Discussion
The concept of biosimilar products essentially refers to copies of
biologic products whose patent protection has expired. Given the
complexity of manufacturing biologics, these products are obtained
differently from generics (copies of small-molecule drugs) through a
specific regulatory process. In this context, obtaining a biosimilar
status requires evidence of physico-chemical, pharmacological and
clinical similarity, including comparative trials for at least one
”sensitive” indication for which the reference product is licensed. The
most important benefits of biosimilars include reduced healthcare
expenditures and ease of access.9
G-CSF is primarily produced by fibroblasts, bone marrow endothelial
cells, monocytes and macrophages. G-CSF exerts its main effect by
ensuring the production, maturation, mobilization and survival of
neutrophils.10 It also plays a role in chemotaxis by
stimulating the release of arachidonic acid from neutrophils, production
of leukocyte alkaline phosphatase (LAP), myeloperoxidase, and superoxide
anions.11 In addition to being used to prevent or
shorten the duration of severe neutropenia after chemotherapy,
especially in the pediatric age group, G-CSF is also commonly used for
stem cell mobilization. Currently, while PBSC mobilized with G-CSF is
widely used as a stem cell source, stem cells are rarely obtained from
BM, and G-CSF is rarely used to provide mobilization in this setting.12
Although PBSC is the more commonly preferred source of stem cells for
adult patients, BM remains the main stem cell source for standard
allogeneic HSCT performed in children due to a variety of conditions,
including certain malignancies, hemoglobinopathies, bone marrow failure
syndromes, immunodeficiency, and congenital metabolic
diseases.13
Compared to BM, a PBSC graft contains roughly 3-10 times as many CD34+
and CD3+ cells. Preparation by using G-CSF for stem cell collection from
BM substantially alters the growth and proliferative properties of the
bone marrow cells. After G-CSF stimulation to healthy donors, the number
of CD34+ cells increase by 26-fold on average in peripheral blood, while
this increase is only 1.4-1.7-fold in the bone marrow. These results
suggest that G-BM stem cells may acquire proliferative properties
leading to a faster hematopoietic recovery after HSCT. Furthermore,
modulating the expression of certain adhesion molecules involved in the
pathogenesis of GvHD, such as VLA-4, ICAM-1, L-selectin, and LFA-1 as
well as the migration and homing of T-cells, significantly reduces the
development of GvHD in G-BM. Selective inhibition of these adhesion
molecules may explain the reduced incidence of GvHD after G-BM
transplantation.14
The objective of G-BM transplantation is to ensure faster engraftment
without increasing the risk of GvHD and allow the patient’s recovery in
a shorter period of time. When the outcomes in patients receiving G-BM
are compared to historic records or case-control cohort studies of
patients receiving BM only, study results reveal that G-BM patients
achieve higher numbers of total nucleated cells, CD34+ cells, CFU-GM,
and faster neutrophil and platelet engraftment. 7,15
BM prepared with G-CSF is an alternative stem cell source that can
provide a higher number of stem cells without increasing the risk of
GvHD. Kim et. al. reported faster engraftment in their study including
33 patients who underwent G-BM transplantation (median time: 13 days for
neutrophils and 18 days for platelets) as well as a lower incidence of
acute GvHD (> grade II, 12%) and chronic GvHD (34%), and
the cumulative incidence of TRM was 15%. The probability of 10-year
overall and event-free survival (EFS) was 68% and 62%, respectively.16 Similarly, Isola et. al. observed faster neutrophil
and platelet engraftment in 10 patients who received G-CSF 10 g/kg two
days before allogeneic BM harvesting compared to the control group who
underwent BM transplantation without G-CSF.15
In a prospective randomized study comparing G-CSF-stimulated BM and PBSC
in adult patients with malignant disease, there was no significant
difference in the duration of neutrophil and platelet engraftment, but
when compared in terms of GvHD risk, PBSC recipients had a much higher
risk of acute (17% vs. 46%) and chronic (27% vs. 77%) GvHD.3
While the ideal G-CSF dose for PBSC is well-established in studies, the
ideal G-CSF dose for preparation before BM harvesting appears to be less
understood. A prospective multicenter study in children who received
