Originator Granulocyte Colony-stimulating Factor Research Articles

Comparison of Biosimilar Filgrastim (Nivestym) Versus Originator Filgrastim (Neupogen) for Peripheral Blood Stem Cell Mobilization for Allogeneic Hematopoietic Stem Cell Transplantation

Background: Allogeneic hematopoietic stem cell transplantation (HSCT) is an optimal and potentially curative therapy for patients with hematologic malignancies. Granulocyte colony-stimulating factor (G-CSF) is used for the mobilization of peripheral blood stem cells (PBSCs) in allogeneic donors, and an optimal CD34 cell dose plays a critical role in successful transplantation. Nivestym, a biosimilar G-CSF to the originator Filgrastim (Neupogen), is now used by multiple institutions as it has become more available; however, there is a lack of data in this regard among healthy donors for allogeneic HSCT mobilization. In this study, we aim to compare the efficacy of Nivestym compared to Neupogen for allogeneic donor PBSC mobilization. Methods: For this retrospective single-center study, we included all (n=541) adult allogeneic HSCT donors at the University of Kansas Medical Center receiving Nivestym (January 2013-July 2020) or Neupogen (July 2020-June 2023) for donor PBSC mobilization. We conducted a bivariate analysis utilizing the ANOVA test. Statistical analyses were performed using SPSS version 28. Statistical significance was determined at p<0.05. Results: Our study included 541 allogeneic HSCT donors who received Neupogen (n=345, 64%) or Nivestym (n=196, 36%) for PBSC mobilization. The median age was 47 (range 17-76) years. The median donor weight was 86 (95% CI 87-91) kilograms. Donors receiving Neupogen had similar pre-GCSF WBC count (median 45 vs 47 K/uL, p=0.739), pre-GCSF CD34 percentages (median 17% vs 17%, p=0.527), and pre-GCSF circulating CD34 count (median 74 vs 74 million cells/kg, p=0.842) compared to donors receiving Nivestym. Neupogen recipients had similar median PBSC product total neutrophil count (TNC, 6.8 vs 6.5 K/uL, p=0.347), product CD34 percentage (75% vs 79%, p=0.068), absolute CD34 count (503 vs 533 million cells, p=0.636), and final CD34 dose (6.1 vs 6.3 million cells/kg, p=0.365) compared to Nivestym recipients. Seven percent (n=28) of donors needed two days of PBSC collection to achieve the target PBSC dose, with a statistically similar proportion noted in Neupogen (n=25, 7.3%) and Nivestym (n=13, 6.6%) cohorts. In a subgroup analysis stratified by age, donors aged 35 or older (n=154) had similar responses in all mentioned variables (p>0.05); however, for donors under the age of 35 years, the CD34 dose was higher in donors receiving Neupogen compared to Nivestym (median 6.9 vs 6.3 million cells/kg, p=0.044). Most of the PBSC collections (98%) were completed in one day, except for five donors in both Neupogen (5%) and Nivestym (8.5%) cohorts. Conclusions: Biosimilar G-CSF (Nivestym) demonstrated similar efficacy for peripheral blood stem cell mobilization compared to the originator G-CSF (Neupogen) among allogeneic HSCT donors. In donors aged 35 years or younger, a slightly lower PBSC product CD34 count was noted with Nivestym compared to Neupogen.

A Systematic Literature Review of Overall Survival and Delivered Dose Intensity in Cancer Patients Receiving Chemotherapy and G-CSF in Randomized Control Trials

IntroductionAdvances in cancer diagnosis, treatment and supportive care have contributed to improvements in overall survival (OS) in recent decades. Granulocyte colony-stimulating factor (G-CSF) has been shown to reduce neutropenic complications associated with chemotherapy. G-CSF support may improve disease control and survival by minimizing dose reductions and treatment delays as well as enabling administration of dose-dense regimens, dose escalation and additional chemotherapeutic agents when indicated. With the introduction of biosimilar G-CSFs, the impact of G-CSF on OS reported in recent randomized clinical trials is of considerable interest. We undertook an updatedsystematic literature review to determine the impact of G-CSFon delivered dose intensity and OS in cancer patients receiving chemotherapy for solid tumors or malignant lymphoma.MethodsFollowing our previous review (Lyman G et al, Ann Oncol 2013;24:2475-84), relevant publications between September 1, 2012 and March 20, 2017 were identified according to best-practice principles and reported in compliance with PRISMA requirements. Randomized, controlled trials comparing primary G-CSF support vs no initial G-CSF and reporting survival measures or occurrence of secondary tumors including acute myeloid leukemia [AML] or myelodysplastic syndrome [MDS]) with a minimum follow-up of 24 months were identified. Following the initial treatment cycle, control subjects may have received no G-CSFs, G-CSFs at the discretion of the treating physician, or secondary use of G-CSFs. Exclusion criteria included non-random assignment to the treatment group; G-CSF administered from the start in all study arms; use of granulocyte macrophage colony-stimulating factor; patients receiving stem cell or bone marrow transplantation, or a prior diagnosis of leukemia of any type.Full electronic search was undertaken of of Embase, Medline In-Process and Cochrane libraries. No language restrictions were imposed on the literature search. Abstracts of papers initially identified were evaluated independently by two investigators for eligibility using specified inclusion/exclusion criteria. All potentially relevant papers were evaluated in detail. Bibliographies of all identified relevant studies were used to perform a recursive search. Full papers were assessed independently by two investigators according to the predefined eligibility criteria. Any disagreement between investigators was resolved by discussion.A meta-analysis was conducted to estimate the relative risk (RR) and risk difference for OS between patients who did or did not receive primary G-CSF support. As previously reported, four prospectively-defined study designs reflecting differing dosing schedules were evaluated for impact of primary G-CSF support.Statistical software R was utilized for these analyses.ResultsA total of2604 publications were identified. After removing duplicate reports and further screening, 14 recent studies met the inclusion criteria. Nine studies reported OS and 2 reported incidence of AML/MDS. Sample sizes ranged from 85 to 2091 patients with solid tumors or lymphoma at various stages.The updated meta-analysis showed that OS was significantly improved in patients receiving primary G-CSF vs patients who did not (relative risk [RR] of death during follow-up = 0.92; 95% confidence intervals [CI]: 0.90, 0.95; p<0.0001) [Table]. Study design groups 2, 3 and 4 also had significant RRs favoring G-CSF (see table). Based on the reported and extracted data, it was not possible to make any conclusions regarding OS differences between originator and biosimilar G-CSF formulations.Of the 2 studies evaluating AML/MDS, 1 reported no cases during follow-up in either arm and the other reported 9 occurrences in the G-CSF arm and 2 in the control arm: RR = 1.85; 95% CI: 1.19, 2.88; p=0.0064.ConclusionsResults of this systematic literature review and meta-analysis confirm a modest but statistically significant increase in OS in patients undergoing chemotherapy with primary G-CSF support for solid tumors and lymphoma. [Display omitted] DisclosuresYau:Hexal: Employment. Nakov:Hexal: Employment. Krendyukov:Hexal: Employment.

