Cost-efficiency analysis of conversion to biosimilar filgrastim for supportive cancer care and resultant expanded access analysis to supportive care and early-stage HER2+ breast cancer treatment in Saudi Arabia: simulation study.

AIMS: This study estimated, for Saudi Arabia, the cost-efficiency of converting patients from reference Neupogen and Neulastim to one of two filgrastim biosimilars (Nivestim, Zarzio); the budget-neutral expanded access to supportive care with biosimilar filgrastim and therapeutic care to ado-trastuzumab emtansine thus afforded; and the number-needed-to-convert (NNC) to provide supportive or therapeutic treatment to one patient. MATERIALS AND METHODS: Replicating prior studies, we modeled the cost-efficiencies gained from converting varying proportions of a hypothetical panel of 4,000 patients undergoing six cycles of cancer treatment from Neupogen or Neulastim to one of the two biosimilar G-CSF formulations, using national cost inputs. Cost-savings in USD were used to estimate the additional doses of biosimilar G-CSF and expanded access to ado-trastuzumab emtansine on a budget-neutral basis, and NNC to purchase one additional dose of supportive or therapeutic treatment. RESULTS: Savings from conversion from reference to a biosimilar filgrastim were $3,086,400 (Nivestim) and $3,460,800 (Zarzio). With reference pegfilgrastim, savings from conversion were $11,712,240 (Nivestim) and $12,086,640 (Zarzio). Biosimilar conversion from reference to biosimilar filgrastim enabled expanded access to ado-trastuzumab emtansine ranging from 61 patients (5 days, Nivestim) to 191 patients (14 days, Zarzio). For supportive care, biosimilar conversion enabled expanded access ranging from 8,244 patients (5 days, Nivestim) to 25,882 patients (14 days, Zarzio). For biosimilar conversion from daily filgrastim, the NNC for treatment with ado-trastuzumab emtansine decreased as days of injections increased [5 days: 395 (Nivestim), 352 (Zarzio); 14 days: 141(Nivestim), 126 (Zarzio)]. Alternately, for biosimilar conversion from single-injection pegfilgrastim to daily biosimilar filgrastim, the NNC for treatment with ado-trastuzumab emtansine rose as days of injections increased, being highest under the 14-day scenario (146, Nivestim; 130, Zarzio). CONCLUSION: This simulation study demonstrated significant potential cost-savings from biosimilar conversion. These savings provide budget-neutral increased access to supportive and therapeutic cancer care.

Outcome and Cost-Effectiveness Analysis of Long-acting G-CSF as Primary Prophylaxis of Neutropenia Induced by Chemotherapy in Breast Cancer Patients, From a Retrospective Study.

PURPOSE: This retrospective analysis aimed to evaluate the clinical outcomes and cost-effectiveness of long-acting granulocyte-colony stimulating factor as primary prophylaxis of neutropenia caused by chemotherapy for breast cancer. METHODS: Patients with breast cancer who received long- or short-acting granulocyte-colony stimulating factor as primary prophylaxis of neutropenia were enrolled in this study, and incidences of neutropenia were compared between two groups. A decision-analytic and a Markov model were used to compare the health benefits and costs of utilizing long- vs short-acting granulocyte-colony stimulating factor as the primary prophylaxis from the perspective of the Chinese health service system. Subsequently, one-way deterministic and probabilistic sensitivity analyses were conducted. The incremental cost-effectiveness ratios were calculated in baseline and sensitivity analyses. RESULTS: Patients receiving long-acting granulocyte-colony stimulating factor as the primary prophylaxis of chemotherapy-induced neutropenia experienced a significant lower incidence of this adverse event, compared with the short-acting one for 2 to 7 days. The outcomes of baseline analysis indicated that long-acting granulocyte-colony stimulating factor had a gain of 0.08 quality-adjusted life years and costed $149 more than the short-acting one, yielding an incremental cost-effectiveness ratio of $1792 per quality-adjusted life year. The sensitivity analysis proved the stability of our models and economic efficiency of long-acting granulocyte-colony stimulating factor. CONCLUSIONS: Patients receiving long-acting granulocyte-colony stimulating factor as primary prophylaxis of neutropenia experienced lower risk of this event compared with those underusing short-acting one. The long-acting granulocyte-colony stimulating factor may be a more cost-effective strategy for primary prophylaxis of neutropenia than short-acting one, considering the Chinese willingness-to-pay threshold of $12158.6 per quality-adjusted life year.

