Consensus survey on the management of children with chemotherapy-induced febrile neutropenia and at low risk of severe infection.

Our aim was to identify national consensus criteria for the management of children with chemotherapy-induced febrile neutropenia (FN), for evidence-based step-down treatment approaches for patients classified at low risk of severe infection. In 2018, a five-section, 38-item survey was e-mailed to all pediatric hematology and oncology units in France (n = 30). The five sections contained statements on possible consensus criteria for the (i) definition of FN, (ii) initial management of children with FN, (iii) conditions required for initiating step-down therapy in low-risk patients, (iv) management strategy for low-risk patients, and (v) antibiotic treatment on discharge. Consensus was defined by respondents' combined answers (somewhat agree and strongly agree) at 75% or more. Sixty-five physicians (participation rate: 58%), all specialists in pediatric onco-hematology, from 18 centers completed the questionnaire. A consensus was reached on 22 of the 38 statements, including the definition of FN, the criteria for step-down therapy in low-risk children, and the initial care of these patients. There was no consensus on the type and duration of antibiotic therapy on discharge. In conclusion, a consensus has been reached on the criteria for initiating evidence-based step-down treatment of children with FN and a low risk of severe infection but not for the step-down antimicrobial regimen.

The impact of new and emerging agents on outcomes for febrile neutropenia: addressing clinical gaps.

PURPOSE OF REVIEW: While chemotherapy treatment options for patients with solid and hematologic malignancies have dramatically improved over recent years, chemotherapy-induced neutropenia (CIN) and febrile neutropenia (FN) remain major barriers to delivering treatment at full doses and optimal timing. Despite concurrent advances in granulocyte colony-stimulating factor (G-CSF) administration, multiple barriers to the administration of and disparities in the access to these agents remain. The introduction of new, emerging agents, including biosimilars and novel therapies show promise in improving outcomes for CIN. RECENT FINDINGS: The introduction of biosimilar filgrastim products has improved access to G-CSF administration by driving marketplace competition and has reduced costs for both patients and healthcare systems without sacrificing efficacy. Emerging therapies to address similar issues include long-acting G-CSF products, efbemalenograstim alfa and eflapegrastin-xnst, as well as agents with novel mechanisms of action, plinabulin and trilaciclib. These agents have shown efficacy and cost-saving benefits in certain populations and disease groups. SUMMARY: Multiple emerging agents show promise in decreasing the burden of CIN. Use of these therapies will reduce access disparities and will improve outcomes for patients with cancer receiving cytotoxic chemotherapy. Many ongoing trials are underway to evaluate the roles of these agents for more widespread use.

Two decades of pegfilgrastim: what have we learned? Where do we go from here?

Chemotherapy-induced febrile neutropenia (FN) is a medical emergency that may occur in patients with malignancies receiving myelosuppressive chemotherapy. FN requires early therapeutic intervention since it is associated with increased hospitalizations and high mortality risk of 5%-20%. FN-related hospitalizations are higher in patients with myeloid malignancies than in those with solid tumors due to the myelotoxicity of chemotherapy regimens and the compromised bone marrow function. FN increases the burden of cancer by causing chemotherapy dose reductions and delays. The administration of the first granulocyte colony-stimulating factor (G-CSF) filgrastim reduced the incidence and duration of FN in patients undergoing chemotherapy. Filgrastim later evolved into pegfilgrastim, which has a longer half-life than filgrastim and is associated with a lower rate of severe neutropenia, chemotherapy dose reduction, and treatment delay. Nine million patients have received pegfilgrastim since its approval in early 2002. The pegfilgrastim on-body injector (OBI) is an innovative device facilitating the time-released auto-injection of pegfilgrastim approximately 27 h after chemotherapy, as clinically recommended for the prevention of FN, thus eliminating the need for a next-day hospital visit. Since its introduction in 2015, one million patients with cancer have received pegfilgrastim using the OBI. Subsequently, the device was approved in the United States (US), European Union, Latin America, and Japan, with studies and a postmarketing commitment demonstrating device reliability. A recent prospective observational study conducted in the US demonstrated that the OBI substantially improved the adherence to and compliance with clinically recommended pegfilgrastim therapy; patients receiving pegfilgrastim via the OBI experienced a lower incidence of FN than those receiving alternatives for FN prophylaxis. This review discusses the evolution of G-CSFs leading to the development of the OBI, current recommendations for G-CSF prophylaxis in the clinic, continued evidence supporting next-day pegfilgrastim administration, and improvements in patient care made possible with the OBI.