Real World Clinical Experience of Biosimilar G-CSF (Grastofil) for Autologous Peripheral Blood Stem Cell Mobilization: Single Center Experience in Canada Following Early Adoption.

Introduction: Granulocyte colony-stimulating factor (G-CSF) is the first line treatment for mobilization, most commonly using a regimen of daily filgrastim. The use of biosimilars can provide substantial cost savings to the health care system while delivering comparable efficacy outcomes. In 2016, the Saskatchewan Cancer Agency was a leader in Canada, instituting formulary changed from a G-CSF originator product to a cost savings alternative biosimilar for stem cell mobilization prior to autologous stem cell transplant (ASCT) and for engraftment. The purpose of this study was to investigate the clinical comparability of biosimilar G-CSF to its reference product in a real-world clinical setting and to validate use of the biosimilar in mobilization and engraftment—an indication which had been granted by extrapolation. Methods: A retrospective chart review was completed including all patients diagnosed with a hematological malignancy between 2012 and 2018 who underwent ASCT. To assess real-world outcomes across a diverse population, successful CD34+ stem cell collection was compared between patients mobilized with originator filgrastim, Neupogen, and biosimilar filgrastim, Grastofil. Additional comparisons included the number of apheresis required, time to absolute neutrophil count (ANC) engraftment, platelet engraftment, length of hospital stay, and Plerixafor use. Results: 217 patients were mobilized and transplanted during the study period. There was no statistically significant difference in success rate between patients mobilized with biosimilar filgrastim and those who had received originator G-CSF (100% vs. 92.4%, p = 0.075). Neither disease type, nor concurrent chemomobilization regimen resulted in a detectable difference between the two G-CSF products in successful stem cell harvest. Engraftment was highly similar between groups, as demonstrated by ANC recovery (11.6 days Neupogen vs. 11.6 days Grastofil), platelet recovery (14.0 days Neupogen vs. 14.2 days Grastofil), and total length of hospital stay (22.4 days Neupogen vs. 22.3 days Grastofil). No statistically significant difference in adjunctive use of Plerixafor® was observed between Neupogen and Grastofil patients (25.9% vs. 23.4%, p = 0.72). Conclusion: Extrapolation of indications for biosimilars is justified. This real-world evidence builds upon registrational studies to confirm that no clinically meaningful differences were detected between originator Neupogen and biosimilar Grastofil in the setting of PBSC mobilization and engraftment post ASCT. Biosimilars are as safe and effective as originator products. Implementation across all approved indications without hesitation maximizes cost savings to the provincial system, allowing for more optimal allocation of health care resources.

Efficacy and Safety of Nivestim Versus Neupogen for Mobilization of Peripheral Blood Stem Cells for Autologous Stem Cell Transplantation

A retrospective cohort study was conducted in Singapore General Hospital to study the safety and efficacy of biosimilar granulocyte-colony stimulating factor (G-CSF) Nivestim for chemo-mobilization of stem cells for autologous stem cell transplant (autoSCT). All patients who underwent an autoSCT between January 2011 and December 2016 were screened for eligibility. A total of 194 patients were screened, and 131 were included. Nivestim was used in 65 patients and the originator G-CSF (Neupogen) in 66. Patient characteristics were similar between both arms except for chemo-mobilization regimen used (p < 0.0001). Mobilization success rates were found to be comparable, at 96.9% (Nivestim) and 97% (Neupogen). Adverse events rates were also similar. Median duration of G-CSF use and hospitalization were both found to be shorter in the Nivestim arm. Median drug acquisition cost per mobilization cycle was significantly lower in the Nivestim arm at $533.40 (range $213.40–$1280.20) as compared to $1261.90 (range $574–$2755.20) in the Neupogen arm (p < 0.0001). No difference was observed for neutrophil and platelet engraftment after autoSCT. Nivestim was found to be safe and non-inferior to Neupogen for chemo-mobilization of stem cells for autoSCT, and associated with lower cost and shorter length of hospitalization.

