Data about biosimilar Peg-filgrastim (bioPEG) in autologous stem cell transplant (ASCT) are still scarce. The aim of this study has been to assess efficacy and safety of bioPEG among lymphoma and myeloma patients undergoing ASCT, comparing these data with historical controls receiving other G-CSFs. Furthermore, an economic evaluation has been included to estimate the savings by using bioPEG. This is a prospective cohort study comparing lymphoma and myeloma patients undergoing ASCT and receiving bioPEG (n = 73) with three historical consecutive cohorts collected retrospectively who received other G-CSFs (Lenograstim - Leno - n = 101, biosimilar Filgrastim - bioFIL n = 392, and originator Peg-filgrastim - oriPEG n = 60). We observed a significantly shorter time to neutrophils and platelet engraftment (p < 0.001) in patients treated with bioPEG and oriPEG. Moreover, patients who received bioPEG showed a shorter hospitalization time (p < 0.001) and a lower transfusion need (p < 0.001). We did not observe any significant difference in terms of transplant-related mortality, mucositis, and diarrhea among the four groups. No serious adverse events were associated with bioPEG. Similar data were obtained after running a stratified analysis for lymphomas and myeloma separately conducted by using a propensity score matching. The average total cost per patient of bioPEG was € 18218.9 compared to € 23707.8, € 20677.3 and € 19754.9 of Leno, oriPEG, and bioFIL, respectively. In conclusion, bioPEG seems to be as effective as the originator and more effective than short-acting G-CSFs in terms of post-transplant engraftment in myeloma and lymphoma patients undergoing ASCT. Moreover, bioPEG was cost-effective when compared with the other G-CSFs.

OBJECTIVE: Preoperative chemoradiation (CRT) is expected to increase the rate of curative resection and complete histological response. In this trial, we investigated the efficacy of a neoadjuvant CRT regimen in gastric adenocarcinoma (NCT01565109 trial).
METHODS: Patients with stage IB to IIIC gastric adenocarcinoma, endoscopy ultrasound and computed tomography-scan diagnosed, were eligible for this phase II trial. Neoadjuvant treatment consisted of 2 cycles of chemotherapy with DCF (docetaxel, cisplatin, and 5-fluorouracil [5FU]) followed by preoperative CRT with oxaliplatin, continuous 5FU and radiotherapy (45 Gy in 25 fractions of 1.8 Gy, 5 fractions per week for 5 weeks) administered before surgery. R0-resection rate, pathological complete response (pathCR) rate, and survival (progression-free survival [PFS] and overall survival [OS]) were evaluated as primary endpoints.
RESULTS: Among 33 patients included, 32 patients (97%) received CRT and 26 (78.8%) were resected (R0 resection for all patients resected). Among resected patients, we report pathCR in 23,1% and pathologic major response (tumor regression grade 2 according to Mandard\'s classification) in 26,9%. With a median follow-up duration of 5.82 years (range, 0.4 to 9.24 years), the estimated median OS for all 33 patients was not reached; 1-, 3-, and 5-year OS rates were 85%, 61%, and 52%, respectively. Among resected patients, those whose histological response was tumor grade regression (TRG) 1-2 had significantly better OS and PFS rates than those with a TRG 3-4-5 response (p=0.019 and p=0.016, respectively).
CONCLUSIONS: Promising results from trials involving preoperative chemoradiation followed by surgery in gastric cancer need to be further evaluated in a phase III trial.