For over 20 years, treatment with pegfilgrastim (a therapy that supports the growth of immune cells) has been used in patients with cancer to prevent febrile neutropenia (FN) ­ an unwanted effect of cancer treatment or chemotherapy. FN is defined as the loss of healthy immune cells and development of fever possibly due to an infection. Patients with FN may be very ill or may die, depending on the seriousness of the condition. However, treatment with pegfilgrastim reduces the occurrence of FN and improves survival.Treatment guidelines recommend that pegfilgrastim should be given 24 h after chemotherapy, requiring patients to travel to the hospital on the next day of chemotherapy. Some patients may choose the less helpful option of receiving pegfilgrastim on the same day of chemotherapy to avoid travel. This need led to the development of an on-body injector (OBI) device that is applied on the skin on the last day of chemotherapy and administers pegfilgrastim approximately 27 h after chemotherapy. The highly reliable OBI ensures timely delivery of therapy with a success rate of 99.9%, reduces the travel burden, and helps in following the recommended guidelines for pegfilgrastim administration. For two decades, pegfilgrastim has played a significant role in the treatment and prevention of FN, and the new OBI device provides the required treatment support for improving patient care.

Risk of chemotherapy-induced febrile neutropenia in intermediate-risk regimens: Clinical and economic outcomes of granulocyte colony-stimulating factor prophylaxis.

BACKGROUND: Chemotherapy-induced neutropenia increases the risk of febrile neutropenia (FN) and infection with resultant hospitalizations, with substantial health care resource utilization (HCRU) and costs. Granulocyte-colony stimulating factor (GCSF) is recommended as primary prophylaxis for chemotherapy regimens having more than a 20% risk of FN. Yet, for intermediate-risk (10%-20%) regimens, it should be considered only for patients with 1 or more clinical risk factors (RFs) for FN. It is unclear whether FN prophylaxis for intermediate-risk patients is being optimally implemented. OBJECTIVE: To examine RFs, prophylaxis use, HCRU, and costs associated with incident FN during chemotherapy. METHODS: This retrospective study used administrative claims data for commercial and Medicare Advantage enrollees with nonmyeloid cancer treated with intermediate-risk chemotherapy regimens during January 1, 2009, to March 31, 2020. Clinical RFs, GCSF prophylaxis, incident FN, HCRU, and costs were analyzed descriptively by receipt of primary GCSF, secondary GCSF, or no GCSF prophylaxis. Multivariable Cox regression analysis was used to examine the association between number of RFs and cumulative FN risk. RESULTS: The sample comprised 13,937 patients (mean age 67 years, 55% female). Patients had a mean of 2.3 RFs, the most common being recent surgery, were aged 65 years or greater, and had baseline liver or renal dysfunction; 98% had 1 or more RFs. However, only 35% of patients received primary prophylaxis; 12% received secondary prophylaxis. The hazard ratio of incident FN was higher with increasing number of RFs during the first line of therapy, yet more than 54% of patients received no prophylaxis, regardless of RFs. Use of GCSF prophylaxis varied more by chemotherapeutic regimen than by number of RFs. Among patients treated with rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride (doxorubicin hydrochloride), vincristine, and prednisone, 76% received primary prophylaxis, whereas only 22% of patients treated with carboplatin/paclitaxel received primary prophylaxis. Among patients with a first line of therapy FN event, 78% had an inpatient stay and 42% had an emergency visit. During cycle 1, mean FN-related coordination of benefits-adjusted medical costs per patient per month ($13,886 for patients with primary prophylaxis and $18,233 for those with none) were driven by inpatient hospitalizations, at 91% and 97%, respectively. CONCLUSIONS: Incident FN occurred more often with increasing numbers of RFs, but GCSF prophylaxis use did not rise correspondingly. Variation in prophylaxis use was greater based on regimen than RF number. Lower health care costs were observed among patients with primary prophylaxis use. Improved individual risk identification for intermediate-risk regimens and appropriate prophylaxis may decrease FN events toward the goal of better clinical and health care cost outcomes. DISCLOSURES: This work was funded by Sandoz Inc., which participated in the design of the study, interpretation of the data, writing and revision of the manuscript, and the decision to submit the manuscript for publication. The study was performed by Optum under contract with Sandoz Inc. The author(s) meet criteria for authorship as recommended by the International Committee of Medical Journal Editors. The authors received no direct compensation related to the development of the manuscript. Dr Li is an employee of Sandoz Inc. Drs Bell and Lal and Mr Peterson-Brandt were employees of Optum at the time of the study. Ms Anderson and Dr Aslam are employees of Optum. Dr Lyman has been primary investigator on a research grant from Amgen to their institution and has consulted for Sandoz, G1 Therapeutics, Partners Healthcare, BeyondSpring, ER Squibb, Merck, Jazz Pharm, Kallyope, Teva; Fresenius Kabi, Seattle Genetics, and Samsung.

