Introduction
Pegfilgrastim (PF) and lipegfilgrastim (LF), both
pegylated granulocyte colony-stimulating factors (PGCSFs), are
recommended and widely used to reduce the incidence of febrile
neutropenia (FN). This occurs by prolonged stimulation of the
proliferation, differentiation, and activation of neutrophile
precursors in the bone marrow through binding to the G-CSF receptor
following high-risk chemotherapy (CHT) in a variety of cancer
types, such as breast cancer, lymphomas, sarcomas and
gynaecological cancers, with broader utilisation to mitigate the
risk of FN during the COVID-19 pandemic by preventing or shortening
the duration and severity of neutropenia (1–8). The
Delphi expert consensus also supports the use of PGCSFs in primary
and secondary prophylaxis to maintain CHT intensity in CHT regimens
with the potential to induce severe neutropenia
(≤0.5×109/l) (1).
Biosimilar pegfilgrastim and filgrastim molecules are considered as
effective and safe as their originator products (1–5). In
terms of adherence and reported use by the patients, there is a
guidelines-based preference for PGCSFs, which are administered once
per chemotherapy cycle, over filgrastim, a short acting G-CSF,
which requires daily injections for 10–14 days (1,6).
A meta-analysis of 8 clinical and 3 observational
studies, which encompassed 1,303 high-risk patients, demonstrated
that prophylactic PF significantly reduced FN incidence (5 vs. 29%,
P<0.0001), with a benefit observed in patients aged ≥65 years
(9,10). Similarly, in the NADIR and LEOS
observational studies, prophylactic LF reduced the incidence of FN
to 2 and 2.4%, respectively (11,12).
LF and PF have demonstrated comparable efficacy in reducing severe
neutropenia and FN in patients with breast cancer receiving
adjuvant doxorubicin/docetaxel CHT (13,14)
and in patients with aggressive B-cell NHL treated with CHOP-21,
with an FN incidence of 2% after either LF or PF prophylaxis
(15).
While PGCSFs are generally considered safe, their
long-term safety profile, particularly regarding secondary
haematological malignancies, remains a topic of ongoing discussion.
The incidence of secondary haematological malignancies in patients
treated for solid tumours is complex, with varying estimates and
contributing factors, such as the type of CHT used, radiotherapy
and individual genetic predispositions; however, the potential
leukaemogenic effect of GCSFs is a subject of controversy (16–22).
Real-world data are key for verifying the long-term safety of these
medications in everyday clinical practice. The present study
therefore aimed to conduct a large retrospective analysis to
address these concerns and further evaluate the safety of PF and LF
with respect to the incidence of secondary haematological
malignancies.
Materials and methods
A retrospective analysis of an electronically
managed database of drug administrations and patients registered at
Charles University Hospital (Pilsen, Czech Republic) since 2005
(first application of PF in September 2005) was performed, with
maximum follow-up until December 2023. The present analysis
included only adult patients treated for solid tumours with CHT
supported with the administration of PF or LF. Patients with
haematological malignancies and patients with any granulocyte or
granulocyte-macrophage colony-stimulating factor administered in
their history prior to PGCSF administration were excluded from the
present study. The incidence of haematological malignant neoplasms
was evaluated within the period of the first application of PGCSF
until the last contact with each patient. Statistical univariate
analyses (Fisher's exact test two-tailed) were performed using the
GraphPad Prism 10 Software (Dotmatics) to compare incidence of
secondary haematological malignancy in patients treated with PF and
LF, and patients with breast cancer and with other malignancies.
P<0.05 was considered to indicate a statistically significant
difference.
Results
A total of 1,577 consecutive patients with solid
malignancy, who had ≥1 application of PGCSF in the period of
September 2005 to December 2019 and no evidence of any previous
application of granulopoiesis growth factor in their history, were
assessed and evaluated. From 2005–2010, PGCSFs were administered to
214 (13.6%) patients; from 2011–2015 to 537 (34.1%) patients; and
from 2016–2019 to 826 (52.3%) patients.
The PGCSFs administered included PF originator
(Neulasta®; Amgen, Inc.), PF biosimilar (Pelgraz; Accord
Healthcare) and LF (Lonquex; Teva Pharmaceutical Industries, Ltd.).
PF originator was administered in 1,218 (77.3%) patients from
September 2005-April 2019; PF biosimilar in 143 (9%) patients from
March-December 2019; and LF in 216 (13.7%) patients from August
2014-December 2019.