Economic evaluation of plerixafor addition in the mobilization and leukapheresis of hematopoietic stem cells for autologous transplantation: a systematic review.

INTRODUCTION: Although plerixafor in association with granulocyte colony-stimulating factor (G-CSF) can improve mobilization and collection of hematopoietic stem cells (HSC) by leukapheresis, cost may limit its clinical application. The present study systematically reviews economic evaluations of plerixafor plus G-CSF usage compared to G-CSF alone and compares different strategies of plerixafor utilization in multiple myeloma and lymphoma patients eligible for autologous HSC transplantation. AREAS COVERED: Relevant economic evaluations, partial or complete, were searched on PubMed, Embase, LILACS, and Cochrane Central Register of Controlled Trials for a period ending 30 June 2021. This systematic review was reported following the PRISMA Statement. Six economic evaluations were included, considering the use of upfront or just-in-time plerixafor compared to G-CSF alone or other plerixafor strategies. Most comparisons showed both increased cost and health benefits with the addition of plerixafor. Most analyses favored just-in-time plerixafor compared to upfront plerixafor, with a probable preference for broader cutoffs for just-in-time plerixafor initiation. EXPERT OPINION: Plerixafor is a potentially cost-effective technology in the mobilization of HSC in patients with multiple myeloma and lymphomas eligible for autologous HSC transplantation. There is a decreased number of leukapheresis sessions and remobilizations and a higher yield of CD34+ cells.

On-demand plerixafor added to high-dose cyclophosphamide and pegylated recombinant human granulocyte colony-stimulating factor in the mobilization of patients with multiple myeloma: a treatment with high effectiveness, convenient, and affordable cost.

Objective: The combination of high-dose cyclophosphamide (HD-Cy) (3g/m2) plus granulocyte colony-stimulating factor (G-CSF) and on-demand plerixafor (PXF) has been considered an effective mobilization regimen of patients with multiple myeloma(MM). However, the daily multi-injection regimen of G-CSF poses challenges. This study delves into the efficiency and cost implications of a novel approach, using HD-Cy alongside pegylated G-CSF (PEG G-CSF) and on-demand PXF. Unlike G-CSF, which necessitates daily injections, the half-life of PEG G-CSF extended allows for a single injection. Methods: A retrospective analysis was conducted on 350 MM patients, which were categorized based on their mobilization regimens: Cy+PEG G-CSF+/-PXF (n=66), Cy+PEG G-CSF (n=91), Cy+ G-CSF (n=169), and G-CSF+PXF (n=24). Results: Mobilization with Cy+PEG G-CSF+/-PXF(8.79)yielded a notably higher median CD34+ cell count compared to the other regimens: Cy+PEG G-CSF(4.96), Cy+G-CSF (4.65), and G-CSF+PXF (2.99) (P<0.001). The percentage of patients who achieved >6×106/kg CD34+ cells was significantly higher in the Cy+PEG G-CSF+/-PXF group (77.3%) than in the other mobilization regimens: Cy+PEG G-CSF (41.8%), Cy+ G-CSF (37.3%), and G-CSF+PXF (8.3%) (P<0.001). From a cost perspective, the Cy+PEG G-CSF+/-PXF approach was more economical than the G-CSF+PXF strategy but was marginally costlier than the other two methods. A multivariate assessment highlighted that the combination of Cy+PEG G-CSF with on-demand PXF had a superior potential to achieve the desired harvest (6×106/kg) compared to the Cy+PEG G-CSF protocol without PXF. The incremental cost-effectiveness ratio for each 1% increase in the probability of achieving a successful optimal harvest was $ 97.02 per patient. The incidence of neutropenic fever was 3.0% in the Cy+PEG G-CSF+/-PXF group. Conclusion: The combination of on-demand PXF with HD-Cy and PEG G-CSF offers a cost-effective approach with a high mobilization success rate, manageable side effects, and the convenience of fewer injections. It stands as a promising mobilization strategy for MM patients.