Chemotherapy-induced neutropenia among breast Cancer patients in a tertiary care hospital: Risk and consequences.

STUDY OBJECTIVE: To identify the risk factors that may predispose breast cancer patients to Chemotherapy-induced neutropenia (CIN) and its associated complications for the years 2018 and 2020. CIN is an established complication of breast cancer treatment. Clinical Pharmacists can play an important role in the treatment of CIN through involvement in risk assessment to identify patients for oral antimicrobial therapy, drug therapy monitoring, and development of suitable guidelines or policies. METHODOLOGY: A retrospective study was performed by collecting data of 72 breast cancer patients for the last two years from department of Medical Oncology in a tertiary care hospital. RESULTS: The overall occurrence of CIN was 59.7% in our study population. Out of 72 patients studied, 43 patients were found to be neutropenic. Using Pearson Chi square test, chemotherapy-induced neutropenia was associated with older age (over 60 y) (p < 0.038), diabetes mellitus (p < 0.050), tumour stage IIIa (p < 0.024), AC (p < 0.051) and taxane chemotherapy regimens (p < 0.041). Febrile neutropenia occurred in 37.28% of patients and the incidence of infection-related mortality [severe septicaemia] was 3.38%. CONCLUSION: The incorporation of clinical pharmacist must be brought into practice in our country for providing proper guidance to the patient on CIN and its complications. By identifying risk factors for neutropenia, the safe management of CIN may be possible in patients with breast cancer.

Population pharmacokinetics and pharmacodynamics of imipenem in neutropenic adult patients.

