Human granulocyte colony-stimulating factor (G-CSF) is a granulopoietic growth factor used in the treatment of neutropenia following chemotherapy, myeloablative treatment, or healthy donors preparing for allogeneic transplantation. Few hypersensitivity reactions (HRs) have been reported, and its true prevalence is unknown. We aimed to systematically characterize G-CSF-induced HRs while including a comprehensive list of adverse reactions. We reviewed articles published before January 2024 by searching in the PubMed, Embase, Cochrane Library, and Web of Science databases using a combination of the keywords listed, selected the ones needed, and extracted relevant data. The search resulted in 68 entries, 17 relevant to our study and 7 others found from manually searching bibliographic sources. A total of 40 cases of G-CSF-induced HR were described and classified as immediate (29) or delayed (11). Immediate ones were mostly caused by filgrastim (13 minimum), with at least 9 being grade 5 on the WAO anaphylaxis scale. Delayed reactions were mostly maculopapular exanthemas and allowed for the continuation of G-CSF. Reactions after first exposure frequently appeared and were present in at least 11 of the 40 cases. Only five desensitization protocols have been found concerning the topic at hand in the analyzed data. We believe this study brings to light the research interest in this topic that could benefit from further exploration, and propose regular updating to include the most recently published evidence.

BACKGROUND: The timing of prophylactic pegylated granulocyte colony-stimulating factor (G-CSF) administration during cancer chemotherapy varies, with Day 2 and Days 3-5 being the most common schedules. Optimal timing remains uncertain, affecting efficacy and adverse events. This systematic review sought to evaluate the available evidence on the timing of prophylactic pegylated G-CSF administration.
METHODS: Based on the Minds Handbook for Clinical Practice Guideline Development, we searched the PubMed, Ichushi-Web, and Cochrane Library databases for literature published from January 1990 to December 2019. The inclusion criteria included studies among the adult population using pegfilgrastim. The search strategy focused on timing-related keywords. Two reviewers independently extracted and assessed the data.
RESULTS: Among 300 initial search results, only four articles met the inclusion criteria. A meta-analysis for febrile neutropenia incidence suggested a potential higher incidence when pegylated G-CSF was administered on Days 3-5 than on Day 2 (odds ratio: 1.27, 95% CI 0.66-2.46, p = 0.47), with a moderate certainty of evidence. No significant difference in overall survival or mortality due to infections was observed. The trend of severe adverse events was lower on Days 3-5, without statistical significance (odds ratio: 0.72, 95% CI 0.14-3.67, p = 0.69) and with a moderate certainty of evidence. Data on pain were inconclusive.
CONCLUSIONS: Both Day 2 and Days 3-5 were weakly recommended for pegylated G-CSF administration post-chemotherapy in patients with cancer. The limited evidence highlights the need for further research to refine recommendations.

Filgrastim is approved for several indications, including reduction of the incidence and duration of chemotherapy-induced neutropenia and for stem cell mobilization. The filgrastim biosimilar, EP2006, has been available in Europe since 2009, and in the United States since 2015. In this time, preclinical and clinical data used to support the approval of EP2006 have been published. These data established the biosimilarity of EP2006 to reference filgrastim in terms of structure, pharmacokinetics, pharmacodynamics, efficacy, safety, and immunogenicity. Additional real-world evidence studies have also demonstrated equivalent efficacy and safety of EP2006 compared with reference filgrastim, both in the reduction of neutropenia and in stem cell mobilization in clinical practice. This review summarizes these preclinical, clinical, and real-world data, as well as the available cost-effectiveness data, for EP2006 since its approval 15 years ago.

BACKGROUND: To ascertain the efficacy and safety of cladribine, cytarabine, and filgrastim-based regimen in relapsed or refractory (R/R) AML patients.
METHODS: Clinical studies were searched in PubMed, Cochrane Library, Embase data. We selected available factors including complete remission (CR), overall response rate (ORR), overall survival (OS) to evaluate the efficacy, and early death (ED), and adverse events to evaluate safety.
RESULTS: 15 records with 812 R/R AML patients were finally included and analyzed using the R software. Subgroups analysis was also conducted. The pooled CR rate for CLAG regimen, CLAG-M regimen, and CLAG combined with any other drugs regimen is 56% (95% CI: 46-66), 46% (95% CI: 34-56), 44% (95% CI: 26-64), respectively. The relapsed and refractory groups showed a CR rate of 68% (95% CI: 53-80), and 51% (95% CI: 45-58) with CLAG related regimens. As risk grade decreases, the pooled CR rate increases. Regarding the safety for CLAG-related protocols, systematic review was conducted.
CONCLUSIONS: The CLAG-related regimen is an effective and safe therapy for R/R AML patients, CLAG seems to have more superiority than CLAG combined therapy, though further studies including cladribine combination treatment protocols, are still needed to confirm our results further.