Current guidelines recommend using filgrastim or tbo-filgrastim to mobilize hematopoietic progenitor cells in an autologous setting. However, previous studies have suggested other forms of granulocyte colony-stimulating factor (G-CSF) are equally efficacious, possibly with fewer leukaphereses required. Thus, we prospectively studied the efficacy of lenograstim, a glycosylated recombinant form of G-CSF, in multiple myeloma (MM) patients.
From November 2011 to January 2020, 98 MM patients undergoing autologous stem cell transplant (ASCT) from five academic centers in Korea were enrolled. Patients were mobilized with subcutaneous lenograstim (Neutrogin®) with fixed doses of 10 μg/kg for 4 days.
Most of the patients ( N  = 90, 91.8%) achieved at least the targets of 2 × 106 CD34+ cells/kg body weight, and more than half of MM patients ( N  = 57, 58.2%) reached a target of 5 × 106 CD34+ cells/kg body weight. The mobilization failure rate was 8.2% ( N  = 8). The median number of CD34 + cell/kg using G-CSF only was 5.25 × 106 /kg (range 0.49-13.47). Adverse events included transfusion (TF, N  = 53, 54.1%), bone pain ( N  = 6, 6.1%), fever ( N  = 2, 2.0%), and gastrointestinal troubles ( N  = 2, 2.0%). There were no grade 3 or 4 adverse events during mobilization. Body surface area (BSA) at mobilization and platelet TF were factors associated with CD34+ collection. Most patients achieved neutrophil ( N  = 93, 98.9%) and platelet ( N  = 89, 95.7%) engraftment.
Lenograstim can safely and effectively mobilize stem cells in MM autologous settings.

OBJECTIVE: The objective of this study is to evaluate the toxicity of autologous transplantation of non-frozen peripheral blood stem cells in Moroccan patients with multiple myeloma.
METHODS: This was a bicentric retrospective study conducted in the Clinical Haematology Department of Mohammed V Military Teaching Hospital and at the Al Madina Clinic in Casablanca. The study period was from January 2015 to June 2019. All patients with multiple myeloma who had undergone an autologous peripheral stem cell transplant without freezing were included. Mobilisation was performed with lenograstim alone and the collected stem cells were stored for 24-48hours in a blood bank refrigerator at a temperature of 4°C. After standard conditioning with high-dose melphalan, the peripheral blood stem cells were reinjected 24 h following conditioning.
RESULTS: Over the study period, 55 patients received an autologous transplant using non-frozen peripheral blood stem cells. The median richness of the CD34 cells collected was 4.5×106 CD34/kg (range: 2-12.2). The time required for neutrophil recovery was 12 days (range: 7-19). The time required for platelet recovery was 14 days (range: 9-32). The mortality rate within 100 days post-transplant was 3.6%. We did not observe any cases of graft failure.
CONCLUSIONS: Our study finds good feasibility and low toxicity of autologous peripheral stem cell transplantation without freezing in patients with multiple myeloma.

This study evaluated the correlation between the pharmacokinetics and pharmacodynamics of granulocyte colony-stimulating factor (lenograstim) and the impact of initiation time of apheresis on stem cell mobilization in patients with multiple myeloma.
Twenty-four patients with multiple myeloma were randomized into one of the two groups (early vs. late). Lenograstim at 10 μg/kg/day once daily was injected for at least 4 consecutive days. Apheresis was initiated 2 hours after the fourth dose of lenograstim in the early collection group and 16 hours after the fourth dose of lenograstim in the late collection group. Blood sampling for pharmacokinetics was performed within 30 minutes before, and 1, 2, 6, and 24 hours after the fourth dose of lenograstim.
Overall, the two groups (early vs. late, n = 10 vs. 14) exhibited similar baseline characteristics including age, sex, subtype of myeloma, stage distribution, and myeloma-associated symptoms. No correlation was found between plasma lenograstim concentration and peripheral blood (PB) CD34+ cell counts or hematopoietic progenitor cells. In the late collection group, the median number of apheresis procedures for minimal collection was significantly lower (early vs. late: 2 vs. 1; p = 0.04) and there was a higher number of total collected PB CD34+ cells in a single session of apheresis (1.4 vs. 3.1; p = 0.06). There were no differences in median overall PB stem cell collection efficiency.
Late collection positively impacted the number of apheresis procedures for minimal collection, with numerically improved PB stem cell collection efficiency at first apheresis in patients with multiple myeloma.

