Keywords
Chemotherapy - children - filgrastim - neutropenia - polyethylene glycol-filgrastim
Introduction
Neutropenia is one of the most common side effects after chemotherapy in patients
with malignancy. This is caused by chemotherapeutic drugs and cytotoxic agents due
to the lack of the detection of tumor cells from myeloid normal cells.[1],[2] Severe or prolonged neutropenia may lead to treatment discontinuation in addition
to patients' admission to the hospital for the treatment of neutropenia and fever
with it. Neutropenia following chemotherapy may occur in patients receiving a standard
dose that is prescribed for the treatment of various malignancies.[3],[4],[5] Severe decrease in neutrophil cell counts (<500 cells/ml) results in decreased immunity
and increased risk of infection. Hence, the patient will be susceptible to bacterial
and fungal infections.[3],[4]
Recombinant human granulocyte colonystimulating factor (G-CSF) and recombinant human
granulocyte- macrophage CSF are two drugs that are commonly used to reduce the risk
of infection in patients with neutropenia. These drugs could decrease the severity
and duration of neutropenia in patients with malignancy after chemotherapy.[1],[2]
G-CSF can be used as a secondary prophylaxis of neutropenia at the end of, chemotherapy
which reduces the cases of hospitalization to receive antibiotics, infection, and
fever associated with neutropenia.[5],[6],[7] However, fewer studies have been performed in children compared to adults.[8],[9]
Polyethylene glycol (PEG)-filgrastim is a pegylated G-CSF and new drug. The half-life
of PEG-filgrastim is 46–62 h and is used as a single dose instead of the daily dose
of G-CSF. One molecule of PEG binds to N-terminal of filgrastim and gets converted
to PEG-filgrastim that provides low antigenicity, minimal toxicity, and appropriate
excretion.[10],[11] The recommended dose of PEG-filgrastim is 6 mg in adults and 100 μg/kg in children
(maximum 6 mg) that is given to patients 24 h after chemotherapy.[12],[13]
PEG-filgrastim in adults has better efficiency and can be easily administered compared
to G-CSF,[14],[15] but research on the effectiveness these drugs in children is limited.[16],[17]
This study is the 1st clinical trial in Iran that was done for evaluating the side
effects and the efficacy of PEG-filgrastim.
Materials and Methods
This clinical study (Phase I clinical trial) was conducted among patients that referred
to the Oncology Department at Ali Asghar Hospital, Tehran, Iran, in 2013–2014. Inclusion
criteria were as follows: age <16 years, leukemia, neutropenia followed by chemotherapy,
and no leukemia induction phase. Exclusion criteria were as follows: intolerable side
effects of drugs in patients, potentially dangerous complications after initiation
of drug use, lack of patient cooperation in conducting follow-up visits, need for
other concomitant medicines to improve the patient's neutropenia, and existence of
other causes for neutropenia such as infection and patient death before completing
the study.
Convenience sampling was performed, and the patients who met the inclusion criteria
were selected for the study. This study was done as self-control study, and the same
patients were considered as a control group in the specified time interval.
All the patients were treated with filgrastim in the 1st period. The same patients
were been placed in the opposite group if the patient was readmitted after the 1st
treatment period at least one course later. All the patients had similar chemotherapy
regimens in both groups. In the 1st period, the patients were treated by filgrastim
(PDgrastim® 300 μ, Pooyesh Darou Pharma, Tehran, Iran). Filgrastim was administered
at a dose of 5–10 μg/kg/day subcutaneously for 7 consecutive days (standard dose).
The patients received PEG-filgrastim after the 2nd course. Each prefilled syringe
contains 6 mg of PEG-filgrastim (Pega Gen®, 6 mg/syringe, Cinna Gen, Co, Iran) in
0.6 ml (0.6 mg/ml). The patients received a single subcutaneous injection of 100 μg/kg
of PEG-filgrastim. Absolute neutrophil count (ANC) was checked 7 days after the last
injection in the two groups. Chemotherapy regimens were similar in the two groups.
Paired t-test and Chi-square test were utilized to determine the difference between
categorical variables of the two groups. This study was approved by the Ethics Committee
of Tehran University of Medical Sciences and also was recorded in the Iranian Registry
of Clinical Trials with IRCT201205279875N1.
Results
A total of 11 patients, 6 boys (54.5%) and 5 girls (45.5%), participated in the study.
None of the patients were excluded from the study. The mean age of the patients was
8.82 ± 4.36 years (3–15 years). The patient characteristics are described in [Table 1].