Reuse of the same or different PGCSFs in a
subsequent chemotherapy line, or a change to a different PGCSF
molecule within the same treatment line (i.e. PF originator changed
to PF biosimilar, or PF biosimilar changed to LF) was observed in
179 patients. Of these, 166 received a different PGCSF molecule
than the original one (Table I). In
a total of 18 patients, the consecutive use of PF originator, PF
biosimilar and LF was observed during their overall oncological
treatment. At the time of evaluation in December 2023, the median
time of follow-up was 57 (0.25–217) months, 4.75 (0–18.1) years,
respectively, with 757 (36.4%) patients followed -up for ≥5 years
and 203 (18.1%) patients for ≥10 years. A total of 629 (39.8%)
patients were alive (39.8%) at the time of the last follow-up in
December 2023, 749 (47.6%) had died and 199 (12.6%) had been lost
to follow-up.
 | Table I.Characteristics of patients (n=1,577)
from 2005–2019 and PGCSF use. |
Table I.
Characteristics of patients (n=1,577)
from 2005–2019 and PGCSF use.
| Characteristics | Patients, n (%) |
|---|
| Age, median (range),
years | 54 (18–84) |
| Sex |
|
|
Female | 1,116 (71.0) |
| Male | 461 (29.0) |
| Type of cancer |
|
|
Breast | 751 (47.6) |
|
Gastrointestinal (C15-20) | 204 (12.9) |
|
Germinal | 185 (11.7) |
|
Tubo-ovarian | 123 (7.7) |
|
Pancreatic cancer | 50 (3.1) |
| Uterus
(C53-54) | 50 (3.1) |
|
Sarcomas | 40 (2.5) |
| Urinary
tract | 35 (2.2) |
| Head and
neck | 34 (2.2) |
|
Prostate | 23 (1.4) |
|
Other | 82 (5.1) |
| PGCSF molecule |
|
| PF
originator | 1,218 (77.3) |
| PF
biosimilar | 143 (9.0) |
| LF
original | 216 (13.7) |
| Sequence of molecules
when using different PGCSFa |
|
| PF
originator changed to LF | 54 (32.5) |
| PF
originator changed to PF biosimilar | 49 (29.5) |
| LF
changed to PF originator | 33 (19.8) |
| LF
changed to PF biosimilar | 18 (10.8) |
| PF
biosimilar changed to LF | 12 (7.2) |
| PF
biosimilar changed to PF originator | 0 (0.0) |
Within the cohort of 1,577 patients, a total of 7
haematological malignancies were diagnosed (0.44%) during the
follow-up period. In total, 2 patients were diagnosed with
myelodysplastic syndrome, 3 patients with multiple myeloma and 2
patients with non-Hodgkin lymphoma (Table II and III). All cases with haematological
malignancy development were observed in the cohort of patients
treated with PF originator (PF originator 7/1,218 vs. PF biosimilar
0/143, P<0.999; PF originator 7/1,218 vs. LF 0/216, P=0.6). In
total, 5 out of 7 patients that developed haematological
malignancies were treated for breast cancer in their history; of
the total cohort, haematological malignancies developed in 5 out of
751 (0.66%) patients with breast cancer. The difference in the
incidence of secondary haematological malignancies between patients
with breast cancer (0.66%) and patients with other malignancies
(0.24%) was not statistically significant (patients with breast
cancer 5/751 vs. other malignancies 2/826; P=0.26). It is important
to note that one patient had a proven germline mutation in
PALB2 (c.3256C>T) (Table
III).
| Table II.Secondary haematological malignancy
incidence by PGCSF type and tumour. |
Table II.
Secondary haematological malignancy
incidence by PGCSF type and tumour.
| PGCSF molecule | No. of patients
with secondary haematological malignancy | Type of secondary
haematological malignancy | Type of primary
tumour |
P-valueb |
|---|
| PF originator | 7 | Multiple
myelomaa (n=2) | Breast cancer
(n=5) | - |
| (n=1,218) |
| Gastric diffuse
large B-cell lymphoma (n=1) |
|
|
|
|
| Follicular lymphoma
(n=1) |
|
|
|
|
| Myelodysplastic
syndrome with AML transformation (n=1) |
|
|
|
|
| Myelodysplastic
syndrome with pancytopenia (n=1) | Ovarian cancer
(n=1) |
|
|
|
| Multiple
myelomaa (n=1) | Germinal tumour
seminoma (n=1) |
|
| PF biosimilar
(n=143) | 0 | - | - | >0.999 |
| LF original
(n=216) | 0 | - | - | 0.6 |
| Table III.Patients with secondary
haematological malignancy. |
Table III.