Granulocyte colony stimulating factor use and adherence to clinical practice guidelines among women with breast cancer living in Puerto Rico: a population-based study.

BACKGROUND: Febrile Neutropenia (FN) is a common and serious condition related to cancer chemotherapy. Human recombinant Granulocyte-Colony Stimulating Factor (G-CSF) prevents and attenuates the severity and duration of FN. We evaluated the use and predictors of G-CSF adherence among women with breast cancer with a high risk of FN in Puerto Rico. METHODS: This retrospective cohort study used the Puerto Rico Central Cancer Registry-Health Insurance Linkage Database. Women with invasive breast cancer diagnosed during 2009-2015 who received selected chemotherapy regimens (n = 816) were included. The risk of FN was categorized as high and low risk based on the chemotherapy regimens according to the National Comprehensive Cancer Network guidelines and literature. Adherence was defined as the use or no use of G-CSF at the start of the first chemotherapy cycle among women with breast cancer based on the risk of developing FN. We used a multivariate logistic model to identify factors associated with G-CSF use in women classified at high risk for FN. RESULTS: Adherence to G-CSF clinical practice guidelines was low (38.2%) among women with a high risk of FN. Women at high risk of FN with Medicaid (aOR: 0.14; CI 95%: 0.08, 0.24) and Medicare/Medicaid (aOR: 0.33; CI 95%: 0.15, 0.73) were less likely to receive G-CSF than women with private health insurance. Women with regional stage (aOR: 1.82; CI 95%: 1.15, 2.88) were more likely to receive G-CSF than women with localized cancers. CONCLUSIONS: Adherence to clinical practice guidelines was poor among women with a high risk of FN. Furthermore, disparities in the adherence to G-CSF use in terms of health insurance, health region, and cancer stage granted the opportunity to implement strategies to follow the recommended guidelines for using G-CSF as part of cancer treatment.

Patterns of primary prophylactic granulocyte colony-stimulating factor use in older Medicare patients with cancer receiving myelosuppressive chemotherapy.

PURPOSE: Guidelines recommend primary prophylactic (PP) granulocyte colony stimulating factor (G-CSF) for prevention of febrile neutropenia (FN) in patients receiving myelosuppressive chemotherapy with high risk (HR: > 20%), or intermediate risk (IR:10-20%) of FN and ≥ 1 patient risk factor (e.g., age ≥ 65y). The current retrospective cohort study describes patterns of PP-G-CSF in older Medicare patients undergoing myelosuppressive chemotherapy with HR/IR of FN. METHODS: Patients aged ≥ 66y initiating chemotherapy regimens with HR/IR of FN to treat breast, colorectal, lung, or ovarian cancer, or Non-Hodgkin's Lymphoma were selected using Medicare 20% sample (2013-2015) and 100% cancer patient (2014-2017) data. PP-G-CSF use was identified in the first cycle. Timing of pegfilgrastim pre-filled syringe (PFS) administration, proportion of patients completing all cycles (adherence) with pegfilgrastim PFS or on-body injector (OBI), and duration of short-acting G-CSF (sG-CSF) was described across all cycles. RESULTS: Of 64,893 patients receiving HR/IR for FN, 71% received HR and 29% IR regimens. Overall, PP-G-CSF use in the first cycle was 53% (HR: 74%; IR: 44%) and varied across cancers. Adherence with pegfilgrastim was slightly higher among OBI initiators (78%) than PFS (74%). Number of PP-sG-CSF administrations (mean [SD]) per cycle was 5.1 (SD: 2.7) overall, 5.4 (2.6) for HR, and 4.9 (2.7) for IR. CONCLUSION: Despite cancer treatment guidelines recommending PP-G-CSF use to reduce risk of FN associated with HR and IR (with ≥ 1 patient risk-factor) regimens, PP-G-CSF remains underutilized in older patients, across cancer types and regimens. Opportunities exist for improvement in use of PP-G-CSF.

Assessment of Congenital Neutropenia in Children: Common Clinical Sceneries and Clues for Management.

