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Background F-627 (efbemalenograstim alfa) is a novel long acting granulocyte colony-stimulating factor (G-CSF) that contains two human G-CSF fused to a human immunoglobulin G2 (hIgG2) -Fc fragment with a peptide linker. This studyevaluated the efficacy and safety of F-627, also known as efbemalenograstim alfa (Ryzneuta®) in reducing neutropenia compared with filgrastim (GRAN®). Methods This was a multicenter, randomized, open-label, active-controlled non-inferiority study. Two hundred thirty nine (239) patients were enrolled in thirteen centers and received the chemotherapy with epirubicin (100 mg/m 2 ) and cyclophosphamide (600 mg/m 2 ) on day 1 of each cycle for a maximum of four cycles. Patients were randomized to receive either a single 20 mg subcutaneous (s.c.) injection of F-627 on day 3 of each cycle or daily s.c. injection of filgrastim 5 µg/kg/d starting from day 3 of each cycle. The primary endpoint was the duration of grade 3 or 4 neutropenia in cycle 1. The safety profile was also evaluated. Results The mean (SD) duration of grade 3 or 4 neutropenia in cycle 1 was 0.68 (1.10) and 0.71 (0.95) days for the F-627 and the filgrastim groups, respectively. The Hodges-Lehmann estimate of the between-group median difference (F-627 vs filgrastim) in the duration of grade 3 or 4 neutropenia in cycle 1 was 0 day and the upper limit of the one-sided 97.5% CI was 0 day, which was within the prespecified non-inferiority margin of 1-day. Results for all efficacy endpoints in cycles 2 − 4 were consistent with the results in cycle 1, however a trend towards a lower incidence and a shorter duration of grade 3 or 4 neutropenia and grade 4 neutropenia was observed in the F-627 group compared with the filgrastim group. The ANC nadir in the F-627 group was significantly higher than that in the filgrastim group in each cycle. A single fixed dose of F-627 was well tolerated and as safe as standard daily filgrastim. Conclusions A single fixed dose of 20 mg of F-627 in each cycle was as safe and effective as a daily dose of filgrastim 5 µg/kg/d in reducing neutropenia and its complications in patients who received four cycles of EC. Trial registration ClinicalTrials.gov: NCT04174599, on 22/11/2019.

Purpose The study aims to assess the relative efficacy of granulocyte colony-stimulating factor (G-CSF) products administered as primary prophylaxis (PP) to patients with cancer receiving myelosuppressive chemotherapy. Methods A systematic literature review identified publications (January 1990 to September 2013) of randomized controlled trials evaluating PP with filgrastim, pegfilgrastim, lenograstim, or lipegfilgrastim in adults receiving myelosuppressive chemotherapy for solid tumors or non-Hodgkin lymphoma. Direct, indirect, and mixed-treatment comparison (MTC) were used to estimate the odds ratio and 95 % credible interval of febrile neutropenia (FN) during cycle 1 and all cycles of chemotherapy combined without adjusting for differences in relative dose intensity (RDI) between study treatment arms. Results Twenty-seven publications representing 30 randomized controlled trials were included. Using MTC over all chemotherapy cycles, PP with filgrastim, pegfilgrastim, lenograstim, and lipegfilgrastim versus no G-CSF PP or placebo were associated with statistically significantly reduced FN risk. FN risk was also significantly reduced with pegfilgrastim PP versus filgrastim PP. Over all chemotherapy cycles, there was a numerical but statistically nonsignificant increase in the FN risk for lipegfilgrastim PP versus pegfilgrastim PP. Using MTC in cycle 1, PP with filgrastim, pegfilgrastim, and lipegfilgrastim versus no G-CSF PP or placebo were associated with statistically significantly reduced FN risk. Conclusions In this meta-analysis, using MTC without adjustment for RDI, PP with all G-CSFs evaluated reduced the FN risk in patients receiving myelosuppressive chemotherapy. Future studies are needed to assess the influence of RDI on FN outcomes and to eliminate potential bias between G-CSF arms receiving more intensive chemotherapy than control arms.

Purpose Chemotherapy-induced febrile neutropenia (FN) causes treatment delays and interruptions and can have fatal consequences. Current guidelines provide recommendations on granulocyte colony-stimulating factors (G-CSF) for prevention of FN, but guidance is unclear regarding use of short- vs long-acting G-CSF (e.g., filgrastim vs pegfilgrastim/lipegfilgrastim, respectively). An international panel of experts convened to develop guidance on appropriate use of pegfilgrastim for prevention of chemotherapy-induced FN. Methods Guidance recommendations were developed following a literature review, survey, evaluation of current practice, and an expert meeting. Consensus was established using an anonymous Delphi-based approach. Results Guidance recommendations for prevention of treatment-associated FN were as follows: for treatment with curative intent, maintenance of dose intensity using G-CSF to prevent dose delays/reduction should be standard of care; for treatment-associated FN risk ≥ 20%, short-acting G-CSF/pegfilgrastim should be given from cycle 1 onwards; and for treatment-associated FN risk < 20%, short-acting G-CSF/pegfilgrastim should be given if factors suggest overall risk (including treatment-related and patient-related risk factors) is ≥ 20%. It was agreed that pegfilgrastim and 11 days’ filgrastim have similar efficacy and safety and that pegfilgrastim is preferred to < 11 days’ filgrastim (and may be preferred to ≥ 11 days’ filgrastim based on adherence and convenience); pegfilgrastim is not appropriate in weekly chemotherapy; in split-dose chemotherapy, pegfilgrastim is recommended 24 h after last chemotherapy dose; and during palliative chemotherapy, patient adherence and convenience may favor pegfilgrastim. Conclusion In this era of targeted therapies, additional trials with G-CSF are still required. These recommendations should be used with existing guidelines to optimize pegfilgrastim use in clinical practice.

