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Abstract Background Safety, tolerability and efficacy of granulocyte colony-stimulating factor (G-CSF) for mobilization of hematopoietic stem and progenitor cells (HSPCs) from healthy donors have been conclusively demonstrated. This explicitly includes, albeit for smaller cohorts and shorter observation periods, biosimilar G-CSFs. HSPC donation is non-remunerated, its sole reward being “warm glow”, hence harm to donors must be avoided with maximal certitude. To ascertain, therefore, long-term physical and mental health effects of HSPC donation, a cohort of G-CSF mobilized donors was followed longitudinally. Methods We enrolled 245 healthy volunteers in this bi-centric long-term surveillance study. 244 healthy volunteers began mobilization with twice-daily Sandoz biosimilar filgrastim and 242 underwent apheresis after G-CSF mobilization. Physical and mental health were followed up over a period of 5-years using the validated SF-12 health questionnaire. Results Baseline physical and mental health of HSPC donors was markedly better than in a healthy reference population matched for ethnicity, sex and age. Physical, but not mental health was sharply diminished at the time of apheresis, likely due to side effects of biosimilar G-CSF, however had returned to pre-apheresis values by the next follow-up appointment after 6 months. Physical and mental health slightly deteriorated over time with kinetics reflecting the known effects of aging. Hence, superior physical and mental health compared to the general healthy non-donor population was maintained over time. Conclusions HSPC donors are of better overall physical and mental health than the average healthy non-donor. Superior well-being is maintained over time, supporting the favorable risk–benefit assessment of volunteer HSPC donation. Trial registration National Clinical Trial NCT01766934

Purpose: Limited knowledge is available on the incidence of febrile neutropenia (FN) in intermediate-risk patients and the rationale for use of granulocyte colony-stimulating factor (G-CSF) in these patients. We aimed to estimate the rate at which patients associated with intermediate risk (10-20%) of FN would develop ≥ 1 episode of FN with a commonly used chemotherapy regimen in clinical practice., Methods: This prospective, real-world, observational, multinational, multicenter study (December 2016-October 2019) recruited patients with solid tumors or Hodgkin's/non-Hodgkin's lymphoma. Patients receiving chemotherapy with intermediate risk of FN, but not G-CSF as primary prophylaxis were included and observed for the duration of the chemotherapy (≤ 6 cycles and ≤ 30 days after the last chemotherapy administration)., Results: In total, 364 patients (median age, 56 years) with 1601 cycles of chemotherapy were included in the analysis. The incidence of FN was 5% in cycle 1, 3% in cycles 2-3, and 1% in cycles 4-6. The rate of patients with ≥ 1 episode of FN was 9%, and 59% of FN events were reported during cycle 1. The rate of grade 4 neutropenia in cycle 1 was 11%, and 15% of patients experienced ≥ 1 episode of grade 4 neutropenia., Conclusions: Overall, the incidence of FN was low, with a high incidence in cycle 1 and a decrease in the subsequent cycles. These results provide the real FN risk for common chemotherapy regimens in patients generally excluded from clinical trials. Prophylactic G-CSF in intermediate-risk patients could be considered as per clinician's judgement., (© 2023. The Author(s).)

Objective: The totality-of-evidence approach requires that similarity between a proposed biosimilar and a reference biologic is demonstrated across a range of analytical, preclinical, and clinical parameters to establish biosimilarity. We describe the totality of evidence for Sandoz biosimilar pegfilgrastim (LA-EP2006 [marketed as Ziextenzo]) that supported its regulatory approval in Europe and the United States., Methods: Analytical similarity to the reference biologic [marketed by Amgen as Neulasta] was first investigated with regard to physiochemical quality attributes such as primary structure, pegylation, higher-order structures, variants and impurities, molecular size variants, and formulation (protein content, pH, excipients, etc.). In vitro biological activity studies were performed to examine the primary mechanism of action of pegfilgrastim. Bioequivalence (clinical pharmacokinetics [PK] and pharmacodynamics [PD]) of Sandoz biosimilar pegfilgrastim to the reference biologic was studied in healthy volunteers; efficacy, safety, and immunogenicity were assessed during confirmatory clinical efficacy studies in patients undergoing treatment for breast cancer., Results: No meaningful or relevant differences were identified between Sandoz biosimilar pegfilgrastim and the reference biologic during analytical testing. Similar receptor binding and induction of cellular proliferation in vitro confirmed no functional differences between the biologics. Clinical studies in healthy adult participants demonstrated PK/PD biosimilarity and a similar safety profile between biosimilar and reference pegfilgrastim. Clinical studies in a sensitive patient population also demonstrated similar efficacy, safety, and immunogenicity between Sandoz biosimilar pegfilgrastim and the reference biologic., Conclusions: The totality of evidence confirms that Sandoz biosimilar pegfilgrastim matches the reference biologic and will therefore provide equivalent efficacy and safety in all eligible indications.