OBJECTIVE: Imipenem is recommended in patients with chemotherapy-induced febrile neutropenia. Although alterations of antibiotic pharmacokinetic parameters have been reported in such patients, little data is available on imipenem. METHODS: Prospective, single-center, non-interventional pharmacokinetic cohort study in adults with chemotherapy-induced febrile neutropenia. Critically ill patients were excluded. Imipenem was administered as a 30-min infusion of 1000 mg/8h. Total imipenem plasma concentrations were assayed by high-performance liquid chromatography during neutropenia and just after neutrophil recovery. We estimated population pharmacokinetic parameters of imipenem by non-linear mixed-effect modelling using the SAEM algorithm. RESULTS: Sixteen patients were included in the study, including nine women (56.3%), median age 37 years (range, 18.3; 78.3). Eight patients had an hematological malignancy (50.0%) and seven had a solid tumor (43.8%). Imipenem pharmacokinetics were best described by a one-compartment model with first-order elimination. Mean values for imipenem were: clearance 14.3L/h and 10.9L/h and volume of distribution 20.7L and 14.5 L during neutropenia and after recovery, respectively. Imipenem plasma area under the curve at steady state was reduced by 23% during neutropenia. However, all patients achieved a pharmacodynamic target of %fT>MIC ≥ 40% with a regimen of 1000 mg/8 h or 500 mg/6 h, for MICs up to 2 mg/L. The pharmacodynamics profile for a target of %fT > MIC = 100% was however less favorable with 500 mg/6 h or 1000 mg/8 h either during or after neutropenia. CONCLUSION: Pharmacokinetic/pharmacodynamic goals for imipenem were similar in patients during and after neutropenia, despite reduced plasma exposure.

Management of chemotherapy-induced febrile neutropenia and use of granulocyte colony-stimulating factor in patients with soft tissue or bone sarcoma.

INTRODUCTION: Febrile neutropenia, an oncological complication related to myelosuppressive chemotherapy, can lead to unplanned hospitalization, morbidity, mortality, and changes in the oncological therapeutic plan. The present study aimed (1) to determine the prevalence of chemotherapy-induced febrile neutropenia requiring hospitalization and the use of granulocyte colony-stimulating factor and (2) to evaluate its consequences for the oncological treatment of patients with soft tissue or bone sarcomas. METHODS: This is a cross-sectional and retrospective study (January 2018 to December 2019) carried out in a reference oncology hospital in the Brazilian public health system. Inpatients diagnosed with chemotherapy-induced febrile neutropenia, older than the age of 18 years, and treated with granulocyte colony-stimulating factor were included in the study. RESULTS: Twenty-nine chemotherapy-induced febrile neutropenia events were identified, involving 25 patients. Among the febrile neutropenia events, 90% were grade 4, and 59% occurred during palliative chemotherapy. Among patients with febrile neutropenia, 31% had arterial hypertension or/and diabetes mellitus comorbidities, 34% had infectious skin sites, such as compression ulcers and tumor wounds, and 31% had infections with defined etiologic agents. Treatment of hospitalized patients was performed with cefepime in combinations or alone (97%) and filgrastim. The outcomes related to chemotherapy-induced febrile neutropenia were chemotherapy dose reduction (31%), chemotherapy cycle delays (21%), chemotherapy treatment suspension (17%), deaths (7%), and other associated complications (10%). Granulocyte colony-stimulating factor prophylaxis was prescribed in 72.41% of febrile neutropenia events. The frequency of febrile neutropenia concerning total chemotherapy cycles was 2.15%. CONCLUSION: Even with granulocyte colony-stimulating factor prophylaxis, an overall prevalence of 2.15% of febrile neutropenia associated with hospitalization was observed, causing negative outcomes in chemotherapy treatment of patients.

Efficacy of same-day versus next-day administration of pegfilgrastim for the prevention of chemotherapy-induced febrile neutropenia in breast cancer patients receiving dose-dense doxorubicin and cyclophosphamide: A retrospective multi-site analysis.

