilar products. Our hospital was the first center in the Kingdom of Saudi Arabia to start using biosimilar filgrastim (Zarzio®) in mobilization of CD34+ve stem cells in both allogenic and autologous stem cell transplant patients. Many centers are still using originator filgrastim (Neupogen®) for mobilization of stem cells in autologous stem cell transplant patients and healthy donors. Therefore, this was an innovative study in this part of the world and outcomes of the study are likely to gain the confidence of health care professionals and change practice in the region.
Few trials have proven the efficacy and safety of biosimilar filgrastim with the originator filgrastim used for mobilization of PBSCs in both autologous SCTs and allogenic SCTs. However, for allogenic SCTs, there has been no significant use of biosimilar filgrastim, particularly in the Middle East, due to lack of long-term safety data [6]. An Italian trial evaluated the effectiveness of originator (Neupogen®) and biosimilar (Zarzio®) filgrastim in autologous peripheral blood stem cell mobilization in adult patients with acute myeloid leukemia for mobilization [7], but our study evaluated Zarzio® vs Neupogen® for mobilization CD34+ in both autologous and allogenic SCTs with different types of cancer patients. The present study has the largest sample of both cancer patients and healthy donors to date, particularly in the Middle East. In our trial, there were no significant differences in the harvest of total CD34+ stem cells across groups. Additionally, there were no significant differences in the time to achieve neutrophil and platelet engraftment across both groups. Pham et al found no significant differences between biosmilar Nivestim® and Zarzio® and Neupogen® for peripheral stem cells moblization, but did find a delay in platlet recovery in autologus stem cell transplantation [8]. Antelo et al studied allogenic SCT and found no significant differences in the collection of the CD34+ stem cells between Zarzio® and Neupogen®, but the engraftment results were comparable between groups. This trial of total of 35 healthy donors supports the safety of Zarzio® but was not equally effective as originator Neupogen® [9]. The CD34+ was 6.7×106 in the Zarzio® group whereas the CD34+ was 8.4×106 in the Neupogen® group (P=0.04). There were 3 donors who failed to achieve optimum cell mobilization in the Zarzio® group, whereas no donors failed in the Neupogen® group. More prospective trials are needed to support the effectiveness of biosimilar filgrastim as a mobilizing agent. Becker et al published a large trial including 244 healthy donors in 2 centers, supporting use of Zarzio® for mobilization for healthy donors in allogenic SCT. There were no significant differences between Zarzio® and Neupogen® in the collection of CD34+ stem cells and safety issues [10]. Moreover, Schmitt et al published a metanalysis which also showed that there was no significant difference in mobilization and engraftment between Zarzio® and Neupogen® in a study of a total 1892 persons including 351 healthy donors in both autologous and allogenic SCT [11]. Our trial supports the use of biosimilar filgrastim in mobilization both in cancer patients and in healthy donors.
Using biosimilar requires stringent pharmacovigilance efforts to monitor any adverse effects found for patients and healthy donors to support the safety of biosimilar. Many previous trials found that the adverse effects and tolerability were comparable between the innovator and biosimilar Zarzio® [9–13]. In our study, we found that there were no significant differences in adverse effects regarding back and bone pain and allergic reactions.
Khan et al reported that the cost saving since 2014 after addition of biosimilar Zarzio® in the formulary was approximately 60 million SAR at the Ministry of National Guard Health Affairs, Saudi Arabia [14]. We found that using biosimilar filgrastim reduces healthcare expenditure without affecting patient outcomes.
Limitations
This was a single-center retrospective study.
Conclusions
Biosimilar G-CSF (Zarzio®) has comparable efficacy to the original G-CSF (Neupogen®) when used for mobilization in both autologous and allogenic stem cell transplantation and was associated with significant cost saving. Further prospective comparisons are needed.
Footnotes
Conflict of interest: None declared
Declaration of Figure’s Authenticity
The authors created all the figures submitted and we also confirm that the images are original with no duplication and have not been previously published in whole or in part.
Financial support: None declared
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