BACKGROUND: The intravenous form of fosfomycin, a bactericide antibiotic used to treat multiresistant bacterial infections is little prescribed. The most common reported adverse effects are hypokaliemia and hypernatremia. We describe a case of agranulocytosis, a rarely described side effect that may be fatal.
METHODS: A 45 year-old woman was admitted to the intensive care unit for post-surgical meningitis following meningioma resection. Meropenem and vancomycin were first introduced. A DRESS-syndrom with meropenem was suspected. Neutropenia was diagnosed three days after the introduction of parenteral fosfomycin and agranulocytosis four days later. Eosinophilia was also observed. A bone marrow aspiration was performed showing a disappearance of the neutrophil granulocyte line and a significant eosinophilia. Meropenem was discontinued. Fosfomycin was maintained and filgrastim was added. As filgrastim had no effect, the relationship with fosfomycin was suspected, so it was then withheld. An increase of the neutrophil count was observed. Because of the complexity of the case, the unfavorable course of the illness and the urgent need for revision surgery, a rechallenge with fosfomycin was done followed by a decrease of the neutrophil count.
CONCLUSIONS: This is the third paper reporting agranulocytosis induced by fosfomycin, and the first detailed description of a case. Based on chronological and semiological criteria and bibliographic data, the event was qualified as probable with the Naranjo adverse drug probability scale. Literature data is scarce. The summary of product characteristics mentions that only a few cases of transient neutropenia and agranulocytosis have been reported. An analysis of the FDA Adverse Event Reporting System Database highlighted a higher than expected frequency of agranulocytosis in patients treated with fosfomycin. Parenteral fosfomycin is often used in patients receiving other medications, so that it is rarely the only suspect. In our case, the results of the bone marrow aspiration, the sudden drop of the neutrophil count with concomitant eosinophilia and the absence of improvement despite the dose decrease, point towards an immuno-allergic mechanism. However, the overlap between the suspected DRESS induced by meropenem and the agranulocytosis do not allow to conclude with certainty on the causality. Awareness should be raised about this side effect.

We herein report an 83-year-old woman with filgrastim-associated aortitis during chemotherapy for relapsed diffuse large B-cell lymphoma. She had been treated with filgrastim as a prophylaxis for neutropenia during the fourth cycle of chemotherapy from day 9 to 18. On day 21, she developed a fever. Contrast-enhanced computed tomography revealed aortitis of the descending aorta. The fever abated with non-steroidal anti-inflammatory drug treatment. A literature review identified a small number of aortitis cases all caused by prophylactic use of granulocyte colony-stimulating factors (G-CSFs), among which short-acting filgrastim was rarely encountered. The present and previous findings imply a possible relationship between aortitis and prophylactic G-CSF usage.

BACKGROUND: It is crucial that the safety profiles of biosimilars are similar to those of the original biologics. A better understanding of biosimilars and their relative safety and immunogenicity profiles are required for healthcare providers to prescribe them to patients with life-threatening cancer diseases who receive chemotherapies with potentially serious adverse events (AEs).
OBJECTIVE: The purpose of this study was to collate and analyze currently available safety and immunogenicity outcomes of biosimilars used in oncology and compare their safety information with those of the original biologics.
METHODS: The MEDLINE and Cochrane Library databases were searched as at 28 February 2022. Four anti-cancer biosimilar molecules were considered: bevacizumab, trastuzumab, rituximab, and (peg)filgrastim. Through a systematic review, we selected the randomized controlled trials (RCTs) comparing safety outcomes between the biosimilars and original biologics of the four molecules. As safety outcomes, various treatment-emergent adverse events (TEAEs) were collated, such as any TEAE, serious AE, and TEAE higher than grade 3. A risk ratio (RR) per category of TEAE was estimated through a meta-analysis. A network meta-analysis (NMA) was also conducted to compare the safety among the biosimilar brands for TEAEs over 25% with higher variability in addition to the serious AE cases.
RESULTS: Forty-nine RCTs were identified. The results from the meta-analysis showed that the safety and immunogenicity profiles of all four biosimilar molecules are comparable with that of the original biologics at the TEAE level without statistically significant differences, except for diarrhea for (peg)filgrastim. The incidence of diarrhea with (peg)filgrastim was less than that with the original biologic (RR 0.66, 95% confidence interval 0.50-0.89). The NMA results showed similar safety profiles among the biosimilar brands for all four biosimilar molecules, except for the serious adverse event of a trastuzumab biosimilar (RR 0.296, 95% credible interval 0.109-0.840).
CONCLUSIONS: The meta-analysis and NMA for all four biosimilars showed that the safety and immunogenicity profiles of biosimilar products in oncology are generally comparable with that of the original biologics at the TEAE level. However, additional evidence needs to be collected since several TEAEs of specific biosimilars were out of the equivalent range. The results of this study provide comparative safety information and a better understanding of oncology biosimilars for healthcare providers to prescribe them to patients.

