Abstract

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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Notes

  1. 1.

    WMDA member organisations can report using a central reporting system at https://www.wmda.info/professionals/promoting-donor-care/adverse-events-searspear/

References

  1. 1.

    European Medicines Agency: Biosimilars in the EU (Information guide for healthcare professionals). http://www.ema.europa.eu/docs/en_GB/document_library/Leaflet/2017/05/WC500226648.pdf. Last accessed date 23 October 2017

  2. 2.

    European Medicines Agency: Biosimilar medicinal products containing recombinant granulocyte-colony stimulating factor. http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_001386.jsp&mid=WC0b01ac058002958c. Last accessed date 23 October 2017

  3. 3.

    European Medicines Agency: Similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues. http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_001386.jsp&mid=WC0b01ac058002958c. Last accessed date 23 October 2017

  4. 4.

    Biologics Price Competition and Innovation Act. https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/UCM216146.pdf. Last accessed date 23 October 2017

  5. 5.

    FDA: Information on biosimilars. https://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/default.htm. Last accessed date 23 October 2017

  6. 6.

    List of FDA-approved biosimilars. https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/UCM560162.pdf. Last accessed date 23 October 2017

  7. 7.

    ClinicalTrials.gov trial no. NCT00785525. https://clinicaltrials.gov/ct2/show/NCT00785525. Last accessed date 23 October 2017

  8. 8.

    Shaw BE, Confer DL, Hwang WY, Pamphilon DH, Pulsipher MA. Concerns about the use of biosimilar granulocyte colony-stimulating factors for the mobilization of stem cells in normal donors: position of the World Marrow Donor Association. Haematologica. 2011;96:942–7.

  9. 9.

    Liumbruno GM, Petrini C. Ethical issues and concerns about the use of biosimilar granulocyte colony-stimulating factors for the mobilisation of stem cells in normal donors. Blood transfusion. 2012;10:550–2.

  10. 10.

    Uddin S, Russell P, Farrell M, Davy B, Taylor J, Agrawal SG. Use of biosimilar filgrastim compared with lenograstim in autologous haematopoietic stem-cell transplant and in sibling allogeneic transplant. Ther Adv Hematol. 2015;6:53–60.

  11. 11.

    Lown RN, Philippe J, Navarro W, van Walraven SM, Philips-Johnson L, Fechter M, et al. Unrelated adult stem cell donor medical suitability: recommendations from the World Marrow Donor Association Clinical Working Group Committee. Bone Marrow Transplant. 2014;49:880–6.

  12. 12.

    Niederwieser D. European Group for Blood and Marrow Transplantation (EBMT). Position statement. Biosimilar granulocyte-colony stimulating factor (G-CSF) for stem cell mobilization in related and unrelated donors, 2009. http://www.worldmarrow.org/fileadmin/Committees/CLWG/Biosimilars/Biosimilars_9Jan09.pdf. Last accessed 23 October 2017.

  13. 13.

    Position statement of the Japan Society for Hematopoietic Cell Transplantation regarding the use of biosimilar granulocyte-colony stimulating factors for the mobilization of hematopoietic stem cells in healthy donors 2013. http://www.jshct.com/english/. Last accessed date 23 October 2017

  14. 14.

    Gastl G, Geissler D, Geissler K, Lang A, Ludwig H, Müller M, et al. ASHO position paper on Biosimilars. memo—Magazine of European. Med Oncol. 2009;2:232–3.

  15. 15.

    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;96:937–42.

  16. 16.

    Gascon P, Fuhr U, Sorgel F, Kinzig-Schippers M, Makhson A, Balser S, et al. Development of a new G-CSF product based on biosimilarity assessment. Ann Oncol. 2010;21:1419–29.

  17. 17.

    Azar NCS, Garnier A, et al. Use of a biosimilar G-CSF in allogeneic stem cell mobilisation. Bone Marrow Transpl Abstr Book. 2012;47(Suppl.1 s):244. Abstract p727

  18. 18.