Biosimilar G-CSF Versus Originator G-CSF for Autologous Peripheral Blood Stem Cell Mobilization: A Comparative Analysis of Mobilization and Engraftment

Biologic agents are among the fastest-growing classes of therapeutic products. A biosimilar therapeutic product is defined as one that is similar to an already licensed reference product in regard to quality, safety, and efficacy and is often priced more competitively (Expert Committee on Biological Standardization, 2009; Publicover, et al., 2013).In 2016, the Saskatchewan Cancer Agency effectively changed from a granulocyte colony-stimulating factor (G-CSF) brand name product (Neupogen®) to a biosimilar (Grastofil®) for stem cell mobilization prior to autologous stem cell transplants (ASCT). However, because its efficacy in this setting is currently unknown, many institutions continue to use the brand name product. To address this, we reviewed patient charts and compared the efficacy of CD34+ collection in 170 patients who received Neupogen® and 47 patients who received Grastofil® between 2012 and 2018.Additionally, we analyzed efficacy of mobilization with both G-CSF products either alone or in combination with chemotherapy, patients requiring more than one apheresis day and requirement for Plerixafor®. Time to engraftment, and length of stay in hospital post ASCT were used as clinical efficacy parameters. This analysis is important to ensure that patient outcome is not compromised upon use of Grastofil® as opposed to the already approved reference, Neupogen®. The increased use of biosimilars would allow for decreased costs and more sustainable healthcare.ResultsNeupogen® and Grastofil® had similar efficacy for stem cell mobilization as 92.4% of the patients harvested with the brand name had a successful harvest compared to 100% of the patients given the biosimilar. A successful harvest is defined as a collection of ≥2x106 CD34+ cells for patients planned for one stem cell transplant and ≥4x106 CD34+ cells for patients planned for two transplants. Additionally, the two drugs did not display a statistically significant difference in Plerixafor requirement in a situation with low CD34+ count. Amongst all 217 patients, 25.9% of patients given Neupogen® required Plerixafor® as compared to 23.4% of Grastofil® patients.As seen from Table 1, by using the Wilcoxon test to compare the efficacy of Neupogen® and Grastofil® without chemotherapy for stem cell mobilization, there was no significant difference seen with a p-value of 0.53. Similarly, in patients mobilized with chemotherapy in addition to either Neupogen® or Grastofil®, similar efficacy was seen between the groups given a p-value of 0.95.There was no statistically significant difference between the patient groups with respect to requiring more than 1 day of apheresis. 59.4% of patients mobilized with Neupogen® required more than 1 apheresis day compared to 76.9% of Grastofil® patients (p = 0.11). Similarly, of the Neupogen® and Grastofil® groups mobilized with chemotherapy, 42.5% and 38.1%, respectively, required more than one apheresis day which was not statistically different (p = 0.71). Table 2 presents the engraftment data which also suggests that the two drugs behave with similar efficacy in this respect.Length of stay in hospital post autologous stem cell transplant was an additional variable analyzed. Again, there was no significant difference in length of stay between patients who received Neupogen® (median=18.5 days, IQR=17.0-21.0) or Grastofil® (median=19.0 days, IQR =17.0-22.0) without chemotherapy (p = 0.75). When chemotherapy was added to the mobilizing regimen, lengths of stay post autologous stem cell transplant increased but there was no statistically significant difference in length of stay between Neupogen® plus chemotherapy mobilization (median=22.0, IQR =20.0-26.0) versus Grastofil® plus chemotherapy (median=24.0 days, IQR =21.0-29.0) mobilization (p-value =0.10).In conclusion, when comparing the use of either a Neupogen® or Grastofil® based mobilization regimen in terms of stem cell harvest success, Plerixafor® use, more than one apheresis day required, time to engraftment, and length of stay in hospital, no significant difference was found indicating that both products, the reference agent and its biosimilar have similar efficacy. The use of such biosimilars can provide substantial cost savings to the health care system. [Display omitted] DisclosuresElemary:Roche: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Lundbeck: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding.

What is the role of biosimilar G-CSF agents in hematopoietic stem cell mobilization at present?

Mobilization of hematopoietic stem cells, which has largely replaced bone marrow harvesting as a source of hematopoietic stem cells, using recombinant agents such as filgrastim or lenograstim has become a standard procedure in both patients and healthy donors prior to peripheral blood stem cell collection for autologous and allogeneic stem cell transplantation. Published literature data suggest that mobilization with recombinant granulocyte-colony stimulating factor (G-CSF) is safe and mobilization outcomes are satisfactory. In recent years, besides G-CSF originators, biosimilar G-CSF agents have been approved by the regulatory agencies for the same indications. Current data showed that by using the biosimilar G-CSF, similar results regarding safety and efficacy of hematopoietic stem cell mobilization may be achieved compared to the originator G-CSF. Although the issues such as the similarity to a licenced biological medicine, differences in manufacturing processes, the potential to cause immunogenicity, extrapolation and interchangeability of these biosimilar products are still being discussed by the scientific area, however, more experience with these agents now exists in approved endications and there seems to be no reason to expect significant differences between biosimilar G-CSF and originator G-CSF regarding their efficacy and safety in both patients and healthy donors. Also, the significant cost savings of biosimilars in real life setting may enhance the use of these agents in the future. Nonetheless, the collection of long-term follow-up data is mandatory for both patients and healthy donors, and multicentre randomized clinical trials that directly compare biosimilar G-CSF with the originator G-CSF are needed in order to allow the transplant community to make informed decisions regarding the choice of G-CSF.

Evaluation of a biosimilar granulocyte colony-stimulating factor (filgrastim XM02) for peripheral blood stem cell mobilization and transplantation: a single center experience in Japan.

