Despite biosimilars of the granulocyte-colony stimulating factor (G-CSF) filgrastim being approved by the European Medicines Agency since 2008, there is still some debate regarding their use in related and unrelated healthy haematopoietic stem cell donors. We present a review of published experiences using biosimilar filgrastim for healthy donor mobilisation as well as the results of a survey by the World Marrow Donor Association (WMDA) of its current use by register-associated transplant and collection centres for both related and unrelated donors. A total of 1287 healthy donors and volunteers are included in the reviewed studies. The pharmacokinetics and pharmacodynamics studies show a high degree of similarity to the reference product Neupogen. Mobilisation of CD34 + cells as well as reported adverse events are also found to be comparable, although there is still a lack of long-term follow up for both Neupogen and filgrastim biosimilars. No evidence is found of a higher risk of filgrastim antibody formation using filgrastim biosimilars. Based on this increased experience, the WMDA therefore recommend that Stem Cell Donor Registries can use filgrastim biosimilars for the mobilisation of peripheral blood progenitor cells in healthy donors, provided that they are approved by national and/or regional agencies.
A biosimilar medicine is a biological medicine highly similar, but not identical to, an already approved biological medicine, the reference product. In 2008, the European Medicines Agency (EMA) approved the first biosimilar for healthy donor stem cell mobilisation, the Granulocyte-Colony Stimulating Factor (G-CSF) filgrastim XM02, manufactured by SICOR Biotech UAB, Vilnius, Lithuania, and marketed as Ratiograstim (Ratiopharm GmbH) or Tevagrastim (Teva GmbH). The reference product for all filgrastim biosimilars is Neupogen (Amgen, Vienna, Austria). Currently there are seven biosimilar filgrastim brands, from four manufacturers, centrally approved by the EMA for mobilisation of peripheral blood progenitor cells in healthy donors, as detailed in Table 1. Neupogen, as well as all of the approved filgrastim biosimilars, is produced in E. coli cells transformed with recombinant G-CSF DNA. The resulting 175 amino acid sequence is identical to that of natural human G-CSF, except for the addition of an N-terminal methionine necessary for the expression in E. coli and that it is not glycosylated.
The authorisation of biosimilar medicines by the EMA is based on a demonstrated biosimilarity defined as ‘high similarity in terms of structure, biological activity and efficacy, safety and immunogenicity profile’ , and the approval process follows specific guidelines for assessing similarity [2, 3].
Similarly, since 2010 there has existed an ‘abbreviated licensure pathway’ in the USA for biosimilar drugs, detailed in the Biologics Price Competition and Innovation Act, part of the Patient Protection and Affordable Care Act [4, 5]. In 2015, the Sandoz filgrastim biosimilar, under brand name Zarxio, was approved by the U.S. Food & Drug Administration (FDA) for all indications of the reference product Neupogen, including mobilisation of stem cells in autologous stem cell donors, although not with an indication for allogeneic donors. There is currently no FDA-approved biosimilar G-CSF with indication for mobilisation of allogeneic stem cell donors , although previously Neupogen has been used in the USA for healthy donor stem cell mobilisation outside of FDA-licensed indications, usually under an Investigational New Drug permission .
There have, however, been some concerns that biosimilar filgrastim may exhibit relevant differences in clinical efficacy, adverse events and immunogenicity compared to Neupogen [8, 9]. The World Marrow Donor Association (WMDA) is a global association currently representing 72 blood stem cell donor registries and 25 cord blood bank registries from 52 different countries. In order to further the interests of blood stem cell donors, and the safe exchange of blood stem cells for clinical transplantation, the WMDA issues guidelines, opinions and scientific reports on matters concerning blood stem cell donation [10, 11]. A position paper regarding the use of biosimilar drugs in healthy donors was published in 2011, with a recommendation that ‘biosimilars not be used for mobilisation in normal donors unless the donor is followed on a study’, due to insufficiencies in data on safety and long-term follow up. Almost no published post-marketing experience was available at the time . Similar positions were also taken by the European Society for Bone and Marrow transplantation (EBMT) , and by national associations in Austria, Italy and Japan [13,14,15]. Since these statements there has been an increased experience of the use of biosimilars, both for autologous and allogeneic donor stem cell mobilisation, warranting a revision of previous recommendations.