INTRODUCTION: Administering pegfilgrastim on the same day as chemotherapy can improve patient satisfaction through convenience and may increase the utilization of cost-effective biosimilars compared to next-day administration, but the effect on clinical outcomes with commonly used breast cancer regimens is unclear. METHODS: This multi-site, retrospective cohort study included breast cancer patients age 18 years or older who received dose-dense doxorubicin and cyclophosphamide (ddAC) and pegfilgrastim between 1 June 2016 and 31 May 2020. Pegfilgrastim was given on the same day as chemotherapy at one site and the day after chemotherapy at the other two sites. The primary endpoint compared the incidence of febrile neutropenia associated with pegfilgrastim administration timing. RESULTS: A total of 360 patients were reviewed (146 same-day administration and 214 next-day administration). In the same-day group 36 patients (24.6%) developed FN compared to 25 patients (11.7%) in the next-day group (p = 0.002). Same-day administration also significantly increased the incidences of additional acute care visits (11.6% vs 2.8%, p = 0.0016), grade ≥ 3 neutropenia (38.4% vs 13.6%, p < 0.0001), chemotherapy dose reductions (21.2% vs 6.1%, p < 0.0001), and antibiotic use (26.7% vs 12.6%, p = 0.001). Same-day administration did not significantly increase the rate of hospitalization (15% vs 11.2%, p = 0.36) and delay of next chemotherapy cycle by ≥1 day (8.2% vs 6.1%, p = 0.57) due to neutropenic complications. CONCLUSIONS: Administering pegfilgrastim on the same day as ddAC led to a significant increase in neutropenic complications. This study confirms the need to administer pegfilgrastim the day after chemotherapy in breast cancer patients receiving ddAC.

Cost-effectiveness of pegfilgrastim versus filgrastim for prevention of chemotherapy-induced febrile neutropenia in patients with lymphoma: a systematic review.

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.

Supportive therapies in the prevention of chemotherapy-induced febrile neutropenia and appropriate use of granulocyte colony-stimulating factors: a Delphi consensus statement.

PURPOSE: Data indicate that the use of prophylactic granulocyte colony-stimulating factors (G-CSFs) for chemotherapy-induced febrile neutropenia (FN) in routine practice is not consistent with guideline recommendations. The initiative "supportive care for febrile neutropenia prevention and appropriateness of G-CFS use" was undertaken to address the issue of inappropriate prescription of G-CSFs and to improve guideline adherence in the treatment of FN. METHODS: In a two-round Delphi procedure, 36 medical oncologists reviewed clinically relevant recommendations on risk assessment, the appropriate use of G-CSFs, and the prevention of FN based on available literature and individual clinical expertise. RESULTS: The consensus was reached on 16 out of 38 recommendations, which are backed by evidence from randomised clinical trials and routine clinical practice. The medical oncologists agreed that the severity of neutropenia depends on patients' characteristics and chemotherapy intensity, and therefore, the risk of severe neutropenia or FN should be assessed at each chemotherapy cycle so as to initiate prophylaxis with G-CSFs if required. The use of biosimilar G-CSFs, with similar efficacy and safety profiles to the originator biologic, has improved the availability and sustainability of cancer care. The timing of supportive therapy is crucial; for example, long-acting G-CSF should be administered 24-72 h after chemotherapy administration. Each biological agent has a recommended administration dose and duration, and it is important to follow these recommendations to avoid complications associated with under-prophylaxis. CONCLUSION: It is hoped that these statements will help to increase adherence to guideline recommendations for appropriate G-CSF use and improve patient care.

[Chemotherapy-induced febrile neutropenia in a Tunisian Department of Pediatric Oncology]. / Neutropénie fébrile chimio-induite dans une unité d'oncologie pédiatrique tunisienne.

Chemotherapy-induced neutropenia (FN) is the most common infectious complication in pediatric oncology. To our knowledge, no pediatric research has been published in Tunisia. The purpose of our study was to describe the features of FN among Tunisian children and to investigate factors correlated with FN. We conducted a prospective study of children with chemotherapy-induced FN at the Department of Pediatric Medicine A of the Tunis Children´s Hospital from July 2019 to December 2019. We recorded 50 episodes of FN in 32 patients whose mean age was 5.3 years (3 months-16 years). We included 26 patients with solid tumors (81%) and six patients with hemopathies (18.7%). The mean time between last treatment and fever onset was 10.67 days. Bacteriological investigation was contributory in 18% of cases and mainly showed gram positive cocci. Therapeutic protocol including 1st line empirical antibiotic therapy (3rd generation cephalosporin with aminoglycoside) was effective in 62% of cases. Mortality rate of patients with FN was 2%. The statistical study did not reveal any factor of correlation with late-onset neutropenia. In conclusion, our results are consistent with literature data on bacteriological documentation and mortality. Our 1st line treatment option based on 3rd generation cephalosporin associated with aminoglycoside was effective in 2/3 of the cases. In the future, oral antibiotics may be considered in patients at low risk for infection.