A disparate group of rare hematological diseases characterized by impaired maturation of neutrophil granulocytes defines congenital neutropenias. Neutropenic patients are prone to recurrent infections beginning in the first months of life. Of interest is "cyclic neutropenia," an ultra-rare disorder revealed by sinusoidal variations in the neutrophil count and recurring infections every 21 days. Diagnosis of these disorders is frequently obscured by the multiple causes of recurrent fevers in children. The aim of this overview is to outline the physical assessment of children presenting with early-onset symptomatic neutropenia, identify the disease between the many medical conditions and even emergencies which should enter in differential diagnosis, hint at the potential management with granulocyte-colony stimulating factor, define the risk of evolution to hematologic malignancy, and summarize inter-professional team strategies for improving care coordination and outcomes of patients.

Safety Assessment of Autologous Stem Cell Combination Therapy in Patients With Decompensated Liver Cirrhosis: A Pilot Study.

BACKGROUND: Haematopoietic stem cell (HSC) infusion has demonstrated short-term improvement in liver functions in patients with chronic liver disease. The combination of HSC with mesenchymal stem cells (MSCs), which has an immunomodulatory effect, may augment the effects and enhance the duration of improvements on liver functions. The aim of the present study was to assess the safety of infusing the combination of autologous HSCs and MSCs in decompensated liver cirrhosis. METHODS: In phase I of the study, in vitro assessment was performed to observe the effect of coculturing MSCs with HSCs on their viability and cytokine profiles. Phase II of the study was to assess the safety of combination of stem cell infusions. Bone marrow (50 ml) was aspirated for MSC isolation and expansion using standard protocol. Patients received subcutaneous doses (n = 5) of granulocyte colony-stimulating factor (G-CSF) for stem cell mobilization followed by leukapheresis for harvesting HSCs using CliniMacs. HSCs and MSCs were infused through the hepatic artery under fluoroscopic guidance and were monitored for any adverse effects. RESULTS: In vitro studies revealed 94% viable HSCs in coculture similar to monoculture. HSCs released only interleukin (IL)-8, whereas MSCs secreted IL-8 and IL-6 in monocultures, and both IL-8 and IL-6 were secreted in coculture. G-CSF administration- and bone marrow aspiration-related complications were not observed. Infusion of the cells through the hepatic artery was safe, and no postprocedural complications were noted. CONCLUSION: The combination of autologous HSC and MSC infusion is a safe procedure in patients with decompensated liver cirrhosis, and the outcomes needed to be assessed in larger studies. TRIAL NUMBER: NCT04243681.

Novel G-CSF conjugated anionic globular dendrimer: Preparation and biological activity assessment.

The most crucial role of granulocyte colony-stimulating factor (G-CSF) in the body is to increase the strength of immune system. In recent years, research on the use of nanoparticles in pharmaceuticals has been considered, most of which have been for drug-loading purposes. In this study, a novel G-CSF conjugated dendrimer was synthesized and characterized using different techniques. In vitro cytotoxicity was assessed on A549 and L929 cells, while abnormal toxicity was studied in mice. In vitro and in vivo biological activities were assessed in NFS60 cells and rats, respectively. In addition, in vivo distribution, plasma half-life, and histopathological effect were studied in rat. The characterization tests confirmed the successful conjugation. There was no difference between G-CSF cytotoxicity before and after conjugation, and no difference with the control group. No mice showed abnormal toxicity. Although in vitro biological activity revealed both conjugated and free G-CSF promote proliferation cells, biological activity decreased significantly after conjugation about one-third of the unconjugated form. Nonetheless, in vivo biological activity of conjugated G-CSF increased by more than 2.5-fold relative to the unconjugated form, totally. Fortunately, no histopathologic adverse effect was observed in vital rat tissues. Also, in vivo distribution of the conjugate was similar to the native protein with an enhanced terminal half-life. Our data revealed that G-CSF conjugated dendrimer could be considered as a candidate to improve the in vivo biological activity of G-CSF. Moreover, multivalent capability of the dendrimer may be used for other new potentials of G-CSF in future perspectives.