BackgroundBiosimilar granulocyte colony-stimulating factor (G-CSF) has recently been introduced into clinical practice. G-CSFs are used to mobilize CD34+ cells and accelerate engraftment after transplantation. However, in Asia, particularly in Japan, data for peripheral blood stem cell (PBSC) mobilization by this biosimilar G-CSF are currently lacking. Therefore, the clinical efficacy and safety of biosimilar G-CSF for hematopoietic stem cell transplantation needs to be evaluated in a Japanese context.Materials and methodsThe subjects included two groups of patients with malignant lymphoma and multiple myeloma. All patients received chemotherapy priming for the mobilization of PBSCs. All patients were treated with chemotherapy followed by the administration of either the biosimilar G-CSF, filgrastim XM02 (FBNK), or the originators, filgrastim, or lenograstim.ResultsThere were no significant differences among FBNK, filgrastim, and lenograstim treatments in the numbers of CD34+ cells in harvested PBSCs, the scores for granulocyte/macrophage colony forming units, or for malignant lymphoma and multiple myeloma patients evaluated as separate or combined cohorts. In addition, there were no significant differences in safety, side effects, complications, or the time to engraftment after autologous hematopoietic stem cell transplantation.ConclusionBiosimilar FBNK shows the same efficacy and safety as originator G-CSFs for facilitating bone marrow recovery in Japanese malignant lymphoma and multiple myeloma patients undergoing stem cell transplantation. In addition, it is less expensive than the originators, reducing hospitalization costs.

Mobilization of autologous and allogeneic peripheral blood stem cells for transplantation in haematological malignancies using biosimilar G-CSF.

Biosimilars of the granulocyte colony stimulating factor (G-CSF) filgrastim were approved by the European Medicines Agency (EMA) for registered indications of the originator G-CSF, including prevention and treatment of neutropenia, as well as mobilization of peripheral blood stem cells in 2008. Nevertheless, there is still an ongoing debate regarding the quality, efficacy and safety of biosimilar G-CSF. This article is a meta-analysis of clinical studies on the use of biosimilar G-CSF for mobilization and transplantation of haematopoietic stem cells as available in public databases. All data sets were weighted for the number of patients and parameters and then subjected to statistical meta-analysis employing the Mann-Whitney U-test followed by the Hodges-Lehmann estimator to assess differences between biosimilar and originator G-SCF. A total of 1892 individuals, mostly with haematological malignancies but also including 351 healthy donors have been successfully mobilized for autologous or allogeneic stem cell transplantation using biosimilar G-CSF (Zarzio(TM) : 1239 individuals; Ratiograstim(TM) /Tevagrastim(TM) : 653 individuals). A total of 740 patients with multiple myeloma, 491 with non-Hodgkin's lymphoma (NHL), 150 with Hodgkin's lymphoma (HL) and other diseases are included in this meta-analysis, as well as 161 siblings and 190 volunteer unrelated donors. For biosimilar and originator G-CSF, bioequivalence was observed for the yield of CD34+ stem cells as well as for the engraftment of the transplants. Biosimilar G-CSF has equivalent effects and safety as originator G-CSF.

Update on biosimilars of granulocyte colony-stimulating factor - when no news is good news.

With the approval of the first biosimilar granulocyte colony-stimulating factor (G-CSF), biosimilars - copies of therapeutic biologicals whose patent protection has expired - have finally reached the US healthcare market. Its advent is an occasion for a closer look at recent insights into biosimilar G-CSF and an attempt at prognosticating the future (future role) of biosimilars in general. Recent literature regarding biosimilar G-CSF orbits significantly around patient access and effects on healthcare expenditure. The advent of biosimilar G-CSF has induced unexpectedly large price reductions for short-acting G-CSF. On the clinical side, little excitement is tangible, probably appropriately so, since clinical data indicate nothing short of biological similarity. Although formal clinical trials are few, the plethora of case series and historic comparisons which have come forth offer reassurance about the appropriateness of the regulators' assessment of biosimilar G-CSF as indeed in all respects biologically similar to the originator. All evidence points to an overwhelming similarity of originator and biosimilar G-CSF in all indications. Overall clinical acceptance, albeit possibly significantly dictated by economic pressures, is good. Price reductions exceed predictions and may jeopardize the economic viability of biosimilar programs. A concurrent shift towards long-acting G-CSF ('biobetters') is observed in Europe.

Efficacy of biosimilar granulocyte colony-stimulating factor versus originator granulocyte colony-stimulating factor in peripheral blood stem cell mobilization in de novo multiple myeloma patients

Background aimsFilgrastim and lenograstim are the standard granulocyte colony-stimulating factor (G-CSF) agents for peripheral blood stem cell mobilization (PBSC) in patients who undergo autologous stem cell transplantation. MethodsTo assess whether biosimilars are effective, we conducted a single-center, prospective study that included 40 consecutive de novo multiple myeloma patients who received cyclophosphamide 4 g/m2 per day plus biosimilar filgrastim G-CSF to mobilize PBSC. These patients were compared with a group of 37 patients matched for age, diagnosis, previous chemotherapy and mobilization who had been treated with originator G-CSF. The mean number of CD34+ cells/μL in the peripheral blood was 199.6 ± 207.4 in the biosimilar and 192.8 ± 154.7 in the originator group (P = 0.87). The median number of CD34+ cells/kg recipient collected was 11.5 ± 5.8 and 12.3 ± 5.3 in the biosimilar and originator groups, respectively (P = 0.51). The mobilization failure rate was 2.5% and 2.7% in the biosimilar filgrastim and originator filgrastim cohorts (P = NS), respectively. ResultsTwenty-nine patients in the biosimilar group and 28 patients in the originator group underwent autologous transplantation. There were no statistically significant differences between the biosimilar and originator G-CSF cohorts in terms of hematopoietic recovery parameters and transplant-related toxicities. ConclusionsThe efficacy of biosimilar G-CSF appears to be equivalent to the reference G-CSF.