Background: Safety, tolerability and efficacy of granulocyte colony-stimulating factor (G-CSF) for mobilization of hematopoietic stem and progenitor cells (HSPCs) from healthy donors have been conclusively demonstrated. This explicitly includes, albeit for smaller cohorts and shorter observation periods, biosimilar G-CSFs. HSPC donation is non-remunerated, its sole reward being "warm glow", hence harm to donors must be avoided with maximal certitude. To ascertain, therefore, long-term physical and mental health effects of HSPC donation, a cohort of G-CSF mobilized donors was followed longitudinally., Methods: We enrolled 245 healthy volunteers in this bi-centric long-term surveillance study. 244 healthy volunteers began mobilization with twice-daily Sandoz biosimilar filgrastim and 242 underwent apheresis after G-CSF mobilization. Physical and mental health were followed up over a period of 5-years using the validated SF-12 health questionnaire., Results: Baseline physical and mental health of HSPC donors was markedly better than in a healthy reference population matched for ethnicity, sex and age. Physical, but not mental health was sharply diminished at the time of apheresis, likely due to side effects of biosimilar G-CSF, however had returned to pre-apheresis values by the next follow-up appointment after 6 months. Physical and mental health slightly deteriorated over time with kinetics reflecting the known effects of aging. Hence, superior physical and mental health compared to the general healthy non-donor population was maintained over time., Conclusions: HSPC donors are of better overall physical and mental health than the average healthy non-donor. Superior well-being is maintained over time, supporting the favorable risk-benefit assessment of volunteer HSPC donation. Trial registration National Clinical Trial NCT01766934., (© 2022. The Author(s).)

