Ten-Year Study Confirms Long-Term Safety of Biosimilar Filgrastim in Healthy Stem Cell Donors
核心洞察
A decade-long prospective surveillance study of 244 healthy stem cell donors found no evidence of long-term safety concerns following treatment with Sandoz's biosimilar filgrastim (Zarzio) for stem cell mobilization.
The study documented 564 adverse events over 10 years, with none of the 98 serious adverse events deemed related to biosimilar filgrastim exposure by treating physicians.
Donors maintained superior physical health scores compared to the general German population even after 10 years (53.0 vs 43.1, p<0.0001), while mental health scores remained comparable to population averages.
A comprehensive 10-year prospective surveillance study has provided reassuring evidence for the long-term safety of biosimilar filgrastim in healthy stem cell donors, addressing lingering concerns about potential adverse effects from granulocyte colony-stimulating factor (搜索) (G-CSF) exposure in this population.
The noninterventional EP06-501 (SMART; NCT01766934) study enrolled 244 adult, healthy, unrelated stem cell donors from the Deutsche Stammzellspenderdatei (搜索) registry at two German centers. Participants received at least one dose of Sandoz's filgrastim biosimilar, Zarzio (marketed as Filgrastim Hexal in Germany), administered subcutaneously for up to five days to mobilize hematopoietic stem and progenitor cells (搜索) for collection by leukapheresis.
Study Population and Design
The donor cohort had a median age of 34 years (mean 35.8 ± 9.8 years; range 19-60 years), with approximately three-fourths being male. The median body mass index was 26.9 kg/m², placing the cohort in the overweight category. Follow-up included structured assessments of physical and mental health, self-reported outcomes via the SF-12 questionnaire, and adverse event reporting at baseline, 1, 6, and 12 months after apheresis, and annually for 10 years.
Adverse Event Profile
Nearly all donors (95%) reported at least one adverse event during the initial mobilization period, with bone pain (搜索) being the most common. After this period, a total of 564 adverse events were documented across all participants, with median onset occurring approximately four years after mobilization (3.86 years for women and 4.02 years for men).
The majority of adverse events were musculoskeletal or connective tissue disorders (n=134) and infections (搜索) or infestations (n=130). Other categories included gastrointestinal (n=29), endocrine (n=18), and vascular disorders (搜索) (n=16). A total of 98 serious adverse events were reported in 56 donors, but none were deemed related to biosimilar filgrastim by treating physicians.
Age and Sex Differences
Significant demographic patterns emerged in adverse event reporting. Younger donors had significantly lower adverse event rates compared with older donors (rate ratio 0.64; 95% CI, 0.43-0.95; P=0.026). Female donors experienced higher annual adverse event rates than male donors (0.40 vs 0.21 events per year; rate ratio 1.87; 95% CI, 1.32-2.64; P<0.001).
The sex difference was most pronounced in the youngest age group, where females had significantly higher adverse event rates than males (0.41 vs 0.12 events per year, rate ratio 3.43, 95% CI 2.02-5.83; P<0.001). In middle and older age tertiles, while females still experienced higher rates, the differences were not statistically significant.
Pregnancy Outcomes
Twelve women reported 13 pregnancies following donation, resulting in 14 live births including one set of twins. Pregnancy-related adverse events such as gestational diabetes (搜索), cervical incompetence (搜索), and gestational hypertension (搜索) occurred only once each, with no clustering or suspected relationship to prior biosimilar filgrastim exposure. No miscarriages, congenital anomalies, or neonatal complications were reported.
Long-Term Well-Being Assessment
SF-12 assessments indicated that donors maintained superior average physical health scores compared with the general German population even after 10 years (53.0 ± 6.9 vs 43.1 ± 6.9; P<0.0001). Mental health scores remained comparable to population averages. Neither long-term declines in health nor increased incidence of malignancies were observed.
The study authors noted that the COVID-19 pandemic did not appear to affect donor well-being during follow-up, providing an unexpected opportunity to assess pandemic-related impacts on physical and mental health without subject-expectancy bias.
Clinical Implications
"No new or excessive adverse events were identified during a 10-year follow-up of mobilized stem cell donors and therefore reassure about the overall safety of stem cell mobilization with G-CSF in healthy volunteers," wrote the investigators.
The findings confirm the established safety profile of filgrastim biosimilars and provide critical long-term reassurance for donor safety in the context of allogeneic transplantation. The results bolster confidence in biosimilar filgrastim products as safe, cost-effective alternatives to reference filgrastim for hematopoietic stem and progenitor cell mobilization.
Regulatory Context
Sandoz's filgrastim biosimilar was first approved in Europe in 2009 under the brand name Zarzio, based on phase 3 confirmatory clinical data in patients with breast cancer (搜索) undergoing myelosuppressive chemotherapy and regulatory extrapolation to other indications. In the United States, the product (filgrastim-sndz, branded as Zarxio) became the first FDA-approved biosimilar on March 6, 2015, representing a major milestone in biosimilar development.
The study, funded by Sandoz, supports the continued integration of biosimilar filgrastim products into transplantation practice and managed care formularies, providing evidence-based reassurance for healthcare providers and patients regarding long-term safety outcomes in healthy donor populations.