    Ribeil J-A, Turner M, Hermine O, Blanche S, Cavazzana-Calvo M. Biosimilar compared with originator filgrastim for related-donor allogeneic stem cell mobilisation: A Prospective-Historical Control Study. Blood. 2013;122:5512.

  19. 19.

    Sorgel F, Schwebig A, Holzmann J, Prasch S, Singh P, Kinzig M. Comparability of biosimilar filgrastim with originator filgrastim: protein characterization, pharmacodynamics, and pharmacokinetics. BioDrugs. 2015;29:123–31.

  20. 20.

    Antelo ML, Zabalza A, Sanchez Anton MP, Zalba S, Aznar M, Mansilla C, et al. Mobilization of hematopoietic progenitor cells from allogeneic healthy donors using a new biosimilar G-CSF (Zarzio(R)). J Clin Apher. 2016;31:48–52.

  21. 21.

    Becker P, Schwebig A, Brauninger S, Bialleck H, Luxembourg B, Schulz M, et al. Healthy donor hematopoietic stem cell mobilization with biosimilar granulocyte-colony-stimulating factor: safety, efficacy, and graft performance. Transfusion. 2016;56:3055–64.

  22. 22.

    Farhan R, Urbanowska E, Zborowska H, Krol M, Krol M, Torosian T, et al. Biosimilar G-CSF versus filgrastim and lenograstim in healthy unrelated volunteer hematopoietic stem cell donors. Ann Hematol. 2017;96:1735–9.

  23. 23.

    Lubenau H, Sveikata A, Gumbrevicius G, Macijauskiene J, Fokas V, Kazlauskas S, et al. Bioequivalence of two recombinant granulocyte colony-stimulating factor products after subcutaneous injection in healthy volunteers. Int J Clin Pharmacol Ther. 2009;47:275–82.

  24. 24.

    Lubenau H, Bias P, Maly AK, Siegler KE, Mehltretter K. Pharmacokinetic and pharmacodynamic profile of new biosimilar filgrastim XM02 equivalent to marketed filgrastim Neupogen: single-blind, randomized, crossover trial. BioDrugs. 2009;23:43–51.

  25. 25.

    Schmitt M, Xu X, Hilgendorf I, Schneider C, Borchert K, Glaser D, et al. Mobilization of PBSC for allogeneic transplantation by the use of the G-CSF biosimilar XM02 in healthy donors. Bone Marrow Transplant. 2013;48:922–5.

  26. 26.

    Danylesko I, Sareli R, Bloom-Varda N, Yerushalmi R, Shem-Tov N, Shimoni A, et al. Biosimilar filgrastim (Tevagrastim, XMO2) for allogeneic hematopoietic stem cell mobilization and transplantation in patients with acute myelogenous leukemia/myelodysplastic syndromes. Biol Blood Marrow Transplant. 2016;22:277–83.

  27. 27.

    European Medicines Agency: Grastofil Public Assessment Report http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002150/WC500154066.pdf. Last accessed date 21 August 2017

  28. 28.

    Matsuguma K, Matsuki S, Sakamoto K, Shiramoto M, Nakagawa M, Kimura M, et al. A comparative pharmacokinetic and pharmacodynamic study of FSK0808 versus reference filgrastim after repeated subcutaneous administration in healthy Japanese men. Clin Pharmacol Drug Dev. 2015;4:99–104.

  29. 29.

    Crobu D, Spinetti G, Schrepfer R, Tonon G, Jotti GS, Onali P, et al. Preclinical and clinical phase I studies of a new recombinant Filgrastim (BK0023) in comparison with Neupogen(R). BMC. Pharmacol Toxicol. 2014;15:7.

  30. 30.

    Sivgin S, Karakus E, Keklik M, Zararsiz G, Solmaz M, Kaynar L, et al. Evaluation of the efficacy and safety of original filgrastim (Neupogen(R)), biosimilar filgrastim (Leucostim(R)) and Lenograstim (Granocyte(R)) in CD34( + ) peripheral hematopoietic stem cell mobilization procedures for allogeneic hematopoietic stem cell transplant donors. Transfus Apher Sci. 2016;54:410–5.

  31. 31.