Usefulness of 18F-fluorodeoxyglucose positron emission tomography for assessment of tumorviability after resection of granulocyte-colony-stimulating-factor -Producing cholangiocarcinoma-a case report.

INTRODUCTION AND IMPORTANCE: Granulocyte colony-stimulating factor (G-CSF)-producing intrahepatic cholangiocarcinoma is rare. Surgical cases with postoperative clinical course have rarely been reported. CASE PRESENTATION: A 63-year-old woman complained upper abdominal pain. Computed tomography (CT) showed intrahepatic mass measuring 9 × 9 × 9 cm in the left lateral segment. 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) showed high uptake by the tumor, with diffuse uptake in the bone marrow. An extended left lobectomy was performed to achieve complete resection. Histopathological examination showed poorly differentiated adenocarcinoma with no lymph node metastasis. Immunohistochemical analysis revealed that tumor cells produced G-CSF. After chemotherapy with S-1 regimen at 10 months after the operation, CT and FDG-PET detected lymph node metastasis in the peri-duodenal area and left kidney metastasis, with no FDG uptake in the bone marrow. Serum G-CSF was normal. Combination chemotherapy with gemcitabine plus cisplatin was administered, and, 12 months after liver resection, metastases were enlarged and FDG uptake in the bone marrow was detected again. Serum G-CSF was elevated at 71.6 pg/mL. The patient was enrolled in a clinical trial of chemotherapy with another regimen and was alive at 19 months after liver resection. CLINICAL DISCUSSION: Because of rapid progression, rapid diagnosis and resection are important. FDG uptake in the bone marrow is characteristic in G-CSF producing tumor. In this case, FDG uptake in the bone marrow reappeared after the enlargement of recurrent lesions, followed by tumor enlargement. CONCLUSION: FDG-PET was useful for differential diagnosis and to assess tumor viability and determine the surgical indication.

Introduction of biosimilar pegfilgrastim in France: Economic analysis of switching from originator.

OBJECTIVES: To assess the economic impact of introducing biosimilar pegfilgrastim compared to the current standard granulocyte colony-stimulating factor (G-CSF) practice in France. METHODS: A budget impact model was developed to investigate the impact of introducing pegfilgrastim biosimilar over 5 years. The model analysed drug acquisition costs, ambulatory costs, as well as costs associated with poor outcomes, and compared the current standard practice of long-acting and short-acting G-CSF to a revised practice including pegfilgrastim biosimilar in addition to standard practice treatments. The cost of switching to pegfilgrastim biosimilar, within a pharmacy setting, was analysed within the model using data from a survey of French pharmacists. RESULTS: The budget impact model calculated a cost saving of €51,007,531 over 5 years switching from the current standard practice to pegfilgrastim biosimilar. A sensitivity analysis accounting for variation in pegfilgrastim biosimilar uptake of 1) 15% in year 1 and 1% in years 2-5 and 2) 15% in years 1-5, estimated savings ranging between €29,377,784 and €79,847,194, respectively. A further analysis predicted cost savings of €287,344,835 over 5 years with the extension of pegfilgrastim biosimilar, at an uptake of 15% in year 1 and 7% in years 2-4, to both long-acting and short-acting G-CSF groups compared to unchanged current practice. CONCLUSIONS: The introduction of pegfilgrastim biosimilar will help to reduce cost and alleviate some of the financial pressure on the French healthcare system.

Economic assessment of continuous processing for manufacturing of biotherapeutics.

Continuous processing offers a promising approach to revolutionize biotherapeutics manufacturing as reflected in recent years. The current study offers a comparative economic assessment of batch and continuous processing for the production of biotherapeutic products. Granulocyte-colony stimulating factor (GCSF), a protein expressed in E. coli, and an IgG1 monoclonal antibody, were chosen as representatives of microbial and mammalian derived products for this assessment. Economic indicators-cost of goods (COGs), net present value (NPV), and payback time have been estimated for the assessment. For the case of GCSF, conversion from batch to integrated continuous manufacturing induced a $COGs/g reduction of 83% and 73% at clinical and commercial scales, respectively. For the case of mAb therapeutic, a 68% and 35% reduction in $COGs/g on translation from batch to continuous process was projected for clinical and commercial scales, respectively. Upstream mAb titer was also found to have a significant impact on the process economics. With increasing mAb titer, the $COG/g decreases in both operating modes. With titer increasing from 2 to 8 g/L, the $COG/g of batch process was reduced by 53%, and that of the continuous process was reduced by 63%. Cost savings in both the cases were attributed to increased productivity, efficient equipment and facility utilization, smaller facility footprint, and reduction in utilization of consumables like resin media and buffers actualized by the continuous processing platform. The current study quantifies the economic benefits associated with continuous processing and highlights its potential in reducing the manufacturing cost of biotherapeutics.