We present an update on the published experiences of the use of biosimilar filgrastim for the mobilisation of stem cells in healthy donors and the results of a survey of past and current G-CSF use among WMDA centres.
Materials and methods
Review of published reports
A search for published reports of use of biosimilar filgrastim for stem cell mobilisation in healthy donors was performed, using the database pubmed.org, the EMA European Public Assessment Reports for each registered biosimilar, as well as the annual meetings abstract books for the European Society for Blood and Marrow Transplantation (EBMT) and the American Society of Hematology (ASH) for the years 2008–2016. Only English-language, peer-reviewed journals were included, alongside abstracts with results not published in manuscript form.
Survey of WMDA centres
A survey was sent to all, 64 at the time of the survey, WMDA-associated registries (www.wmda.info). The survey was completed by representatives of 33 donor registries from Europe, North America, Asia and the Caribbean, as well as from South Africa and Israel. The number of transplant and collection centres associated with each register ranged from one to more than twenty.
Registers were asked to provide information on
What brand of G-CSF that was currently being used by the registers affiliated centres for mobilisation of stem cells in unrelated and related donors
If since 2013 they had made, or were planning to make, a change of G-CSF brand, and, if so, the reasons for changing.
Review of published studies
Our search of the above data sources revealed fifteen peer-reviewed journal publications with data on healthy donor mobilisation using biosimilar filgrastim, as well as two peer-reviewed abstracts containing data not otherwise reported, as outlined in Tables 2a and 2b. Study results for Grastofil/Accofil were not found in any peer-reviewed journal but were drawn from the EMA European Public Assessment Report (EPAR). Mobilisation results and, where available, data on engraftment in recipients, are summarised in Table 3.
Zarzio is the most studied biosimilar filgrastim, with published data from the mobilisation of stem cells in 113 related and 476 unrelated donors.
Gascon et al. in 2010 reported on four randomised, double-blind crossover phase1 studies, EP06-101, 102, 103 and 105, comparing Zarzio with Neupogen. In total, 146 unrelated healthy volunteers were treated with filgrastim 1 to 10 µg/kg/day with 68 of those donors receiving 5 or 10 µg/kg/day for seven consecutive days. Results were considered equivalent both in terms of pharmacokinetics, pharmacodynamics and safety, with no Serious Adverse Events (SAE) registered. No development of neutralising antibodies was observed in biosimilar-treated subjects. The studies were included as part of the documentation for EMA registration .
Azar et al., in an abstract at EBMT 2012, reported on 21 healthy related donors treated with Zarzio 10 µg/kg/day for 4 days. For eleven donors one apheresis was sufficient, nine performed two, and for one donor a third apheresis was needed. The day 5 median CD34 + cell count/μL was 72 (range 16–145). Apart from bone pain, no other adverse events were reported and the result were judged consistent with previous experiences using Neupogen .
In an abstract at ASH 2013, Lefrere et al. compared 26 healthy related donors, treated with filgrastim 10 µg/kg/day for 5 days, with matched historical controls. CD34 + cell count on day 5, CD34 + cells per recipient body weight, and time to three-lineage engraftment were found to be similar. Occurrence and intensity of bone pain was also reported as similar between groups, but no data on other adverse events were provided .
Sörgel et al. in 2015 reported on a randomised crossover study of 28 healthy volunteers comparing a 10 µg/kg single dose of Zarzio with Neupogen. No differences were seen in pharmacokinetics or pharmacodynamics, with similar mobilisation of CD34 + cells (5.8 cells/µL for Zarzio vs 5.5 for Neupogen), and no antibodies to the biosimilar were detected .