Table 1
Characteristics of the patients
|
Groups
|
Year
|
Sex
|
Malignancy
|
Pretreatment ANC
|
Posttreatment ANC
|
|
ANC – Absolute neutrophil count; PEG – Polyethylene glycol
|
|
Filgrastim
|
7
|
Male
|
Leukemia
|
250
|
2000
|
|
Filgrastim
|
12
|
Female
|
Leukemia
|
350
|
400
|
|
Filgrastim
|
7
|
Female
|
Leukemia
|
250
|
450
|
|
Filgrastim
|
15
|
Male
|
Leukemia
|
400
|
500
|
|
Filgrastim
|
5
|
Female
|
Leukemia
|
500
|
1500
|
|
Filgrastim
|
15
|
Male
|
Leukemia
|
100
|
150
|
|
Filgrastim
|
4
|
Female
|
Leukemia
|
450
|
7000
|
|
Filgrastim
|
12
|
Female
|
Leukemia
|
150
|
4000
|
|
Filgrastim
|
12
|
Male
|
Leukemia
|
250
|
6000
|
|
Filgrastim
|
3
|
Male
|
Leukemia
|
500
|
2000
|
|
Filgrastim
|
5
|
Male
|
Leukemia
|
400
|
8000
|
|
PEG-filgrastim
|
7
|
Male
|
Leukemia
|
300
|
5000
|
|
PEG-filgrastim
|
12
|
Female
|
Leukemia
|
450
|
2500
|
|
PEG-filgrastim
|
7
|
Female
|
Leukemia
|
400
|
3000
|
|
PEG-filgrastim
|
15
|
Male
|
Leukemia
|
400
|
4000
|
|
PEG-filgrastim
|
5
|
Female
|
Leukemia
|
300
|
4000
|
|
PEG-filgrastim
|
15
|
Male
|
Leukemia
|
300
|
1500
|
|
PEG-filgrastim
|
4
|
Female
|
Leukemia
|
500
|
15,000
|
|
PEG-filgrastim
|
12
|
Female
|
Leukemia
|
400
|
12,000
|
|
PEG-filgrastim
|
12
|
Male
|
Leukemia
|
500
|
12,000
|
|
PEG-filgrastim
|
3
|
Male
|
Leukemia
|
500
|
8000
|
|
PEG-filgrastim
|
5
|
Male
|
Leukemia
|
450
|
30,000
|
Demographic variables were similar in both groups, and there was no statistical difference
between them.
There was no significant difference between the two groups in ANC before treatment
(P = 0.102). ANC after treatment revealed a significant difference compared to pretreatment
in both groups.
In the filgrastim group, the average number of pretreatment ANC was 327.27 cells/mm3
that elevated to 2909.09 cells/mm3 (P = 0.013). In the PEG-filgrastim group, the average
number of pretreatment ANC was 409.09 cells/mm3 that elevated to 8818.18 cells/mm3
(P = 0.007) [Figure 1]. Comparison of the ANC after treatment indicated significant differences between
the two groups (P = 0.037) [Table 2].
Figure 1: Differences between pre- and post-treatment absolute neutrophil count
Table 2
The mean absolute neutrophil count in two groups
|
ANC
|
Treatment groups
|
P
¥
|
|
Filgrastim
|
PEG-filgrastim
|
|
*Data were analyzed by paired t‑test, P<0.05 was considered significant. ¥Data were
analyzed by Student's t-test, P<0.05 was considered significant. ANC – Absolute neutrophil
count; PEG – Polyethylene glycol
|
|
Pretreatment (cells/mm3)
|
327.27
|
409.09
|
0.102
|
|
Posttreatment (cells/mm3)
|
2909.29
|
8818.18
|
0.038
|
|
P*
|
0.013
|
0.007
|
-
|
Discussion
The use of filgrastim as recombinant G-CSF may reduce the duration of neutropenia
after chemotherapy. This drug is being used as a supportive therapy in patients undergoing
chemotherapy. However, it should be administered daily due to short half-life. A new
and long-acting form of this medication is known as PEG-filgrastim that is already
built and used. The half-life of this drug is more than that of filgrastim due to
the different molecular composition to the extent that it can be administered as a
single dose.[11],[12]
The results of this study showed that a statistically significant difference was in
the patients' ANC before and after treatment in both groups. te Poele et al.[15] also reported that the use of PEG-filgrastim therapy, regardless of the type of
cancer, could be effective in improving neutropenia induced by chemotherapy, which
is consistent with our findings. The major advantage of PEG-filgrastim is that a single
dose may be used that is particularly important in child and adolescent patients.[16],[17],[18] In the present study, the comparison of the effectiveness between the two regimens
showed PEG-filgrastim efficacy to be better than filgrastim, which was consistent
with most previous studies.[15],[16],[17]
Wendelin et al.[14] reviewed the effectiveness of these drugs to improve severe neutropenia in children
with Ewing's sarcoma. They found that the effectiveness of PEG-filgrastim to be better
and easier to use than filgrastim. A retrospective study was performed by Milano-Bausset
et al.,[16] and the findings showed the lower incidence of severe neutropenia, a shorter duration
of severe neutropenia and antibiotic treatment in PEG-filgrastim group less than filgrastim
group.
Fox et al.[18] compared the effectiveness and tolerability of PEG-filgrastim with filgrastim. They
showed that a single dose of PEG-filgrastim is better than filgrastim. This conclusion
was observed based on the frequency and duration of severe neutropenia and febrile
neutropenia.
In the present study, no side effects were reported in patients. However, bone pain
and headache were reported in some studies such as those by Andre and Shi.[19],[20]
This study showed the high cost of PEG-filgrastim is compensated by reducing the number
of visits and less injections. Frequent injections of filgrastim can increase the
risk of drug reactions, several traveling for patients and their families, pain and
fear for children in each injection, and many other problems. However, a more accurate
conclusion requires separate studies in this field.
Limitation
Preparing of PEG-filgrastim by patients was not possible because of no public access
and the high cost of drug. Furthermore, one malignancy was studied due to the limitation
of access to drugs in Iran. We will try to continue our study in other malignancy
in Iranian Children.
Since Iran has restricted access to foreign drugs and because drugs are not covered
by public insurance, their preparation is difficult for patients and their families
and even impossible in some cases. Performing such studies can show the effectiveness
of PEG-filgrastim treatment of neutropenia in malignant children to health managers
and insurance policymakers.
Conclusions
According to the findings, it can be concluded that from is better than filgrastim
to improve neutropenia induced by chemotherapy in patients with acute lymphoblastic
leukemia.