Potential Cost Savings From Chemotherapy-Induced Febrile Neutropenia With Biosimilar Filgrastim and Expanded Access to Targeted Antineoplastic Treatment Across the European Union G5 Countries: A Simulation Study

PurposeThe objectives of this study were to simulate for the European Union G5 countries the potential cost savings of converting patients from originator granulocyte colony-stimulating factor (G-CSF) filgrastim and pegfilgrastim to a biosimilar filgrastim, to evaluate how reallocating these savings could increase patient access to antineoplastic therapy, and to estimate the number of patients needed to convert to provide antineoplastic treatment to one patient. MethodsThree models were built: (1) to estimate the costs of using originator G-CSFs and the savings generated from switching to a biosimilar G-CSF, (2) to estimate the incremental number of patients who could be provided antineoplastic therapy—rituximab or trastuzumab—in a hypothetical panel of 10,000 patients with cancer, and (3) to calculate the number of patients needed to convert to provide access to anticancer therapy. Scenarios were developed in which the rate of conversion was varied to estimate the effect on total cost savings. This study took the perspective of the payer in the European Union. FindingsThe savings associated with the biosimilar filgrastim over the originator filgrastim ranged from €785 (day 4) to €2747 (day 14) and increased with longer duration of therapy. By contrast, the savings associated with the biosimilar filgrastim over pegfilgrastim decreased over time, ranging from €6199 (day 4) to €471 (day 14). In a hypothetical panel of 10,000 patients with cancer, the savings associated with the biosimilar filgrastim over the originator filgrastim and the expanded access to antineoplastic therapy improved over time, irrespective of conversion rates. Conversely, in the same hypothetical panel, the savings associated with the biosimilar filgrastim over pegfilgrastim reduced over time, irrespective of conversion rates, along with the expanded access to antineoplastic treatment. Under conversion of the originator filgrastim to the biosimilar filgrastim, the number needed to convert to expand access to rituximab ranged from 4 to 14 patients, and the number needed to convert to expand access to trastuzumab ranged from 11 to 38 patients. Under conversion of pegfilgrastim to the biosimilar filgrastim, the number needed to convert to expand access to rituximab ranged from 2 to 24 patients, and the number needed to convert to expand access to trastuzumab ranged from 5 to 63 patients. ImplicationsUse of biosimilar G-CSFs for supportive cancer care could yield potential cost savings and improve patient access to antineoplastic therapy in a budget neutral way—a financial effect with an ethical perspective.

Lower Leukocytosis with Biosimilar Compared with Originator G-CSF during Autologous Stem Cell Mobilization after Chemotherapy in Lymphoma and Multiple Myeloma Patients. a Pharmacovigilance Study of “Rete Ematologica Lombarda” (FARMA-REL)

BACKGROUNDBased on therapeutic equivalence extrapolated from originator, the use of biosimilar Granulocyte-Colony Stimulating Factor (G-CSF) in the context of stem cell harvest was approved by the European Medicines Agency (EMA), however “ad hoc” studies are limited. AIMSTo assess the efficacy and safety profile of biosimilar compared with originator G-CSF on PBSC autologous mobilization in association with chemotherapy (CT) in lymphoma (LY) and multiple myeloma (MM) patients (pts) treated in the Hematology Units of “Rete Ematologica Lombarda” (REL). PATIENTS AND METHODSData retrospectively collected from consecutive pts with Hodgkin disease (HD), non-Hodgkin LY (NHL) and MM undergoing PBSC harvest after CT with biosimilar filgrastim between July 2012 and December 2013 (LY) or June 2014 (MM), were compared with a historical control group treated with originator G-CSF. Biosimilar G-CSF was used at doses ranging from 5 (MM and lymphoma HIV-negative) to 10 mcg/kg/d (lymphoma HIV-positive) subcutaneously, starting from the day after the end of CT until the end of leukapheresis. The Shapiro-Wilk test was used to assess normality of data: p-values were derived from chi-square test for categorical data and from Mann–Whitney U-test for continuous data. RESULTSOne hundred-five leukapheresis from 96 consecutive pts including 3 HD, 51 NHL (46 HIV-negative and 5 HIV-positive) and 42 MM cases were analyzed. Median age was 53 yrs (19-65) among LY and 63 (43-72) among MM pts. Thirty-two/54 (59 %) and 19/42 (45 %) cases were male, respectively. Mobilization was planned as part of first line CT in 65% of LY pts; only one case was mobilized during 3rd line CT. Forty-five LY cases (47 %) had been previously treated with alkylating drugs (47 %), three (3 %) with fludarabine-containing regimens. All MM pts mobilized after first line CT.Mobilization started a median of 13 (range 10-21) and 10 (range 10-18) days after CT for LY and MM, respectively; it was completed in a median of one procedure (range: LY 1-4, MM 1-3). Median number of CD34+ cells collected was: 9,1 (range 3,0-47) and 7,8 (range 4,1-12,9) x 106/Kg/pt in LY and MM pts, respectively. Planned end-point was reached in all MM cases and all but 2 LY cases (3 %).Biosimilar G-CSF use was well tolerated in both LY and MM pts: mild bone pain (WHO grade 1-2) was frequently reported (LY: 16/54, 23 %; MM: 16/42, 38 %); two LY pts needed treatment with acetaminophen for headache (1) and bone pain (1), both WHO grade 3.Data were compared with a historical control group of 58 LY pts (HD 10, NHL 45, NHL-HIV 3) and 32 MM pts mobilized with originator G-CSF (filgrastim or lenograstim)(Table): while MM cohorts are similar, LY cohorts differed for a higher frequency of mobilization with high-dose cyclophosphamide (2/54, 4 % vs. 14/58, 24 %, p<0.001) and a slight prevalence of HD cases (3/54, 5 % vs. 10/58, 17%, p= 0.053) only. Median number of procedures, CD34+ count peak and CD34+ collected were similar in both groups; however a difference in median WBC count peak during leukapheresis was documented in both cohort, statistically significant in LY, even if treated without cyclophosphamide.CONCLUSION. We confirm efficacy and safety of biosimilar filgrastim for autologous PBSC mobilization in LY and MM pts. Noteworthy, biosimilar seems to be more selective on CD34+ cells compared with originator G-CSF, inducing efficient CD34+ cells mobilization with lower leukocytosis. This result, confirmed in both LY and MM populations, needs to be proved in larger studies and can play a major role in the setting of voluntary donors. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Biosimilar Granulocyte Colony-Stimulating Factor Is Effective in Reducing the Duration of Neutropenia After Autologous Peripheral Blood Stem Cell Transplantation