Uddin et al. in 2015 published a retrospective single-centre study of 47 related donors treated with Zarzio 5 µg/kg/day for 7–8 days. A mean CD34 + cell count of 6.1 × 106 per kg recipient weight was obtained at the first apheresis, with thirteen donors requiring two aphereses and four donors needing three aphereses. The median time to absolute neutrophil count recovery was 16 days (range: 10–28 days) and for platelet recovery 13 days (range: 9–54 days) .
A 2016 retrospective, observational single-centre study by Antelo et al., comparing 36 related donors treated with either Zarzio or Neupogen, found a higher yield of collected CD34 + cells per kg recipient weight with Neupogen (median 8.4 × 106 vs 6.7 × 106). No SAEs were registered and both engraftment (neutrophils > 0.5 and platelets > 20 both at a median of days), as well as recipient GVHD-development, with 29.4% acute GVHD grade II–IV for Zarzio, was found comparable between substances .
Also in 2016, Becker et al. presented findings from the EP05-601 study (clinicaltrails.gov, id NCT01766934), the largest study published to date of any biosimilar filgrastim for healthy donor stem cell mobilisation. A total of 245 healthy unrelated volunteer donors were treated with Zarzio 10 µg/kg/day for 4–5 days. More than 4 × 106 CD34 + cells per kg recipient weight were collected from all but three donors in two aphereses, and for 91 percent, one apheresis was sufficient. Serious Adverse Events (SAEs) possibly or probably related to biosimilar-treatment were registered for five donors (2%). Engraftment data were reported for 144 transplants with 98% primary engraftment; median neutrophil, erythrocyte and platelet engraftment on day 17, 20 and 14, respectively and any GVHD reported by 56% of recipients by Day + 100. Results were judged comparable to those previously published for Neupogen .
In 2017, Farhan et al. reported on a retrospective single-centre study of 85 unrelated donors treated with biosimilar filgrastim, compared with 107 treated with Neupogen and 121 with Granocyte. A similar number of CD34 + cells per kg recipient weight was collected for all three drugs. For all donors more than 2 × 106 CD34 + cells per kg recipient weight was collected in one or two aphereses, with more donors needing two apheresis after Granocyte than filgrastim (13 vs 7%, p = 0.005). The study did not include any data on adverse events for either drug .
Results of stem cell mobilisation with Ratiograstim/Tevagrastim have been published for 35 related and 200 unrelated donors.
Lubenau et al. in 2009 reported on two randomised phase 1 single-dose crossover studies (XM02-01-DE/ XM02-05-DE), that were part of the EMA registration documentation for Ratiograstim and Tevagrastim. In total, 200 healthy unrelated volunteers were treated with a single dose of XM02, 5 or 10 µg/kg, and the results were compared to Neupogen. Similar pharmacokinetic and pharmacodynamics profiles, as well as blood CD34 + cell counts and adverse events after stimulation, were found [23, 24].
Schmitt et al. (2013) published data from a prospective single-centre study (trial no. ISRCTN94372129) comparing 11 related donors treated with XM02 10 µg/kg/day for 4 days with 11 donors treated with Neupogen. No statistically significant differences were seen in the number of collected CD34 + cells per kg recipient weight, the number of aphereses or the time necessary for three-lineage engraftment .
In 2016 Danylesko et al., published data from a prospective clinical trial (trial no. NCT01542944) of 24 healthy sibling donors treated with XM02 (Tevagrastim) 10 µg/kg for 4 days, compared to historical controls treated with Neupogen. A median of 10.2 × 106 (range 2.5 to 35.4) CD34 + cells per kg recipient weight was collected after a mean number of 1.3 aphereses, not differing significantly from controls. They found adverse events in the XM02-treated donors similar to those reported for Neupogen, and no grade 3 or 4 toxicities where observed. Platelets >50 × 109/L and neutrophils >0.5 × 109 were reached after a median of 17 and 13 days, respectively .