Randomized trials comparing chemomobilization efficiency between lenograstim and biosimilar filgrastim are lacking. Our previous retrospective study suggested that lenograstim could be more effective than biosimilar filgrastim when used at the same conventional dosage (5 µg/kg) only in lymphoma patients undergoing peripheral blood stem cell mobilization. We planned a prospective randomized study comparing lenograstim 5 µg/kg with biosimilar filgrastim 10 µg/kg to verify the hypothesis of lenograstim superiority even at half the dosage (stress test). Herein we report data after enrolling 60% of planned patients.
From October 2014 to November 2017, a total of 42 of 70 planned patients with lymphoma were randomly assigned to receive lenograstim 5 µg/kg (21) or biosimilar filgrastim 10 µg/kg (21). Patients were stratified according to treatment line at the time of mobilization (1 or ≥2). Primary endpoint was the rate of achievement of the CD34+ cell collection target dose (≥ 4 × 106 /kg). An improvement by 23% was expected to validate the hypothesis of lenograstim superiority.
The two cohorts were balanced for all the baseline features. We observed an identical rate of patients able to reach the targeted CD34+ cell dose and of mobilization failures (90.4 and 4.8% in both cohorts) and a perfect equivalence in any of the secondary collection outcomes. The hypothesis of lenograstim superiority was not corroborated at interim analysis.
Lenograstim at conventional dosage has failed to demonstrate its superiority over biosimilar filgrastim at double the dosage at interim analysis in their first head-to-head trial.

Biosimilar filgrastim (Leucostim®) was shown to be similar in terms of efficacy and safety in hematopoietic progenitor cell mobilization (HPCM) compared to originator filgrastim (Neupogen®) and lenograstim (Granocyte®) in healthy donors and chemomobilization settings. Here we report our retrospective experience with Leucostim® (n: 43) compared to Neupogen® (n: 71) and Granocyte® (n: 32) in steady-state mobilization of patients presenting with Hodgkin lymphoma, non-Hodgkin lymphoma and multiple myeloma. The median age of patients on Leucostim® (56) arm was significantly higher compared to patients who received Neupogen® (50) and Granocyte® (49) (p: 0.039). Patients who underwent HPCM with Leucostim® received less chemotherapy lines (p: 0.026) and courses (p: 0.046) compared to others. Otherwise the study cohort was homogenous in terms of gender, primary diagnosis and various risk factors for mobilization failure. Mobilization failure was defined as failure to achieve a minimum threshold (10/μL) for peripheral blood CD34+ cell concentration to initiate leukapheresis or 0.5×106/kg, 0.8×106/kg and 2×106/kg CD34+ cells in first, second and fourth days of apheresis, respectively. The study groups were similar in terms of median number of CD34+ progenitor cell yield (×106/kg) (Neupogen®: 6.18, Granocyte®: 6.2 and Leucostim®: 6.2) (p: 0.959) and median number of leukapheresis sessions (p: 0.615). The treatment arms were also similar in terms of mobilization failure (Neupogen® 11.3% - Granocyte® 21.9% - Leucostim® 16.3%; p: 0.366). No patient experienced any severe adverse effect during HPCM. Leucostim® is equally effective and safe in HPCM compared to originator G-CSF (Neupogen®) and lenograstim (Granocyte®) in steady-state HPCM setting.

OBJECTIVE: To describe the management and costs associated with G-CSF therapy in cancer patients in France.
METHODS: This study analyzed a representative random population sample from the French national healthcare insurance database, focusing on 1,612 patients with hematological or solid malignancies who were reimbursed in 2013 or 2014 for at least one G-CSF treatment dispensed in a retail pharmacy. Patient characteristics and treatment costs were analyzed according to the type of cancer. Then the costs and characteristics of patients associated with the use of different G-CSF products were analyzed in the sub-set of breast cancer patients.
RESULTS: The most frequent malignancies in the database population were breast cancer (23.3%), hematological malignancies (22.2%), and lung cancer (12.4%). The reimbursed G-CSF was pegfilgrastim in 34.1% of cases, lenograstim in 26.7%, and filgrastim in 17.9%. More than one G-CSF product was reimbursed to 21.3% of patients. The total annual reimbursed health expenses per patient, according to the type of G-CSF, were €27,001, €24,511, and €20,802 for patients treated with filgrastim, lenograstim, and pegfilgrastim, respectively. Ambulatory care accounted for, respectively, 35%, 38%, and 41% of those costs. In patients with breast cancer, ambulatory care cost was €7,915 with filgrastim, €7,750 with lenograstim, and €6,989 with pegfilgrastim, and the respective cost of G-CSF was €1,733, €1,559, and €3,668.
CONCLUSIONS: All available G-CSF products have been shown to be effective in cancer patients, and both daily G-CSFs and pegylated G-CSF are recommended in international guidelines. Nevertheless, this analysis of G-CSF reimbursement indicates that the choice of product can markedly affect the total cost of ambulatory care.