BackgroundAutologous peripheral blood stem cell transplantation (APBSCT) is the standard of therapy for patients with multiple myeloma and refractory Hodgkin's and non-Hodgkin's lymphomas. Granulocyte colony-stimulating factor (G-CSF) is widely used to accelerate hematopoietic recovery after transplantation and to reduce the morbidity and mortality associated with prolonged neutropenia. Biosimilar G-CSF is approved for the same indications as the originator G-CSF. This is one of the first reported uses of a biosimilar G-CSF for neutrophil recovery after APBSCT. MethodsA total of 23 consecutive patients with hematological malignancy (multiple myeloma, Hodgkin's and non-Hodgkin's lymphomas, and acute myelogenous leukemia) were recruited at the Department of Haematooncology and Bone Marrow Transplantation at the Medical University of Lublin. Patients (12 men and 11 women; median age, 47 ± 13 years) received biosimilar G-CSF (Zarzio, Sandoz Biopharmaceuticals) after myeloablative chemotherapy (primarily BiCnU, etoposide, cytarabine, and melphalan or melphalan 140/200 mg/m2) followed by PBSCT. The median number of transplanted CD34+ cells was 4.2 ± 0.8 × 106/kg body wt. G-CSF therapy was started when absolute neutrophil count (ANC) was <0.5 × 109/L and was continued until ANC reached >1.5 × 109/L for 3 consecutive days. Hematopoietic recovery parameters were compared with those in the control group, which consisted of 23 consecutive patients transplanted in the period before the biosimilar G-CSF group and receiving originator G-CSF (Neupogen, Amgen). ResultsThe mean duration of treatment with biosimilar and originator G-CSF was 14.4 ± 5.1 and 18.6 ± 11.5 days, respectively (P = .43). The adverse event profile was comparable between the biosimilar G-CSF and originator G-CSF groups, with similar occurrence of neutropenic fever (5 versus 6 patients) and bone pain (7 patients in each group). One patient in the biosimilar group had neutropenic enterocolitis and sepsis. There was no case of death in either group. Granulocyte recovery in the study group was as follows: mean days to ANC >0.5 × 109/L was 13.0 ± 4.0 days; to ANC >1.5 × 109/L, 13.6 ± 4.5 days; and to ANC >1.5 × 109/L, 14.0 ± 4.7 days. Mean duration until platelet recovery >20 × 109/L was 16.1 ± 4.4 days. There were no statistically significant differences between the biosimilar and originator G-CSF groups in hematopoietic recovery parameters. ConclusionsBiosimilar G-CSF is safe and effective in reducing the duration of neutropenia in patients undergoing myeloablative therapy followed by APBSCT and probably in cost savings in transplantation budgets.

Pharmacoeconomics of granulocyte colony-stimulating factor: a critical review.

In the USA, neutropenia-related hospitalization is estimated to occur in 34.2 cases per 1,000 chemotherapy-treated patients. The cost of hospitalization is significant with estimates ranging, on average, from $10,000 to $30,000 per neutropenia-related hospitalization. Prophylactic use of granulocyte colony-stimulating factor (G-CSF) significantly reduces the risk and duration of neutropenia-related negative events. However, the exact economic benefits of using G-CSF prophylactically are not completely known. The objective of this review is to examine the cost of G-CSF as primary prophylaxis (PP) as well as when used reactively to treat severe neutropenia (SN) or febrile neutropenia (FN). Electronic databases were searched for studies published up to January 2014. The evidence supporting the cost-effectiveness of PP use of G-CSF is inconsistent. The cost savings of PP use of G-CSF associated with the reduction of neutropenia-related events are offset by the increased costs associated with improved chemotherapy administration. Cost savings due to the reduction in mortality and disease/symptoms and use of dose-dense regimens have not been adequately incorporated into previous cost-effectiveness studies. Available data suggest that using G-CSF in conjunction with antibiotics is more cost-effective than antibiotics alone when treating patients with SN/FN. Recent studies of biosimilars suggest that they are as effective as originator G-CSFs and, given their lower cost, could represent a cost-effective alternative. Finally, studies have not taken into consideration the indirect patient costs of experiencing a neutropenia-related event. G-CSF use is effective in preventing SN/FN. Costs due to hospitalization and other neutropenia-related events are lower in patients treated with G-CSF as PP versus untreated patients. Despite this, many studies have not found solid evidence for the overall cost-effectiveness of PP use of G-CSF. One possibility for this is that patients receiving G-CSF prophylactically often receive more intense chemotherapy regimens, have better relative dose intensity, and fewer dose delays, and thereby have greater costs associated with chemotherapy administration than patients who do not receive G-CSF.

Biosimilar granulocyte-colony-stimulating factor for healthy donor stem cell mobilization: need we be afraid?