There are no reports available from peer-reviewed journals on the results of the registration studies (KWI-300-101 to 103 and GCSF-SUIN-05SB01-3FA) for Grastofil/Accofil (also known as Apo-filgrastim), but the results have been published by the EMA, and are publicly available in the European Public Assessment Report for Grastofil. Studies included 146 healthy volunteers treated with single doses of 1–5 µg/kg filgrastim, and 35 treated with 5 µg/kg/day for 4 days. In the report, the pharmacokinetics, pharmacodynamics, adverse events and mobilisation results are found to be highly similar to those of Neupogen. No filgrastim antibodies were detected in the studies .
Matsuguma et al. (2015) published a randomised crossover study of 42 Japanese males treated with 400 µg/m2 of filgrastim biosimilar FSK0808 and Neupogen (marketed as Gran in Japan) for 5 days. A similar mobilisation of CD34 + cells and neutrophils into peripheral blood was found, measured as absolute maximum concentrations and ‘area under the curve’ after administration of G-CSF. No adverse reaction greater than grade 1 was observed and adverse reactions were reported to be similar between the substances .
Crobu et al. (2014) published results from a randomised phase-1 crossover study of BK0023 ((Bio-Ker S.r.l., Italy) compared with Neupogen. One hundred healthy volunteers were treated with five to 7 days of the biosimilar at doses 2.5–10 µg/kg/day. Adverse events were comparable, as were results of pharmacokinetic and pharmacodynamic studies, with a mean maximum blood CD34 + cell count per µl for the 10 µg/kg dose, ± a standard deviation of 93.4 ± 35.3 vs 95.4 ± 42.6 .
Sivgin et al. (2016) presented a retrospective analysis of 14 donors treated with Leucostim (Dong-A filgrastim, Dong-A Pharm., Seoul, Korea) compared with 201 donors treated with Neupogen and 28 treated with Granocyte. The median number of collected CD34 + cells per kg recipient weight after biosimilar treatment was 7.27 × 106 (range 6.79–7.55) and the median number of days to platelet and neutrophil engraftment was 14 (range 13–17) and 17 (range 15–20), respectively, which was not different from Neupogen.
Waller et al. (2010) published results from a single-centre, phase 1 crossover pharmacodynamic and safety study of 50 healthy volunteers, comparing Nivestim 5 or 10 µg/kg/day for 5 days with Neupogen at equivalent doses (study no. GCF062). Mean blood CD34 + cell counts (47 and 82 cells/µl for 5 and 10 µg/kg, respectively) at day 5 was equivalent to that of Neupogen. The incidence of all grades’ adverse events was slightly lower for Nivestim than for Neupogen (for 5 μg/kg 79 vs. 83%, and for 10 μg/kg 77 vs. 92%, respectively). No serious adverse events were reported for either drug .
Also in 2010, Waller et al. published results from a single-centre, phase 1 crossover pharmacokinetics and safety study. A total of 48 volunteers were treated with single-dose 10 µg/kg Nivestim and Neupogen s.c. or i.v., finding comparable pharmacokinetics and adverse events, with no serious adverse events reported .
Survey of current G-CSF biosimilar use in healthy donors
The survey was sent to all 64 WMDA-associated registers and answered by 33 registers (52%) from the USA, Europe and Asia as well as Canada, Australia, Israel, and South Africa.
For unrelated donors, 26 out of 30 responding registers reported centres that used a filgrastim brand for routine mobilisation. Thirteen of these used only Neupogen and seven used only biosimilars. Three registers reported use of both Neupogen and a filgrastim biosimilar, while three used both Neupogen and Granocyte (lenograstim). Four registers reported using only Granocyte.
Nine registers reported a change of routine mobilising agent after 2013, while seven were considering a change when surveyed about the matter. Six changes were from Neupogen to a biosimilar brand, one was between different biosimilar brands and one change was from Granocyte to a biosimilar. One register also reported having changed to Neupogen without providing information about previous agents used.
Seven registers reported Price, three reported Safety, and one register each reported Efficacy and Quality as the main reason for a change of mobilising agent. Two Indian registers changed to a biosimilar G-CSF due to the unavailability of Neupogen in India.
The surveyed WMDA registries where asked to provide information about which mobilising agent was used for related donors in centres associated with the register.