allogeneic BM from HLA-identical siblings showed that G-CSF
administration in the pediatric age group was well tolerated and
resulted in a high dose of nucleated and CD34+ cells after using G-CSF
at a dose of 5 μg/kg for five days.2,3
In a single-center study of a small number of pediatric patients, the
investigators used a dose of 5 μg/kg for three days before BM harvesting
and compared the results with similar patients who did not receive G-CSF
stimulation. Patients who received G-CSF prior to BM harvesting had
higher doses of TNC and CD34+ cells; however, faster engraftment was not
achieved although all patients received post-transplant G-CSF. In a
different prospective study involving 57 patients, after receiving 10
μg/kg of G-CSF daily for 5 days, patients were randomized to
G-CSF-stimulated BM (28 patients) and G-CSF-stimulated PBSC (G-PBSC) (29
patients). Patients in the G-PBSC group received three-fold CD34+ cells
and nine-fold CD3+ cells than the patients in the G-BM group. Median
times to neutrophil and platelet engraftment were similar. The
cumulative incidences of refractory aGvHD and extensive cGvHD were
significantly higher for the G-PB group. It was concluded by the authors
that G-BM results in less severe aGvHD and less cGvHD compared to G-PB
graft. Post-transplant recurrence rate and OS were
similar.8 A comprehensive review of the literature
shows numerous studies demonstrating that the use of BM prepared with
G-CSF provides faster neutrophil and platelet engraftment in recipients,
with lower rates of GvHD and TRM.
There are many studies of PBSC that involve different G-CSF products
applied for stem cell mobilization in HSCT and compare the results
obtained with these products. Similarly, while there are studies that
compare the doses of G-CSF used for cell mobilization from BM or test
whether this approach should be adopted, there is no study comparing
different G-CSF products administered and investigating the effect of
G-CSF products on the collected BM product. When we evaluated the
results of our patients in light of the available information, we found
that lenograstim, which was administered as a single dose 24 hours
before transplantation, resulted in obtaining a higher level of CD34/UL
compared to the control group and the groups that received filgrastim or
biosimilar filgrastim. In a PBSC study which compared lenograstim,
filgrastim and biosimilar filgrastim, similar to our study, no
difference was found in terms of CD34/UL. However, the target CD34 cell
count was reached with an apheresis procedure in 87% of the donors
receiving lenograstim and 93% of the donors receiving biosimilar
filgrastim. 17 In a different multicenter study
involving a large number of adult patients who underwent autologous
transplantation, lenograstim, filgrastim and biosimilar filgrastim were
compared, and no difference was found between the groups in terms of
CD34+ progenitor cells (×106/kg). 18 In another study
involving 243 cases of allogeneic PBSC by Sivgin et al., no difference
was found in terms of CD34/UL obtained from healthy donors using
lenograstim, filgrastim or biosimilar filgrastim, and biosimilar
filgrastim (Leucostim®) was found to be comparable with original
Filgrastim (Neupogen®) and lenograstim (Granocyte®) for PBSC
mobilization in donors of patients undergoing
allo-HSCT.19
The limitation of our study is that it was not conducted with a large
number of subjects in the donor and control groups, especially in the
pediatric age group. We acknowledge that the content of the
post-transplantation product should have been evaluated in a high number
of donors and included in this study. We also believe the late effects
of biosimilar filgrastim (Leucostim®), original filgrastim (Neupogen®)
and lenograstim (Granocyte®) should be evaluated. The strength of our
study is that it is the first to use different G-CSF molecules for the
mobilization of stem cells from the bone marrow, and the first to
compare the results of different G-CSFs with one another as well as with
a control group.
In conclusion, biosimilar filgrastim (Leucostim®), original filgrastim
(Neupogen®) and lenograstim (Granocyte®) can be safely used for BM
mobilization in donors of patients undergoing allo-HSCT. However,
lenograstim (Granocyte®) should be preferred with regard to median
CD34/UL count. Further studies are required to determine the ideal dose
and number of administrations in this setting. Our results warrant being
supported by prospective studies with larger case series.