Biosimilars are approved biologics with comparable quality, safety, and efficacy to a reference product. Unlike generics, which are chemically manufactured copies of small-molecule drugs with relatively simple chemical structures, the biosimilar designation is applied to drugs that are produced by living organisms, implying much more difficult to control manufacturing and purification procedures. To account for these complexities, the European Medicines Agency (EMA), the US Food and Drug Administration, the Australian Therapeutic Goods Administration, and other regulatory authorities have devised and implemented specific, markedly more demanding pathways for the evaluation and approval of biosimilars. To date, several biosimilars have been approved, including versions of somatropin, erythropoietin, and granulocyte–colony-stimulating factor (G-CSF), and several biosimilar monoclonal antibodies are currently in development. The reference G-CSF product (Neupogen, Amgen) has been used for many years for prevention and treatment of neutropenia and also for mobilization of peripheral blood stem cells (PBSCs). However, concerns have been raised about the safety and efficacy of biosimilar G-CSF during PBSC mobilization procedures, especially in healthy donors. This article reviews the available evidence on the use of biosimilar G-CSF in this setting. Aggregate clinical evidence supports the assessment by the EMA of biosimilar and originator G-CSF as highly biologically similar, with respect to desired and undesired effects.

A clinical comparison of the efficacy and safety of biosimilar G-CSF and originator G-CSF in haematopoietic stem cell mobilization

BackgroundRecombinant granulocyte colony-stimulating factor (G-CSF) is widely used to mobilize haematopoietic stem cells. We compared the efficacy and safety of a biosimilar G-CSF (Zarzio®, Sandoz Biopharmaceuticals) with the originator G-CSF (Neupogen®, Amgen) in patients with haematological malignancies. MethodsA total of 108 patients were included in this study, 59 of whom were female (49 male), with an overall median age of 51 years (range 19–69). Patients had multiple myeloma (n=46), non-Hodgkin's lymphoma (n=28), Hodgkin's lymphoma (n=26), or other diagnosis (n=8). After administration of mobilizing regimens (primarily high-dose etoposide, high-dose cyclophosphamide, intermediate-dose Ara-C or ESHAP), patients were randomized to a standard daily 10μg/kg dose of biosimilar G-CSF (n=54) or originator G-CSF (n=54). ResultsMedian duration of G-CSF administration was 8 days with both biosimilar G-CSF (range 4–17) and originator G-CSF (range 4–14). Both groups had a median of one apheresis with a median time until first apheresis of 11 days. There were no statistically significant differences between groups in the mean±SD number of mobilized CD34+ cells/μL in peripheral blood or the number of CD34+ cells/kg body weight. Five patients (9%) in the originator G-CSF group and six patients in the biosimilar G-CSF group (11%) did not mobilize sufficient CD34+ cells. The adverse event profile was similar between groups. ConclusionsA biosimilar G-CSF (Zarzio®) demonstrated similar efficacy and safety as the reference originator G-CSF (Neupogen®) in hematopoietic stem cell mobilization in patients with haematological malignancies.

Biosimilar G-CSF Based Mobilization of Peripheral Blood Hematopoietic Stem Cells for Autologous and Allogeneic Stem Cell Transplantation

The use of granulocyte colony stimulating factor (G-CSF) biosimilars for peripheral blood hematopoietic stem cell (PBSC) mobilization has stimulated an ongoing debate regarding their efficacy and safety. However, the use of biosimilar G-CSF was approved by the European Medicines Agency (EMA) for all the registered indications of the originator G-CSF (Neupogen®) including mobilization of stem cells. Here, we performed a comprehensive review of published reports on the use of biosimilar G-CSF covering patients with hematological malignancies as well as healthy donors that underwent stem cell mobilization at multiple centers using site-specific non-randomized regimens with a biosimilar G-CSF in the autologous and allogeneic setting.A total of 904 patients mostly with hematological malignancies as well as healthy donors underwent successful autologous or allogeneic stem cell mobilization, respectively, using a biosimilar G-CSF (520 with Ratiograstim®/Tevagrastim, 384 with Zarzio®). The indication for stem cell mobilization in hematology patients included 326 patients with multiple myeloma, 273 with Non-Hodgkin's lymphoma (NHL), 79 with Hodgkin's lymphoma (HL), and other disease. 156 sibling or volunteer unrelated donors were mobilized using biosimilar G-CSF. Mobilization resulted in good mobilization of CD34+ stem cells with side effects similar to originator G-CSF. Post transplantation engraftment did not significantly differ from results previously documented with the originator G-CSF. The side effects experienced by the patients or donors mobilized by biosimilar G-CSF were minimal and were comparable to those of originator G-CSF.In summary, the efficacy of biosimilar G-CSFs in terms of PBSC yield as well as their toxicity profile are equivalent to historical data with the reference G-CSF.

A non-interventional study of biosimilar granulocyte colony-stimulating factor as prophylaxis for chemotherapy-induced neutropenia in a community oncology centre

Prophylaxis with granulocyte colony-stimulating factor (G-CSF) reduces the severity of chemotherapy-induced neutropenia. Biosimilar G-CSF is now approved for use, based on comparable efficacy, safety and quality with the originator product. We conducted a retrospective review of patients' charts following the switch from originator G-CSF (Neupogen(®)) to biosimilar G-CSF (Zarzio(®)/Filgrastim Hexal(®)) in a large community oncology practice. A total of 77 consecutive patients with cancer who received biosimilar G-CSF were reviewed, as were 25 patients who received originator G-CSF at the same centre. The median age of patients in the biosimilar G-CSF cohort was 67 years (range 20-83). In this cohort 48% had chemotherapy with a febrile neutropenia risk of >20%. Biosimilar G-CSF was given as primary prophylaxis in 52% and as secondary prophylaxis in 48% of patients. Age and febrile neutropenia in medical history or in previous chemotherapy were factors that triggered the use of G-CSF in patients with a febrile neutropenia risk of <20%. One patient developed febrile neutropenia. Neutropenia led to chemotherapy dose reductions in five patients (6.5%) and discontinuation in two patients (2.5%). No unexpected safety findings were observed. Patient characteristics were generally similar in the originator G-CSF cohort. Only 24% of patients had a febrile neutropenia risk >20% and 36% received primary prophylactic G-CSF. One patient developed febrile neutropenia. Neutropenia led to chemotherapy dose reductions in two patients (8%) and discontinuation in two patients (8%). Biosimilar G-CSF was effective and prevented dose reductions/discontinuation in the majority of patients. Biosimilar G-CSF was considered clinically comparable to its reference product.