[Cost-effectiveness of primary prophylaxis with PEG-rhG-CSF in early-stage breast cancer patients receiving chemotherapy in China].

Objective: To evaluate the cost effectiveness of primary prophylaxis (PP) with pegylated recombinant human granulocyte colony stimulating factor (PEG-rhG-CSF), PP with recombinant human granulocyte colony stimulating factor (rhG-CSF) and no prophylaxis in women with early-stage breast cancer in China. Methods: Two phase Markov models were constructed for a hypothetical cohort of patients aged 45 with stage Ⅱ breast cancer. The first phase modelled costs and outcomes of 4 cycles docetaxel combined with cyclophosphamide [TC×4, febrile neutropenia (FN) risk>20%] chemotherapy, which assumptions based on literature reviews, including FN rates [base-case (deterministic sensitivity analysis range), 0.29 (0.24-0.35)] and related events [FN case-fatality, 3.4 (2.7-4.1)]. Second phase modelled the long term survival which was link with the relative dose intensity (RDI) [mortality hazard ratio (HR) of RDI < 85% vs ≥85%, 1.45 (1.00-2.32)]. Clinical effectiveness, therapeutic costs, and economic utilities were estimated from peer-reviewed publications and expert opinions in case of unavailability of published evidences. Results: Compared to rhG-CSF PP and no prophylaxis, the cost of PEG-rhG-CSF PP increased to 5 208.19 RMB and 5 222.73 RMB, respectively. The quality-adjusted life-years (QALYs) enhanced to 0.066 and 0.297, respectively. Accordingly, the incremental cost effectiveness ratios (ICERs) are 79 146.3 RMB and 17 558.77 RMB per QALY, which were both below the willingness to pay (WTP) threshold of three times GDP per capita (18, 000 RMB) recommended by the WHO. Sensitivity analysis suggested that the more clinically effective the primary prophylaxis with PEG-rhG-CSF is, the more cost-effective primary prophylaxis with PEG-rhG-CSF will be. And the lower the mortality HR of RDI<85% vs ≥85% is, the more cost-effective primary prophylaxis with PEG-rhG-CSF will be. Conclusion: Although the cost of PP PEG-rhG-CSF is higher, considering the additional benefits, the administrating of PP PEG-rhG-CSF is likely to be a cost-effective alternative to PP rhG-CSF and no prophylaxis in patients with early stage breast cancer whose FN risks are more than 20% in China.

Biosimilars in oncology: Effects on economy and therapeutic innovations.

AIM: The introduction of new and innovative treatment options for cancer patients is accompanied by a tremendous increase in healthcare costs. Consequently, new financing approaches are strongly needed to reduce the burden on the healthcare system. The introduction of biosimilars - biological drugs containing the active substance of an already approved reference biological drug - can potentially relieve the burden on healthcare systems. Calculating the costs for three frequently used biosimilars, we simulated the health-economic impact of biosimilars in the real world for the German healthcare system. METHODS: Based on available health-economic analyses, the actual prescription and cost containment potential of biosimilars compared to the originator were calculated exemplarily for the cost-intensive therapies trastuzumab in breast cancer, rituximab in follicular lymphoma and G-CSF in supportive care. Incidence calculations were based e.g. on data from the Robert-Koch-Institution, Munich Cancer Registry, and quality indicators of certified centres. Cost calculation was based on Lauer-Taxe® (official reference for pharmaceutical price information). RESULTS: The application of biosimilars would generate potential annual savings for the chosen examples of up to 4.9 Mio EUR for rituximab in follicular lymphoma, 40.5 Mio EUR for filgrastim, 56.4 Mio EUR for pegfilgrastim, and between 95.9 and 120.5 Mio EUR for trastuzumab. CONCLUSIONS: The consequent use of biosimilars allows a considerable reduction of overall treatment costs, especially for cost-intensive long-term maintenance treatments and therapies with high incidences. If the option of biosimilar usage is fully exploited, enormous resources could be released within the healthcare system in order to offset financing new innovative therapies.