Cancer care has been profoundly impacted by the global pandemic of severe acute respiratory syndrome coronavirus 2 disease (coronavirus disease 2019, COVID-19), resulting in unprecedented challenges. Supportive care is an essential component of cancer treatment, seeking to prevent and manage chemotherapy complications such as febrile neutropenia, anaemia, thrombocytopenia/bleeding, thromboembolic events and nausea/vomiting, all of which are common causes of hospitalisation. These adverse events are an essential consideration under routine patient management, but particularly so during a pandemic, a setting in which clinicians aim to minimise patients' risk of infection and need for hospital visits. Professional medical oncology societies have been providing updated guidelines to support health care professionals with the management, treatment and supportive care needs of their patients with cancer under the threat of COVID-19. This paper aims to review the recommendations made by the most prominent medical oncology societies for devising and modifying supportive care strategies during the pandemic., Competing Interests: Disclosure MA has consulted for Accord, Amgen, Bristol-Myers Squibb, Celgene, Clinigen, Eisai, Genomic Health, G1 Therapeutics, GlaxoSmithKline, Helsinn, Hospira, Johnson & Johnson, Lilly, Merck, Merck Serono, Novartis, Pfizer, Pierre Fabre, Roche, Sandoz, Tesaro, Teva and Vifor; and has received honoraria for lectures at symposia of Accord, Amgen, Bayer Schering, Biocon, Boehringer Ingelheim, Cephalon, Chugai, Dr Reed, Eisai, Genomic Health, G1 Therapeutics, GlaxoSmithKline, Glenmark, Helsinn, Hospira, Ipsen, Johnson & Johnson, Kirin Kyowa, Lilly, Merck, Merck Serono, Novartis, OrthoBiotech, Pfizer, Pierre Fabre, Roche, Sandoz, Sanofi, Taiho, Tesaro, Teva and Vifor. GHL reports research grant support from Amgen to the Fred Hutchinson Cancer Center and has consulted for Beyond Spring, G1 Therapeutics, Invitae, Mylan, Partner Therapeutics, Samsung Bioepis, Sandoz and Spectrum, outside the submitted work. CB has consulted for AOK Health Insurance, Bayer Schering Pharma, GSO, Lilly/ImClone, Merck Serono, Merck Sharp & Dohme and Sanofi; declares honoraria from AstraZeneca, Bayer, Bristol-Myers Squibb, Merck KGaA, Merck Sharp & Dohme, Roche and Sanofi; and declares travel/accommodation/expenses from Bristol-Myers Squibb, Merck Serono, Pfizer and Sanofi. BR has participated in advisory boards, received research grants and participated in speaker engagements with Sandoz; and has participated in speaker engagements with Amgen South Africa and Teva. NM and NK are employees of Sandoz. PC declares honoraria from Accord, Amgen, EU Commission, Hospira, Mylan, Pfizer, Roche, Sandoz and Teva. RA declares no conflict of interest. PG has consulted for Accord, Hospira, Pfizer and Sandoz; and has received honoraria for lectures at symposia of Accord, Hospira, Pfizer and Sandoz. NMK has consulted for Beyond Spring, Bristol-Myers Squibb, G1 Therapeutics, Invitae, Janssen and Spectrum, outside the submitted work. Data sharing Data sharing not applicable to this article as no datasets were generated or analysed during the current study., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Guidelines recommend febrile neutropenia (FN) prophylaxis following myelotoxic chemotherapy with either daily injections of filgrastim (Neupogen ® ) or biosimilar filgrastim-sndz (Zarzio/Zarxio ® ), single-injection pegfilgrastim (Neulasta ® ), or pegfilgrastim administered through an on-body injector (PEG-OBI; Neulasta ® Onpro ® ). PEG-OBI failure rates up to 6.9% have been reported, putting patients at incremental risk for FN and FN-related hospitalization. Our objective was to estimate, from a US payer perspective, the incremental costs of FN hospitalizations and the total incremental costs associated with PEG-OBI prophylaxis at varying device failure rates over assured FN prophylaxis with daily injections of filgrastim or filgrastim-sndz or a single injection of pegfilgrastim. Methods: Cost simulations comparing prophylaxis with PEG-OBI at failure rates of 1-10% versus assured prophylaxis in cycle 1 of chemotherapy were performed for panels of 10,000 patients with lung cancer treated with cyclophosphamide, doxorubicin, and etoposide (1 analysis) or non-Hodgkin lymphoma (NHL) treated with CHOP or CNOP (2 analyses). Daily injection scenarios were 4.3, 5, and 11 injections for lung cancer and 5, 6.5, and 11 for NHL. The analyses are from the US payer perspective. Results: For lung cancer, the total incremental cost of PEG-OBI prophylaxis at varying failure rates and durations ranged from $6,691,969‒$31,765,299 over filgrastim and $18,901,969‒$36,538,299 over filgrastim-sndz. For NHL, in scenario 1, the total incremental costs ranged from $6,794,984‒$30,361,345 over filgrastim and $19,004,984‒$35,911,345 over filgrastim-sndz; in scenario 2, the incremental costs ranged from $7,003,657‒$32,448,067 over filgrastim and $19,213,657‒$37,998,067 over filgrastim-sndz. Conclusions: In this simulation, the incremental costs of FN-related hospitalization due to PEG-OBI failure in cycle 1 compared to assured prophylaxis with reference pegfilgrastim, reference filgrastim, and biosimilar filgrastim-sndz varied depending upon the PEG-OBI failure rate and the alternative G-CSF prophylaxis option. Biosimilar filgrastim-sndz offers the greatest cost-efficiency.