Patients with secondary
haematological malignancy.
| Date of initial
diagnosis | Primary
malignancy | Sex | Age, years | Oncological
treatment and PGCSF used | Haematological
malignancy | Date of subsequent
diagnosis |
|---|
| January 2007 | Germinal tumour
(seminoma) | Male | 63 | Adjuvant CHT BEP 4×
with 4× PF originator for FN primary prophylaxis in February-April
2007 | Multiple
myeloma | January 2022 |
| January 2013 | Breast cancer
(HER2+) | Female | 63 | Adjuvant CHT 4× TAC
with 3× PF originator for FN primary prophylaxis in
September-November 2013 and adjuvant trastuzumab | Gastric diffuse
large B-cell lymphoma | January 2020 |
| June 2015 | Triple negative
breast cancer | Female | 82 | Adjuvant CHT 3× FEC
+ 3× docetaxel with 3× PF originator for FN primary prophylaxis in
October-November 2015 and adjuvant RT | Multiple
myeloma | September 2021 |
| July 2015 | Triple negative
breast cancer, (germline mutation, PALB2 c.3256C>T) | Female | 51 | Adjuvant CHT 6× TAC
with 6× PF originator for FN primary prophylaxis in August-December
2015 and adjuvant RT | Follicular
lymphoma | November 2022 |
| March 2016 | Ovarian cancer
(HGS) | Female | 70 | Adjuvant CHT 5× PC
with 1× PF originator and 1× LF for FN primary prophylaxis in
June-August 2016 and palliative CHT 6× liposomal doxorubicin in
September 2016- March 2017 | Myelodysplastic
syndrome with pancytopenia | August 2017 |
| December 2016 | Breast cancer | Female | 70 | Adjuvant CHT 6× AC
with 2× PF originator for FN primary prophylaxis in July 2017 and
adjuvant RT | Myelodysplastic
syndrome; AML transformation | August 2019;
February 2020 |
| June 2017 | Triple negative
breast cancer | Female | 83 | Adjuvant CHT 6× CMF
with 4× PF originator for FN primary prophylaxis in
October-December 2017 and adjuvant RT | Multiple
myeloma | June 2019 |
Discussion
PGCSFs represent an important component of complex
supportive care in patients treated with chemotherapy for solid
tumours. While biosimilar PF is considered to have comparable
efficacy and safety to its originator product, despite LF not
having a biosimilar counterpart, further observations and long-term
safety monitoring are recommended (1–5).
However, the leukaemogenic effect of granulocyte or
granulocyte-macrophage colony-stimulating factor (GCSF or GMCSF)
remains a subject of controversy. Several observational studies
have suggested that patients with cancer receiving CHT and
supportive care with GCSF or GMCSF have a greater incidence of
acute myeloid leukaemia (AML) or myelodysplastic syndromes (MDS)
compared with those not receiving such growth factors (16–18)
However, the results of subsequent reviews and meta-analyses of
randomised controlled trials of CHT with and without GCSF or GMCSF
reported that growth factor support enables the administration of a
greater relative dose intensity of chemotherapeutic agents compared
with CHT without GCSF or GMCSF, and greater dose intensity is known
to be leukaemogenic, which potentially explained the small increase
in the risk of secondary malignancies reported in the previous
studies, but suggested that this risk was balanced by improvements
in overall survival, reduced cancer recurrence and reduced
occurrence of fatal infections (20–22).
In a previous cohort study of 439,704 patients, a
total of 3,046 cases (0.69%) of haematologic malignancies occurred;
breast cancer survivors had significantly higher standardised
incidence rates of AML and MDS compared with that of women in the
general population. A slight increase in the incidence of multiple
myeloma and acute lymphoblastic leukaemia (ALL) was also reported
(19). In a study of 122,373 breast
cancer survivors, 781 cases of haematologic malignancies occurred
(0.63%), an increase was observed in the risk of AML and MDS among
patients treated with chemotherapy plus GCSF compared with
chemotherapy alone although this was not statistically significant,
and a significant increase in the risk of ALL was observed with
increasing cycles of GCSF (≥4 doses; hazard ratio, 2.3; 95% CI,
1.0–5.1) (16).
Therefore, the results of the present analysis
aligned with the aforementioned studies. Overall, of the present
study cohort (n=1,577), haematological malignancy developed in
0.44% (n=7), with a marked increase in the group of patients with
breast cancer (n=751), with the incidence of 0.66% (n=5). Although
the incidence was higher in patients with breast cancer in both
absolute and relative numbers, this difference was not
statistically significant. Thus, the present study did not find any
significantly increased risks of induction of haematological
malignancies compared with previous observations.
Regarding limitations, the retrospective design of
this study raises the possibility of various biases. However, the
single centre study with implemented standard electronic records of
patients and PGCSF drugs administered can be considered a
relatively reduced variability source of data. Additionally, the
present study investigated a consecutive cohort of patients using
primarily PGCSFs for the prophylaxis of FN or severe neutropenia.