Sixteen out of eighteen responding registers reported associated centres routinely using filgrastim G-CSF for stem cell mobilisation in related donors. Of these, three were using only Neupogen and six were using only biosimilar filgrastim. Four reported use of both Neupogen and biosimilar filgrastim, and three used both Neupogen and Granocyte. Two registers reported only centres using Granocyte.
Nine registers reported changes in routine mobilising agent for related donors after 2013, and three more were considering changes. Six had changed from Neupogen to a biosimilar; one had changed from one biosimilar to another and another register had changed from Granocyte to a biosimilar.
Seven registers cited price as the main reason for change, while efficacy, quality and safety were reported by one register each.
There has been a gradual increase of published experiences using different brands of biosimilar filgrastim for stem cell mobilisation in donors since the EMA approval in 2008, especially for autologous transplantation [30, 33,34,35,36,37], but also regarding donors for allogeneic transplantation [10, 17, 18, 20, 21, 25, 26, 30, 33].
A recent meta-analysis by Schmitt et al., based on 30 studies with a total of 1541 autologous transplant patients where biosimilar filgrastim was used for stem cell mobilisation, found no differences in the number of apheresis days, the number of collected CD34 + cells per kg recipient weight, or the time to neutrophil and platelet engraftment compared to Neupogen .
In our review, we have found published results from studies including 492 donors where biosimilar filgrastim was used for stem cell mobilisation at conventional doses of 5–10 µg/kg/day for 4–7 days (Tables 2b and 3), and another 795 healthy volunteers included in pharmacokinetic/pharmacodynamics studies (Table 2a).
Although these studies are generally small, and follow-up times are short, together they suggest that there are no substantial differences between the approved filgrastim biosimilars and Neupogen regarding CD34 + cell mobilisation efficacy, transplant results or donor safety.
One particular concern since the introduction of biosimilar filgrastim has been the risk of immunogenicity and antibody formation. In the phase 1 Nivestim registration study GCF062, two out of 48 subjects tested positive for neutralising G-CSF antibodies, and three more had borderline positive testing without evidence of neutralising antibodies in confirmatory assays . As a comparison, for Neupogen a 3% (11/333) incidence of filgrastim antibodies has been reported, although the clinical significance of this finding for mobilisation results remains uncertain . In this review, we find the results of antibody testing for 397 healthy volunteers without evidence of antibody formation, thereby supporting the safety of biosimilar filgrastim also in this regard [16, 19, 27, 28].
Although the WMDA survey presented here does not include current practices at all WMDA-associated registries, it does show that the use of biosimilar filgrastim for both unrelated and related healthy donors has already been deemed acceptable by a significant number of transplant centres that now use it as part of their standard mobilising strategy.
WMDA takes note that filgrastim biosimilars are not apparently different from historically used filgrastim (Neupogen, Amgen) with respect to quality and efficacy, and with safety at least over a short-term observation period.
WMDA finds it therefore reasonable to recommend Stem Cell Donor Registries that filgrastim biosimilars can be used in place of Neupogen, provided that they are approved by national and/or regional agencies, for the mobilisation of peripheral blood progenitor cells in healthy donors.
WMDA recommends that when a new filgrastim biosimilar is taken into practice by a registry, the registries should have a policy to follow donors and patients with the intention to reveal any abnormality possibly caused by the new biosimilar.
WMDA calls attention to the importance of using SEAR (Serious Events and Adverse Reactions) and SPEAR (Serious Product Events and Adverse Reactions) reportsFootnote 1 whenever appropriate when biosimilars are used, as well as the importance of reporting the trade name of the biosimilar that is used, since all filgrastim biosimilars share the same International Nonproprietary Name.
WMDA member organisations can report using a central reporting system at https://www.wmda.info/professionals/promoting-donor-care/adverse-events-searspear/
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The authors declare that they have no conflict of interest.
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Pahnke, S., Egeland, T., Halter, J. et al. Current use of biosimilar G-CSF for haematopoietic stem cell mobilisation. Bone Marrow Transplant 54, 858–866 (2019). https://doi.org/10.1038/s41409-018-0350-y
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