Biosimilar filgrastim (Sandoz) was approved in Europe in 2009 and, in 2015, was the first biosimilar approved in the USA. These authorizations were based on the "totality of evidence" concept, an approach that considers data from structural and functional characterization and comparability analysis and non-clinical and clinical studies. For biosimilar filgrastim, phase III confirmatory clinical studies were performed in the most sensitive population, patients with breast cancer undergoing myelosuppressive chemotherapy. In Europe and the USA, approval was granted for all indications of the reference biologic. Hence, stem cell mobilization and severe chronic neutropenia indications were approved on the basis of extrapolation, with no clinical data available at the time of market authorization in the EU. Although extrapolation is well-accepted in biologic development and regulatory contexts, it remains a misunderstood part of the biosimilarity concept in the medical community. Since approval, more than a decade of obtained clinical experience supports the totality of evidence and reassures clinicians regarding the efficacy and safety of biosimilar filgrastim. This includes real-world data from MONITOR-GCSF, a multicenter, prospective, observational study describing treatment patterns and clinical outcomes of patients with cancer (n = 1447) receiving biosimilar filgrastim for the prophylaxis of chemotherapy-induced neutropenia in solid tumors and hematological malignancies. Evidence is also available from unrelated healthy donors and those with severe chronic neutropenia. Together, the experience from a decade of use of biosimilar filgrastim includes over 24 million patient-days of exposure, which can help reassure oncologists that extrapolation is based on strong scientific evidence and works in practice.

Myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis, leading to hematopoietic precursor cell apoptosis and peripheral blood cytopenias. Anemia is the most frequently experienced cytopenia and is the main cause of MDS symptoms, with fatigue and dyspnea contributing to reduced quality of life and increased morbidity. As MDS disease course and prognosis is influenced by disease factors, prognostic scoring systems have been developed for MDS to aid clinical and therapeutic decisions following diagnosis. Erythropoiesis- stimulating agents (ESAs) have been used for many years to treat anemia in patients with lower-risk MDS without chromosomal abnormalities. The use of ESAs is recommended by international clinical practice guidelines, due to the large body of evidence demonstrating their effectiveness in lower-risk MDS. In March 2017, the European Medicines Agency approved epoetin alfa for the treatment of anemia in lower-risk MDS patients, based on the results from a Phase 3 clinical trial and three European registry studies. The effectiveness of biosimilar epoetin alfa (Binocrit ® , Sandoz) to correct anemia in lower-risk MDS patients has also been demonstrated in a retrospective, single-center, observational study. The recent approval of epoetin alfa by the EMA in this setting will provide clinicians with a welcome, approved treatment option for lower-risk MDS., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Aim: This meta-analysis compared incidence of grade 3-4 neutropenia with ALK inhibitors versus chemotherapy in patients with non-small-cell lung cancer. Materials & methods: PubMed/MEDLINE was searched to identify Phase II and III randomized clinical trials published up to 25 October 2018. Summary incidence, relative risk and corresponding 95% CIs were calculated for grade 3-4 neutropenia. Results: Five randomized clinical trials were included. Relative risk (95% CI) of developing grade 3-4 neutropenia with ALK inhibitor versus chemotherapy was 0.27 (0.07-1.06). Probabilities of developing grade 3-4 neutropenia were 6.56 and 14.19%, respectively; no significant difference was found. Conclusion: In patients with non-small-cell lung cancer, incidence of grade 3-4 neutropenia with ALK-targeted therapy is not significantly different compared with chemotherapy.