Evaluation of a biosimilar granulocyte colony-stimulating factor for peripheral blood stem cell mobilization in Japanese healthy donors: a prospective study.

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.

Neutropenia during frontline treatment of advanced Hodgkin lymphoma: Incidence, risk factors, and management.

Neutropenia, specifically febrile neutropenia (FN), can have profound sequelae (infection, hospitalization, mortality), and the risk of its development differs across chemotherapy regimens/according to patient characteristics. We conducted a comprehensive literature review regarding neutropenia in frontline treatment of adults with advanced Hodgkin lymphoma. Guidelines state primary prophylaxis (PP) with colony-stimulating factors (CSFs) should be implemented when the risk of FN is ≥20%; CSF PP is given with standard-of-care escalated BEACOPP, but the risk of FN with standard-of-care ABVD does not necessitate routine PP. Notably, the risk of neutropenia (including FN) is higher in clinical practice versus clinical studies, and physicians overestimate their adherence to CSF guidelines. ECHELON-1 demonstrated higher FN rates with brentuximab vedotin plus AVD (A + AVD) compared with ABVD (19% vs 8%) and led to the recommendation of PP with granulocyte-CSF (G-CSF) for all A + AVD patients, highlighting the importance of readjusting our risk-assessment thinking as standard backbone regimens are modified.

The evolution of value with filgrastim in oncology.

The recombinant G-CSF filgrastim was first approved in 1991, and its value has been evolving ever since. Initial health technology assessments suggested low value due to high drug cost and no evidence for significant gain in overall survival. However, more recent meta-analyses of placebo-controlled randomized trial data show falling costs due to biosimilar competition and absolute overall survival gains of 3.2% (95% CI: 2.1-4.2%) from filgrastim support of cytotoxic chemotherapy. The launch of biosimilar alternatives merits a re-evaluation of decisions by health technology assessments and explains the first inclusion of filgrastim in the WHO Essential Drug List for cancer >20 years after its original approval in 1991, thus demonstrating the power of biosimilar medicines in transforming healthcare.

Use of colony-stimulating factor primary prophylaxis and incidence of febrile neutropenia from 2010 to 2016: a longitudinal assessment.

BACKGROUND: Guidelines recommend primary prophylactic use of colony-stimulating factor (PP-CSF) when risk of febrile neutropenia (FN) - based on chemotherapy and patient risk factors - is high. Whether and how PP-CSF use may have changed over time (e.g. due to guideline revisions, increasing use of myelosuppressive regimens, controversy regarding inappropriate CSF use), and whether there has been a concomitant change in the incidence of FN, is unknown. METHODS: A retrospective cohort design and data from two US healthcare claims repositories were employed. The study population included patients who had non-metastatic cancer of the breast, colon/rectum, lung or ovaries, or non-Hodgkin's lymphoma (NHL), and who received myelosuppressive chemotherapy regimens with an intermediate/high risk for FN. For each patient, the first cycle of the first course was characterized in terms of PP-CSF use and FN episodes. Crude incidence proportions for PP-CSF and FN during the first cycle were estimated by calendar quarter (2010-2016); multivariable logistic regression models were used to estimate quarter-specific adjusted mean probabilities of FN by PP-CSF use. RESULTS: The study population totaled 142,730 patients with breast cancer (61%), colorectal cancer (14%), NHL (11%), ovarian cancer (10%) or lung cancer (5%). PP-CSF use increased from 52% in 1Q2010 to 58% in 4Q2016; pegfilgrastim was the most commonly used agent (>96% across quarters). PP-CSF administration on the same day as chemotherapy ranged from 8 to 11% until 1Q2015, and increased to 64% by 4Q2016. Adjusted incidence proportions for FN in the first chemotherapy cycle ranged from 2.7% (95% CI: 2.3-3.0) to 3.7% (95% CI: 3.1-4.3) among those who did not receive PP-CSF, and was 2.6% (95% CI: 2.5-2.7) across quarters among those who received PP-CSF. CONCLUSIONS: Although the use of PP-CSF is commonplace in current US clinical practice, underutilization in cancer patients receiving chemotherapy regimens with an intermediate/high risk for FN may still be an issue. Use of same-day PP-CSF increased markedly from the end of 2015, although this finding reflects (at least in part) increased uptake of pegfilgrastim delivered via an on-body injector as well as the recent change in clinical practice guidelines. Overall, patients receiving PP-CSF appear to have a lower risk of FN during the first cycle of chemotherapy.