PurposeFilgrastim (NEUPOGEN®) is the originator recombinant human granulocyte colony-stimulating factor widely used for preventing neutropenia-related infections and mobilizing hematopoietic stem cells. This report presents findings of a systematic literature review and meta-analysis of efficacy and safety of originator filgrastim to update previous reports.MethodsA literature search of electronic databases, congress abstracts, and bibliographies of recent reviews was conducted to identify English-language reports of clinical trials and observational studies evaluating filgrastim in its US-approved indications up to February 2015. Two independent reviewers assessed titles/abstracts and full texts of publications, and extracted data from studies that compared originator filgrastim vs placebo or no treatment. For outcomes with sufficient homogeneous data reported across studies, meta-analysis was performed and relative risk (RR) determined. Data were summarized descriptively for all other evaluated outcomes.ResultsA total of 1194 unique articles evaluating originator filgrastim were identified, with 25 meeting eligibility criteria for data extraction: 18 randomized controlled trials, 2 nonrandomized clinical trials, and 5 observational studies. In chemotherapy-induced neutropenia (CIN), filgrastim vs placebo or no treatment significantly reduced febrile neutropenia incidence (RR 0.63, 95% CI 0.53–0.75) and grade 3 or 4 neutropenia incidence (RR 0.50, 95% CI 0.37–0.68). The most commonly reported adverse event (AE) with filgrastim was bone pain (RR 2.61, 95% CI 1.29–5.27 in CIN). Additional efficacy and safety outcomes are described within indications.ConclusionsThis systematic literature review and meta-analysis confirms and updates previous reports on the efficacy and safety of originator filgrastim. Bone pain was the commonly reported AE associated with filgrastim use.

Background The objective of this study was to compare the efficacy and side effects of a single dose (Pegfilgrastim or PDL) or repeated six daily injections (Filgrastim or PDG) during chemotherapy courses in breast cancer patients in a non-inferiority clinical trial. Methods In this randomized clinical trial, 80 patients were recruited and allocated randomly to two equal arms. In one group, a single subcutaneous dose of PDL was injected the day after receiving the chemotherapy regimen in each cycle. The second arm received a subcutaneous injection of PDG for six consecutive days in each cycle of treatment. The side effects of GCF treatment and its effect on blood parameters were compared in each cycle and during eight cycles of chemotherapy. Results Hematologic parameters showed no significant differences in any of the treatment courses between the two study groups. The comparison of WBC ( p  = 0.527), Hgb ( p  = 0.075), Platelet ( p  = 0.819), Neutrophil ( p  = 0.575), Lymphocyte ( p  = 705) and ANC ( p  = 0.675) changes during the eight courses of treatment also revealed no statistically significant difference between the two study groups. Side effects including headache, injection site reaction and muscle pain had a lower frequency in patients receiving PDL drugs. Conclusion It seems that PDL is non-inferior in efficacy and also less toxic than PDG. Since PDL can be administered in a single dose and is also less costly, it can be regarded as a cost-effective drug for the treatment of chemotherapy-induced neutropenia. Trial registration IRCT20190504043465N1 , May 2019.

Background Mecapegfilgrastim has been previously validated for efficacy and safety in neutropenia prevention during clinical trials. This nationwide, real-world study (RWS) evaluates its role in protecting against moderate to severe chemotherapy-induced neutropenia (CIN) in Chinese patients with non-myeloid malignancies. Methods In this prospective study conducted in the 46 centers across China, the patients with non-myeloid malignancies were enrolled, and received subcutaneous injections of mecapegfilgrastim 24 h after each chemotherapy cycle. Outcomes were monitored over four subsequent chemotherapy cycles. The primary outcome was safety, while secondary outcomes included the incidence of grade 3 or higher neutropenia, grade 4 neutropenia, and febrile neutropenia (FN), etc. Results From June 2019 to March 2022, 2,859 patients were enrolled, contributing to 7,763 observed chemotherapy cycles. Treatment-related adverse events (TRAEs) were noted in 329 patients (11.5%), with white blood cell count increased being the most common (3.6%). The incidence of grade 3 or higher TRAEs was 1.0%. In the first cycle, 236 (8.3%), 125 (4.4%) and 24 patients (0.8%) reported grade ≥ 3 neutropenia, grade 4 neutropenia, and FN, respectively. Across all cycles, the rates of grade ≥ 3 neutropenia, grade 4 neutropenia and FN were 5.8%, 2.7%, and 0.3%, respectively. Notably, primary prophylaxis was associated with lower incidences of grade ≥ 3 neutropenia (7.9%) and grade 4 neutropenia (4.1%) in the first cycle compared to secondary prophylaxis (11.2% and 6.7%, respectively). Conclusion This RWS reinforces the safety and effectiveness of mecapegfilgrastim in preventing moderate to severe CIN among the patients with non-myeloid malignancies, with primary prophylaxis showing a lower incidence of neutropenia.