UNASSIGNED: There is no meta-analysis about the effects of pegfilgrastim on the occurrence of febrile neutropenia (FN) in pediatric/adolescent cancer patients. The study explored the efficacy of prophylactic pegfilgrastim in preventing FN in children/adolescents with cancer.
UNASSIGNED: PubMed, Embase, and the Cochrane Library were searched for studies published before April 7, 2020. The primary outcome was the rate of FN. Effect size (ES) and odds ratio (OR) with 95% confidence intervals (CIs) were used to evaluate the outcome. The ES represented the rate of FN, and the STATA \'metaprop\' command was used to synthesize the rate.
UNASSIGNED: Eight studies were included, comprising 167 patients and 550 courses of treatment. There was no difference between pegfilgrastim and filgrastim for the rate of FN in children receiving chemotherapy (OR = 0.68, 95% CI: 0.20-2.23, P = 0.520). In patients receiving pegfilgrastim, the rate of FN was 25.6% (95% CI: 14.9%-36.3%), the rate of grade 4 FN was 38.3% (95% CI: 19.2%-59.5%), the rate of severe neutropenia (SN) was 40.5% (95% CI: 35.1%-46.1%), and the rate of treatment delays due to FN was 4.8% (95% CI: 0.8%-11.3%).
UNASSIGNED: The number of studies that could be included was small; therefore, a specific type of cancer or a specific treatment could be studied. Heterogeneity was high.
UNASSIGNED: There was no difference between pegfilgrastim and filgrastim for the rate of FN. The use of pegfilgrastim was still associated with rates of FN, grade 4 FN, severe neutropenia, and treatment delays due to FN in pediatric cancer patients.

BACKGROUND: Febrile neutropenia (FN) is a prevalent and potentially life-threatening complication in patients with lymphoma receiving myelosuppressive chemotherapy. Pegfilgrastim is more effective than filgrastim as prophylaxis for FN. However, its usage has been limited because of its higher cost. Pegfilgrastim\'s value for money remains unclear.
OBJECTIVE: To systematically review the cost-effectiveness of pegfilgrastim compared to filgrastim as a primary or secondary prophylaxis for chemotherapy-induced FN among patients with lymphoma.
METHODS: A systematic literature search was conducted in PubMed, EMBASE, Cochrane Library databases, and Google Scholar. The most widely used economic evaluations (cost-effectiveness analysis, cost-utility analysis and cost-benefit analysis) were included in the review. Data extraction was guided by the Consolidated Health Economic Evaluation Reporting Standards checklist, and the quality of reviewed articles was assessed using the Joanna Briggs Institute (JBI) checklist. Cost-effectiveness data were rigorously summarized and synthesized narratively. Costs were adjusted to US$ 2020.
RESULTS: We identified eight economic evaluation studies (two cost-utility analyses, three cost-effectiveness analyses, and three studies reporting both cost-effectiveness and cost-utility analyses). Half of these studies were from Europe (n = 4), the other half were from Iran, USA, Canada, and Singapore. Six studies met > 80% of the JBI quality assessment criteria. Cost-effectiveness estimates in the majority (n = 6) of these studies were for Non-Hodgkin Lymphoma patients receiving myelosuppressive chemotherapy with high-risk of FN (> 20%). The studies considered a wide range of baseline FN risk (17-97.4%) and mortality rates (5.8-8.9%). Reported incremental cost-effectiveness ratios ranged from US$ 2199 to US$ 8,871,600 per quality-adjusted life-year (QALY) gained, dominant to US$ 44,358 per FN averted, and US$ 4261- US$ 7251 per life-years gained. The most influential parameters were medication and hospitalization costs, the relative risk of FN, and assumptions of mortality benefit.
CONCLUSIONS: Most studies showed that pegfilgrastim is cost-effective compared to filgrastim as primary and secondary prophylaxis for chemotherapy-induced FN among patients with lymphoma at a cost-effectiveness threshold of US$ 50,000 per QALY gained. The findings could assist clinicians and healthcare decision-makers to make informed decisions regarding resource allocation for the management of chemotherapy-induced FN in settings similar to those studied.

Infection following SARS-Co V-2 leading to COVID-19 disease is associated with significant morbidity and mortality. The clinical entity, COVID-19 cytokine storm syndrome (CSS) is a severe immunological manifestation of the disease associated with ominous consequences. Tocilizumab is interleukin-6 inhibitors that has been shown to hamper the catastrophic outcomes of CCS including the need for mechanical ventilation as well as reduce mortality, but the usage is limited by warnings of reactivation of potential latent infections or immune dysfunctions including severe neutropenia. We describe a case of 39-year-old Nepalese male patient with a background of scleritis maintained on azathioprine and rituximab therapy with normal baseline parameters including complete blood count who presented with acute COVID-19 infection including associated leukopenia as well as severe neutropenia (absolute neutrophil count of 300 cells/µl), then progressed to critical disease culminating into CSS. Based on risks and benefits evaluation, the patient was treated with tocilizumab reinforced with granulocytes-colony stimulating factor (G-CSF, Filgrastim) to full recovery and safe outcome including reversal of neutropenia.