Low-cost customizable microscale toolkit for rapid screening and purification of therapeutic proteins.

Biopharmaceutical separations require tremendous amounts of optimization to achieve acceptable product purity. Typically, large volumes of reagents and biological materials are needed for testing different parameters, thus adding to the expense of biopharmaceutical process development. This study demonstrates a versatile and customizable microscale column (µCol) for biopharmaceutical separations using immobilized metal affinity chromatography (IMAC) as an example application to identify key parameters. µCols have excellent precision, efficiency, and reproducibility, can accommodate any affinity, ion-exchange or size-exclusion-based resin and are compatible with any high-performance liquid chromatography (HPLC) system. µCols reduce reagent amounts, provide comparable purification performance and high-throughput, and are easy to automate compared with current conventional resin columns. We provide a detailed description of the fabrication methods, resin packing methods, and µCol validation experiments using a conventional HPLC system. Finite element modeling using COMSOL Multiphysics was used to validate the experimental performance of the µCols. In this study, µCols were used for improving the purification achieved for granulocyte colony stimulating factor (G-CSF) expressed using a cell-free CHO in vitro translation (IVT) system and were compared to a conventional 1 ml IMAC column. Experimental data revealed comparable purity with a 10-fold reduction in the amount of buffer, resin, and purification time for the µCols compared with conventional columns for similar protein yields.

Risks and consequences of travel burden on prophylactic granulocyte colony-stimulating factor administration and incidence of febrile neutropenia in an aged Medicare population.

OBJECTIVE: Granulocyte colony-stimulating factors (G-CSFs) decrease the incidence of febrile neutropenia (FN) in patients receiving myelosuppressive chemotherapy. This study examines the impact patient travel burden has on administration of prophylactic G-CSFs and the subsequent impact on FN incidence. METHODS: Medicare claims data were used to identify a cohort of beneficiaries age 65+ with non-myeloid cancers at high risk for FN between January 2012 and December 2014. Driving distance and time were calculated from patient residence ZIP code to the location of G-CSF and/or chemotherapy administration. Regression models were used to estimate the odds of G-CSF prophylaxis relative to patient driving distance and time, and odds of FN incidence relative to timing of G-CSF administration (optimal [days 2-4 after chemotherapy], sub-optimal [same day], or none). RESULTS: The 52,389 study patients had a mean age of 73.5 years, and were 82% female and 89% white race; 49% had female breast cancer, 12% lung cancer, 15% ovarian cancer, and 24% non-Hodgkin's lymphoma. Of these high FN risk patients, 69% had at least one prophylactic G-CSF administration within at least one chemotherapy cycle. The percentage of patients receiving prophylactic G-CSFs in the first cycle was 56%. Median travel time was slightly longer for patients who did not receive G-CSFs and patients receiving short-acting vs long-acting G-CSFs. The odds of receiving no G-CSFs were 26-52% higher (depending on cancer type) for patients with a >80-min one-way travel time, compared to patients traveling <20-min. Concurrently, the odds of FN (using a "narrow" definition) were 18-93% higher for patients who did not receive G-CSFs in the first cycle of chemotherapy. CONCLUSIONS: Travel burden, linked to clinic visits for G-CSF administration following myelosuppressive chemotherapy, is associated with sub-optimal use of G-CSF prophylaxis, which may result in a higher incidence of FN.