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There are several new treatment options for patients whose asthma remains uncontrolled on free-dose and fixed-dose combinations of inhaled corticosteroids plus long-acting β 2 -agonists (ICS+LABA). In order to evaluate the likely impact of these treatments, we assessed the effect of uncontrolled asthma on healthcare and patient burden within the UK among adult patients treated with ICS+LABA. Data obtained from 2010-2011 UK National Health and Wellness Surveys identified 701 patients treated with ICS+LABA. Patients with not well-controlled asthma (Asthma Control Test™ score <20) were compared with well-controlled asthma (score ≥ 20) patients on multiple measures. Cost burden was calculated using healthcare resource utilisation models and work productivity and impairment questionnaire. Overall, 452 and 249 patients reported not well-controlled and well-controlled asthma, respectively. A greater proportion of not well-controlled patients visited the accident & emergency department (21 vs. 14%, P = 0.016), were hospitalised (13 vs. 8%, P = 0.022) and had lower mental and physical health-related quality of life (P < 0.001) and impaired work productivity and activity scores: presenteeism (23 vs. 11%, P < 0.001), work impairment (29 vs. 17%, P < 0.001) and activity impairment (46 vs. 24%, P < 0.001). Calculated direct and indirect yearly costs/person doubled among not well-controlled compared to well-controlled asthma patients (£6592 vs. £3220). Total cost to society was estimated at £6172 million/year (direct costs, £1307 million; indirect costs, £4865 million). In conclusion, not well-controlled asthma is common among UK adults treated with ICS+LABA, resulting in impairments across a number of important health outcomes and represents a significant unmet need and resource burden., Asthma: DRUG COMBO LEAVES MANY WITH UNCONTROLLED DISEASE: Many people who take inhaled steroids combined with long-acting β2-agonist drugs still have poorly controlled asthma. A team led by Ian Pavord from the University of Oxford, UK, identified 701 people from the 2010-2011 UK National Health and Wellness Surveys who were taking this drug combination for their asthma. The researchers found that nearly two-thirds of these individuals had poorly controlled asthma associated with more visits to the emergency room, worse quality of life (both mentally and physically), impaired productivity and other health problems. The calculated direct and indirect costs per person with poorly controlled asthma were about double that for someone whose asthma was under control. The authors conclude that better treatment and management is needed to reduce costs and address the unmet medical need for people with persistent uncontrolled asthma.

Introduction: There is a lack of agreed and established guidelines for the treatment of acute exacerbations of idiopathic pulmonary fibrosis (AE-IPF). This reflects, in part, the limited evidence-base underpinning the management of AE-IPF. In the absence of high-quality evidence, the aim of this research was to develop a clinician-led consensus statement for the definition, diagnosis and treatment of AE-IPF., Methods: A literature review was conducted to obtain published material on the definition and treatment of AE-IPF. The results of this review were circulated to an online panel of clinicians for review. Statements were then shared with ten expert respiratory clinicians who regularly treat patients with IPF. A Delphi technique was then used to develop a consensus statement for the definition, diagnosis and treatment of AE-IPF. During the first round of review, clinicians rated the clarity of each statement, the extent to which the statement should be included and provided comments. In two subsequent rounds of review, clinicians were provided with the group median inclusion rating for each statement, and any revised wording of statements to aid clarity. Clinicians were asked to repeat the clarity and inclusion ratings for the revised statements., Results: The literature review, online panel discussion, and face-to-face meeting generated 65 statements covering the definition, diagnosis, and management of AE-IPF. Following three rounds of blind review, 90% of clinicians agreed 39 final statements. These final statements included a definition of AE-IPF, approach to diagnosis, and treatment options, specifically: supportive measures, use of anti-microbials, immunosuppressants, anti-coagulants, anti-fibrotic therapy, escalation, transplant management, and long-term management including discharge planning., Conclusion: This clinician-led consensus statement establishes the 'best practice' for the management and treatment of AE-IPF based on current knowledge, evidence, and available treatments.

Introduction: Acute alcohol intoxication has been found to increase perseverative errors on the Wisconsin Card Sorting Test, a well known neuropsychological index of prefrontal cortical functioning, in both laboratory and naturalistic settings., Method: The present study examined the relationship between levels of alcohol consumption at campus drinking venues and performance of the Iowa Gambling Task (IGT), another neuropsychological test designed to assess prefrontal cortex dysfunction, after controlling for potential confounding variables including habitual alcohol intake (as a proxy for alcohol tolerance), trait impulsivity, and everyday executive functioning., Results: The 49 participants of both genders aged 18 to 30years were recruited at the relevant venues and showed a broad range of blood alcohol concentrations (BACs) from virtually zero (.002%) to .19%. After controlling for demographic variables, habitual use of alcohol and illicit drugs, and frontal lobe related behavioural traits including impulsivity and disinhibition, BAC negatively predicted gambling money won on the last two trial blocks of the IGT., Conclusions: Trait impulsivity and habitual alcohol use were also significant predictors. Results are discussed in terms of acute effects of alcohol on brain systems and the behavioural consequences of such effects on decision making., (Copyright © 2014 Elsevier Ltd. All rights reserved.)