Accurately assessing the longer-term risks of LF and PF biosimilar
compared with that of PF originator (which was related to all cases
of secondary haematological malignancies) requires longer
follow-up. The incidence of secondary haematological malignancies
in patients treated for solid tumours is a complex issue depending
on several risk factors, particularly the type and duration of CHT.
The most notable leukaemogenic effect was observed in alkylating
agents, topoisomerase II inhibitors and particularly platinum
compounds, all of which have been used for treatment purposes
(23–25). Radiotherapy is also a known risk
factor, wherein radiation dose was the main determinant of
secondary haematological malignancies (26). In breast cancer specifically,
radiation alone has been reported to more than double the risk of
both MDS and AML (27).
Individual genetic predispositions may also
contribute to the development of a secondary haematological
malignancy, given that the existence of several genetic syndromes
and specific mutations, such as mutations in the FANC genes or SBDS
gene, are known to increase the risk of haematological
malignancies, often through mechanisms involving bone marrow
failure, such as Fanconi anaemia or Schwachman-Diamond syndrome
(28,29). These syndromes are typically linked
to mutations that affect DNA repair, ribosome biogenesis or
telomere maintenance pathways, which compromise genomic stability
and haematopoietic stem cell function. In the context of MDS
specifically, it has been demonstrated that ~7% of patients carry a
pathogenic germline mutation (30).
However, in the present study cohort, routine germline genetic
testing was not performed due to limited access to such testing in
the past. Consequently, individuals with inherited predispositions
could not be excluded. Notably, as aforementioned, within the
present study cohort of patients with secondary haematological
malignancies, one patient had been genetically tested
(next-generation sequencing for germline mutations) and found to
carry a pathogenic hereditary heterozygous gene mutation in
PALB2 (c.3256C>T). Mutations in the PALB2 gene are
reported to increase the risk not only of breast and pancreatic
cancer, but also of lymphomas and leukaemias in both sexes
(31). PALB2 is a tumour
suppressor gene that works as a crucial partner for the
BRCA2 protein, helping to localize it and facilitate its
essential function in DNA double-strand break repair via homologous
recombination (32). Therefore,
there is a possibility that underlying hereditary factors may have
contributed to the development of secondary haematological
malignancies in a subset of patients in the present study.
In conclusion, the present retrospective study
supported the previously established safety of PGCSFs for the
treatment of patients with solid tumours. However, further
observations with longer follow-up are recommended, particularly
for LF and PF biosimilars, which have a relatively shorter safety
follow-up compared with the PF originator.
Acknowledgements
Not applicable.
Funding
The authors received financial support from the Institutional
Conceptual Development of Research Organisation-Faculty Hospital in
Pilsen (Pilsen, Czech Republic) and Cooperatio Onco-Faculty of
Medicine of Charles University in Pilsen. The present study was
partially supported by NEXTIN Plzen grant support for the
scientific and research objectives of the Department of Oncology
and Radiotherapeutics, Faculty of Medicine of Charles University in
Pilsen (grant no. 50769; Pilsen, Czech Republic).
Availability of data and materials
The data generated in the present study may be
requested from the corresponding author.
Authors' contributions
SV organised the research, coordinated the gathering
of scientific data and wrote the main manuscript. VK, JK, JD and TS
collected data from the database. JF designed, supervised and
organized the research, and reviewed the article. LM reviewed and
expanded relevant data into the article. All authors read and
approved the final manuscript. SV and LM confirm the authenticity
of all the raw data.
Ethics approval and consent to
participate
According to the national ethical guidelines of the
Czech Republic, no ethical approval was needed to conduct the
present retrospective study.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing
interests.
Glossary
Abbreviations
Abbreviations:
|
ALL
|
acute lymphoblastic leukaemia
|
|
AML
|
acute myeloid leukaemia
|
|
BEP
|
bleomycin + etoposide + cisplatin
|
|
CHT
|
chemotherapy
|
|
AC
|
doxorubicin + cyclophosphamide
|
|
TAC
|
AC + docetaxel
|
|
FN
|
febrile neutropenia
|
|
FEC
|
fluorouracil + epirubicin +
cyclophosphamide
|
|
GCSF
|
granulocyte colony-stimulating
factor
|
|
GMCSF
|
granulocyte-macrophage
colony-stimulating factor
|
|
HGS
|
high grade serous
|
|
LF
|
lipegfilgrastim
|
|
MDS
|
myelodysplastic syndrome
|
|
PC
|
paclitaxel + carboplatin
|
|
PF
|
pegfilgrastim
|
|
PGCSFs
|
pegylated GCSF
|
|
RT
|
radiotherapy
|
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