    Waller CF, Bronchud M, Mair S, Challand R. Comparison of the pharmacodynamic profiles of a biosimilar filgrastim and Amgen filgrastim: results from a randomized, phase I trial. Ann Hematol. 2010;89:971–8.

  32. 32.

    Waller CF, Bronchud M, Mair S, Challand R. Pharmacokinetic profiles of a biosimilar filgrastim and Amgen filgrastim: results from a randomized, phase I trial. Ann Hematol. 2010;89:927–33.

  33. 33.

    Lefrere F, Brignier AC, Elie C, Ribeil JA, Bernimoulin M, Aoun C, et al. First experience of autologous peripheral blood stem cell mobilization with biosimilar granulocyte colony-stimulating factor. Adv Ther. 2011;28:304–10.

  34. 34.

    Manko J, Walter-Croneck A, Jawniak D, Grzasko N, Gorska-Kosicka M, Cioch M, et al. A clinical comparison of the efficacy and safety of biosimilar G-CSF and originator G-CSF in haematopoietic stem cell mobilization. Pharmacol Rep: Pr. 2014;66:239–42.

  35. 35.

    Publicover A, Richardson DS, Davies A, Hill KS, Hurlock C, Hutchins D, et al. Use of a biosimilar granulocyte colony-stimulating factor for peripheral blood stem cell mobilization: an analysis of mobilization and engraftment. Br J Haematol. 2013;162:107–11.

  36. 36.

    Schmitt M, Publicover A, Orchard KH, Gorlach 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;4:280–9.

  37. 37.

    Remenyi P, Gopcsa L, Marton I, Reti M, Mikala G, Peto M, et al. Peripheral blood stem cell mobilization and engraftment after autologous stem cell transplantation with biosimilar rhG-CSF. Adv Ther. 2014;31:451–60.

  38. 38.

    Schmitt M, Hoffmann JM, Lorenz K, Publicover A, Schmitt A, Nagler A. Mobilization of autologous and allogeneic peripheral blood stem cells for transplantation in haematological malignancies using biosimilar G-CSF. Vox Sang. 2016;111:178–86.

  39. 39.

    European Medicines Agency: Nivestim Public Assesment Report http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/001142/WC500093664.pdf. Last accessed date 23 October 2017.

  40. 40.

    Neupogen Product Information http://pi.amgen.com/~/media/amgen/repositorysites/pi-amgen-com/neupogen/neupogen_pi_hcp_english.ashx. Last accessed date 23 October 2017

Download references

Author information

Affiliations

  1. Department of Medical Sciences, Uppsala University, Uppsala, Sweden

    • Simon Pahnke
    •  & Hans Hägglund
  2. Institute of Immunology, Oslo University Hospital—Rikshospitalet and Institute of Clinical Medicine, University of Oslo, Oslo, Norway

    • Torstein Egeland
  3. Department of Hematology, University Hospital Basel and University of Basel, Basel, Switzerland

    • Jörg Halter
  4. Centre for International Blood and Bone Marrow Transplant Research, Medical College of Wisconsin, Milwaukee, Wisconsin, USA

    • Bronwen E Shaw
  5. Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA

    • Ann E Woolfrey
  6. Department of Medicine, University of Washington, Seattle, Washington, USA

    • Ann E Woolfrey
  7. Integrated Haematology Department, Victorian Comprehensive Cancer Centre, Royal Melbourne Hospital, Melbourne, Victoria, Australia

    • Jeff Szer

Authors

  1. Search for Simon Pahnke in:

  2. Search for Torstein Egeland in:

  3. Search for Jörg Halter in:

  4. Search for Hans Hägglund in:

  5. Search for Bronwen E Shaw in:

  6. Search for Ann E Woolfrey in:

  7. Search for Jeff Szer in:

Consortia

  1. on behalf of the Working Group Medical of the World Marrow Donor Association

    Conflict of interest

    The authors declare that they have no conflict of interest.

    Corresponding author

    Correspondence to Simon Pahnke.

    About this article

    Publication history

    Received

    Revised

    Accepted

    Published

    DOI

    https://doi.org/10.1038/s41409-018-0350-y