This study compared efficacy and safety of lipegfilgrastim with filgrastim in pediatric patients. Children and adolescents receiving chemotherapy (4 cycles) for Ewing sarcoma or rhabdomyosarcoma were randomized 1:1 to lipegfilgrastim (100 µg/kg) once per cycle or filgrastim (5 µg/kg), once daily for ≥ 5 days for up to 14 days or until absolute neutrophil count (ANC) recovery. In 39 evaluable patients, no meaningful difference was observed between lipegfilgrastim and filgrastim treatment groups in duration of severe neutropenia (DSN; mean [standard deviation]) in cycle 1 (2.7 [2.25] vs. 2.5 [2.09] days); least squares mean treatment difference (lipegfilgrastim minus filgrastim) 1.0 day (95% CI: -0.21,2.26) or cycles 2–4, duration of very severe neutropenia in cycles 1–4, incidence of severe neutropenia (85% vs. 84%) or very severe neutropenia (70% vs. 68%). The incidence of febrile neutropenia was numerically lower with lipegfilgrastim (35%) vs. filgrastim (42%). Mean area under the curve of ANC until day 15 in cycle 1 was numerically higher with lipegfilgrastim vs. filgrastim (105 × 10 9 /L*days vs. 84 × 10 9 /L*days). There were no meaningful differences between treatment groups, in cycles 1–4, in mean ANC nadir values, or time to ANC nadir or ANC recovery. Mean administration of lipegfilgrastim was less than filgrastim (4 vs. 31.7 times). No unexpected safety signals were observed. Lipegfilgrastim demonstrated comparable efficacy and tolerability to filgrastim in reducing duration and incidence of neutropenia. A reduced dosing frequency of once per cycle could be particularly beneficial for children, enhancing convenience and improving adherence.

A “biosimilar” is a biotechnological product with a lower cost profile and equivalent efficacy and safety to the originator, but post-marketing clinical evaluation of biosimilar products has not been adequately conducted. We prospectively investigated the utility of biosimilar filgrastim in 13 peripheral blood stem cell (PBSC) donors from June 2014 to January 2017. In addition, we retrospectively compared these to another 13 PBSC donors mobilized with the originator filgrastim in the same period. Donor characteristics were equivalent between the groups. The median number of CD34+ cells per donor body weight (BW) and blood volume processed (BV) were 4.87 × 106/kg and 25.5 × 103/mL in the biosimilar group and 4.93 × 106/kg and 16.6 × 103/mL in the originator group, respectively. There were no significant differences between the groups in the number of CD34+ cells per donor BW or BV. All adverse events associated with G-CSF were permissive. The total G-CSF cost was significantly lower in the biosimilar group than in the originator group. These findings suggest that biosimilar filgrastim has the same efficacy and short-term safety as originator filgrastim for PBSC mobilization in healthy donors, with economic superiority. Longer follow-up studies are needed to evaluate the incidence of long-term adverse events.

ABSTRACT Granulocyte colony‐stimulating factor (G‐CSF) mobilizes peripheral blood (PB) progenitor cells from bone marrow (BM) into circulation for PB stem cell transplantation (PBSCT). This study aimed to develop a population pharmacokinetic–pharmacodynamic (PK‐PD) model of filgrastim in healthy subjects to optimize PB CD34+ cell collection. Plasma filgrastim concentrations and CD34+ cell count data were obtained from a clinical study involving healthy Korean subjects. A total of 1378 plasma concentration measurements and 982 CD34+ cell count data collected from 53 subjects were used in the PK‐PD model. Filgrastim PKs were adequately described by a one‐compartment linear disposition model with an additional transit compartment for absorption. Log‐transformed body weight was the only significant covariate affecting the volume of distribution and clearance. CD34+ cell mobilization was best captured by a modified Friberg model, assuming continual entry of proliferating BM stem cells into PB via a single transit compartment. Simulation results suggested that the 5 μg/kg twice‐daily dosing regimen may yield higher CD34+ cell counts compared to the 10 μg/kg once‐daily regimen for achieving target CD34+ cell counts of 20/μL and 50/μL. We successfully developed a robust PK‐PD model of G‐CSF that optimizes the yield of CD34+ cells during allogeneic PBSCT. This model can guide the efficient determination of optimal G‐CSF dosing regimens and CD34+ cell harvesting strategies.