Original Article
What is the role of biosimilar G-CSF agents in hematopoietic stem cell mobilization at present?

https://doi.org/10.1016/j.transci.2017.11.008Get rights and content

Abstract

Mobilization of hematopoietic stem cells, which has largely replaced bone marrow harvesting as a source of hematopoietic stem cells, using recombinant agents such as filgrastim or lenograstim has become a standard procedure in both patients and healthy donors prior to peripheral blood stem cell collection for autologous and allogeneic stem cell transplantation. Published literature data suggest that mobilization with recombinant granulocyte-colony stimulating factor (G-CSF) is safe and mobilization outcomes are satisfactory. In recent years, besides G-CSF originators, biosimilar G-CSF agents have been approved by the regulatory agencies for the same indications. Current data showed that by using the biosimilar G-CSF, similar results regarding safety and efficacy of hematopoietic stem cell mobilization may be achieved compared to the originator G-CSF. Although the issues such as the similarity to a licenced biological medicine, differences in manufacturing processes, the potential to cause immunogenicity, extrapolation and interchangeability of these biosimilar products are still being discussed by the scientific area, however, more experience with these agents now exists in approved endications and there seems to be no reason to expect significant differences between biosimilar G-CSF and originator G-CSF regarding their efficacy and safety in both patients and healthy donors. Also, the significant cost savings of biosimilars in real life setting may enhance the use of these agents in the future. Nonetheless, the collection of long-term follow-up data is mandatory for both patients and healthy donors, and multicentre randomized clinical trials that directly compare biosimilar G-CSF with the originator G-CSF are needed in order to allow the transplant community to make informed decisions regarding the choice of G-CSF.

Introduction

Human granulocyte-colony stimulating factor (G-CSF) which is a hematopoietic growth factor that stimulates the proliferation, differentiation, and activation of neutrophil precursors, accelerates the maturation of the neutrophil precursors and enhances their function by increasing their cytotoxicity and phagocytic activity [1], [2]. Currently, mobilization procedures has largely replaced bone marrow harvesting as a source of hematopoietic stem cells (HSCs) prior to autologous and allogeneic stem cell transplantation due to ease of collection, avoidance of general anesthesia and more rapid recovery of blood counts. Since peripheral blood contains HSCs in lower numbers, various methods are performed to mobilize the HSCs from bone marrow with the aim to enhance the amount of CD34+ HSCs in bloodstream before the collection period. Today, either G-CSF is used alone or in combination with chemotherapy for HSC mobilization. In recent years, besides G-CSF originators, biosimilar G-CSF agents have been approved by the regulatory agencies for the same indications [3]. In this paper, the role of biosimilar G-CSF agents in current hematopoietic stem cell mobilization practice will be discussed accompanied by the present literature data.

Section snippets

Recombinant G-CSF agents

Mobilization of HSCs using recombinant agents such as filgrastim (Neupogen®) or lenograstim (Granocyte®) has become a standard procedure in both patients and healthy donors prior to peripheral blood stem cell (PBSC) collection for autologous and allogeneic stem cell transplantation. Several mechanisms of action of filgrastim (non-glycosylated recombinant G-CSF) and lenograstim (glycosylated recombinant G-CSF) are the promotion of granulocyte expansion and both protease-dependent and independent

The side effect profile of recombinant G-CSF agents

Mobilization with recombinant G-CSF was found to be safe and associated with only mild and transient side effects [10]. Currently recognised short-term side effects include bone pain, nausea, vomiting, diarrhea, insomnia, chills, fever, and nightsweats [11], [12]. Splenic rupture, pulmonary hemorrhage, and capillary leakage syndrome are very rarely reported side effects [13], [14], [15]. Possible long-term effects may include activation of autoimmune diseases, the development of myelodysplasia

The term ‘Biosimilarity’ and biosimilar G-CSF agents

The US Food and Drug Administration (FDA) describes biosimilar as highly similar to a previously approved biological reference product (biologics). Biosimilars are similar but not an absolute copy of the licenced biological medicine or are not identical to the original product that contains the same active substance because of the manufacturing process. A biosimilar is created by reverse engineering method. Once the biosimilar has been created, biological, pharmacological, and physicochemical

Biosimilar G-CSF agents in clinical setting

Autologous stem cell transplantation is widely used for the treatment of hematological malignancies, and the most common indications are multiple myeloma (MM) and malign lymphomas [33]. Additionally, acute leukemias, in particular acute myeloid leukemia (AML), are the most common hematological malignancies as an indication for allogeneic transplants. Today, mobilization of HSCs using recombinant or biosimilar G-CSFs has become a standard procedure in both patients and healthy donors prior to

Are biosimilar G-CSF agents safe in healthy donors? Is there a need for concern?

As healthy donors gain no personal benefit from the procedure, donor safety has been recognized as an important issue by the transplant pyhsicians. The World Marrow Donor Association (WMDA) concluded that biosimilar G-CSF should only be used in normal donors where the donor is entered into a clinical study [44]. Similarly, the European Group for Blood and Marrow Transplantation (EBMT) Executive Committee issued a letter stating that, ‘Until studies have been performed to provide the required

Conflicts of interest

None.

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