BACKGROUND: Current guidelines recommend prophylaxis with granulocyte colony-stimulating factors (G-CSFs) for patients with cancer who are at greater risk of febrile neutropenia (FN) while receiving chemotherapy. G-CSF biosimilars are available and represent a savings opportunity; however, their uptake has thus far been low.
OBJECTIVE: Our objective was to evaluate prescribing patterns for G-CSFs in the prevention of chemotherapy-related FN and to evaluate the impact of regional guidance on G-CSF prescription.
METHODS: We conducted an observational drug-utilization study in the Lazio region of Italy using the Electronic Therapeutic Plan Registry, which collects information on G-CSF prescriptions reimbursed by the regional health service. This registry includes information on demographics, tumour, indication for G-CSF use and previous G-CSF exposure. All therapeutic plans (TPs) registered from 1 July 2015 to 30 June 2016 were selected. A pharmaceutical policy intervention was implemented in November 2015. We evaluated temporal trends regarding G-CSF substances and compared the frequency of TPs for each G-CSF substance during the pre- and post-intervention periods.
RESULTS: A total of 7082 TPs were eligible for the analysis, corresponding to 6592 patients. The frequency of TPs prescribed after the intervention indicated a significant increase in the use of a filgrastim biosimilar (% difference: 14.4; p < 0.001) and significant decreases in the use of lenograstim (% difference: -6.0; p < 0.001) and pegfilgrastim (% difference: -7.8; p < 0.001). The temporal trends analysis showed an increase in TPs using a filgrastim biosimilar (from 34.4% in July 2015 to 49.8% in June 2016; p < 0.0001) and a decrease in TPs using lenograstim and pegfilgrastim.
CONCLUSIONS: This study shows it is possible to change attitudes towards the prescription of less expensive G-CSFs in the FN setting when the prescriber\'s decision-making processes are supported by evidence that includes both regulatory and clinical information and the analysis of clinical practice data.

TS-DP2 is a recombinant human granulocyte colony stimulating factor (rhG-CSF) manufactured by TS Corporation. We conducted a four-week study of TS-DP2 (test article) in repeated intravenous doses in male and female Sprague-Dawley (SD) rats. Lenograstim was used as a reference article and was administered intravenously at a dose of 1000 μg/kg/day. Rats received TS-DP2 intravenously at doses of 250, 500, and 1000 μg/kg/day once daily for 4 weeks, and evaluated following a 2-week recovery period. Edema in the hind limbs and loss of mean body weight and body weight gain were observed in both the highest dose group of TS-DP2 and the lenograstim group in male rats. Fibro-osseous lesions were observed in the lenograstim group in both sexes, and at all groups of TS-DP2 in males, and at doses of TS-DP2 500 μg/kg/day and higher in females. The lesion was considered a toxicological change. Therefore, bone is the primary toxicological target of TS-DP2. The lowest observed adverse effect level (LOAEL) in males was 250 μg/kg/day, and no observed adverse effect level (NOAEL) in females was 250 μg/kg/day in this study. In the toxicokinetic study, the serum concentrations of G-CSF were maintained until 8 hr after administration. The systemic exposures (AUC0-24h and C0) were not markedly different between male and female rats, between the administration periods, or between TS-DP2 and lenograstim. In conclusion, TS-DP2 shows toxicological similarity to lenograstim over 4-weeks of repeated doses in rats.