First Reported Use of a Biosimilar G-CSF in Allogeneic Stem Cell Mobilisation

Abstract 4571 OBJECTIVES:Biosimilar granulocyte colony-stimulating factor (G-CSF) has been approved on the basis of comparable quality, safety and efficacy as the originator product. Approval of biosimilar G-CSF is in the same indications as the originator, including autologous and allogeneic peripheral blood stem cell (PBSC) mobilisation, for which it is being used throughout our large hospital group in Paris, France. Concerns have been raised by professional bodies over use of biosimilar G-CSF in allogeneic transplants. To our knowledge, this is the first reported use of biosimilar G-CSF in healthy donors for allogeneic transplantation. METHODS:Healthy related donors received biosimilar G-CSF (EP-2006, Sandoz Biopharmaceuticals) 10 μg/kg/day for PBSC mobilisation. G-CSF was administered on days 1–4 with the first leukapheresis performed on day 5. If the required number of CD34+ cells per recipient body weight (4 × 106 CD34+ cells/kg) was not collected, G-CSF administration was continued and a second PBSC collection was performed on day 6. Further G-CSF administration and a third leukapheresis was done on day 7 if required. RESULTS:Twelve healthy donors (7 male, 5 female; mean ± SD age 61.0 ± 7.8 years, range 51–73) received biosimilar G-CSF for PBSC mobilisation. Median donor body weight was 82 kg (range 55–115 kg). Median CD34+ cell count on day 5 was 75/ml (range 23–140). A single leukapheresis after 4 injections of biosimilar G-CSF was sufficient to collect the CD34+ cell dose required in six donors with peripheral blood (PB) CD34+ counts ranging from 80–140 ml. Six donors underwent a second leukapheresis after 5 days of biosimilar G-CSF, one of whom (a 73-year old female) underwent a third leukaphereses on day 7 (PB CD34+ at first apheresis 23 ml). Median number of CD34+ cells per recipient bodyweight was 5.5 × 106 cells/kg (range 2.6–8.9). Five donors reported bone pain (4 mild, 1 moderate severity) which was effectively treated with paracetamol. No other adverse events were reported. Blood measurements were normal in all donors when assessed one week after the end of mobilisation. These findings are consistent with our previous use of originator G-CSF (Neupogen®) in allogeneic stem cell mobilisation. CONCLUSION:These preliminary findings suggest biosimilar G-CSF is effective and well-tolerated in allogeneic stem cell mobilisation. Further studies are required to assess longer-term safety outcomes. The use of biosimilar G-CSF may provide important cost-savings when compared with the originator product. Disclosures:No relevant conflicts of interest to declare.

Efficacy and Safety of Biosimilar G-CSF and Originator G-CSF for Haematopoietic Stem Cell Mobilisation: A Randomised Comparison

Abstract 4392 OBJECTIVES:Recombinant granulocyte colony-stimulating factor (G-CSF) is widely used to mobilise haematopoietic stem cells. Biosimilar filgrastim is now available in Europe. No differences were observed between biosimilar filgrastim (n=40) and a retrospective cohort of patients receiving originator filgrastim for stem cell mobilisation in a previous comparison, although no safety findings were reported (Lefrère et al. Adv Ther 2011;28:304−10). We compared the efficacy and safety of a biosimilar filgrastim (EP-2006, Sandoz Biopharmaceuticals) with originator filgrastim (Neupogen®, Amgen) in patients with haematological malignancies. METHODS:A total of 108 patients were included in this study, 59 of whom were female (49 male), with an overall median age of 51 years (range 19–69). Patients had multiple myeloma (n=46), Hodgkin's lymphoma (n=26), non-Hodgkin's lymphoma (n=28) or other diagnosis (n=8). Median time from diagnosis to mobilisation was 10 months (range 3−122). After administration of mobilising regimens (primarily high-dose etoposide, high-dose cyclophosphamide, intermediate-dose Ara-C or ESHAP), patients were randomised to a standard daily 10 μg/kg dose of EP-2006 (n=54) or originator filgrastim (n=54). RESULTS:Median duration of G-CSF administration was 8 days with both EP-2006 (range 4−17) and originator filgrastim (range 4−14). Both groups had a median of one apheresis with a median time until first apheresis of 11 days. There were no statistically significant differences between groups in the median (range) number of mobilised CD34+ cells/μL in peripheral blood (EP-2006, 62.0 [2−394]; originator filgrastim, 47.5 [2−370]) or the number of CD34+ cells/ kg body weight (EP-2006, 9.1 [0−23]; originator filgrastim, 9.4 [6−48]). Five patients (9%) in each group did not mobilise sufficient CD34+ cells. The adverse event profile was comparable between the EP-2006 and originator filgrastim groups, with similar occurrence of neutropenic fever (9 vs 11 patients) and bone pain (8 vs 6 patients). CONCLUSION:EP-2006 demonstrated similar efficacy and safety as the reference filgrastim in haematopoietic stem cell mobilisation in patients with haematological malignancies. Disclosures:Dmoszynska:Mundipharma: Advisory Board; Roche: Honoraria.