Evaluating the safety and effectiveness of PegaGen® (pegfilgrastim) for the prevention of chemotherapy-induced febrile neutropenia: a post-marketing surveillance study.

PURPOSE: Phase IV clinical trials are required to evaluate the real-world safety and effectiveness of drugs. This study aimed to evaluate the safety and effectiveness of once-per-cycle administration of PegaGen® (pegfilgrastim, CinnaGen, Iran) in cancer patients. METHODS: In this open-label, multicenter, prospective, real-world, post-marketing surveillance study, patients with any type of cancer receiving chemotherapy regimens with a high risk of febrile neutropenia (FN) were included if they were prescribed pegfilgrastim for FN prophylaxis. The primary objective of this study was to assess the safety and the secondary objective was to assess the effectiveness of pegfilgrastim in the prevention of FN in cancer patients. RESULTS: A total of 654 patients (51.73 ± 15.12 years of age) were enrolled and 3615 cycles of pegfilgrastim injections were recorded. The most common malignancies among the study patients were breast cancer (n = 192, 29.36%), lymphoma (n = 131, 20.03%), and gastric cancer (n = 65, 9.94%). The median (Q1, Q3) number of pegfilgrastim cycles per patient was 6 (4, 7). A single 6 mg dose was injected in 99.17% of the cycles. A total number of 816 adverse events (AEs) were reported in 246 patients (37.62%). Bone pain was recorded in 141 patients (21.56%) and in 440 cycles (12.17%). Among all patients, 45 patients (6.88%) experienced FN 51 times, and FN frequency was 1.4% among cycles. Moreover, 14 (2.14%) patients were hospitalized following FN. Antibiotics were administered to 24 patients (3.67%) for FN treatment. CONCLUSION: The results from this post-marketing surveillance study support the safety and effectiveness of PegaGen® used for the prevention of chemotherapy-induced FN in patients with various types of cancer and treatment regimens. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT04460079.

Pegfilgrastim-Apgf (Nyvepria): Biosimilar USFDA Approval for the Treatment of Chemotherapy-induced Febrile Neutropenia and Current Updates on Clinical Trials.

Pegfilgrastim-apgf (nyvepria) was currently approved by FDA for the treatment of febrile neutropenia associated with non-myeloid malignancies receiving myelosuppressive anticancer drugs. It was developed by Pfizer, USA. It is a PEGylated leukocyte growth-stimulating factor indicated to reduce the incidence of febrile neutropenia in patients receiving anticancer drugs. Nyvepria is biosimilar to pegfilgrastim, approved by FDA on June 10, 2020. It is the fourth FDA-approved drug for the treatment of infection exhibiting febrile neutropenia. This review abridges the indicators in the development of nyvepria foremost to approval for the treatment of febrile neutropenia (FN), a biosimilar regulatory framework, and current updates on the clinical trials (CTs).

G-CSF and G-CSF-related vasculitis: a systematic review of the literature and intriguing future research perspectives.

Background: There are several case reports suggesting that G-CSFs may, in rare conditions, produce serious side effects, such as vasculitis. Materials & methods: A systematic search was conducted in Medline via PubMed, Embase and Cochrane Library to describe this unusual side effect to raise awareness among clinicians for early recognition and treatment. Results: Fifty-seven patients were analyzed. The most prevalent cancer type was breast cancer (47%). Long-acting G-CSF was used in 38 patients (67%). Only 47% of patients were treated with steroids. Conclusion: Although the benefit of G-CSF treatment outweighs the potential damage, oncologists should consider the possibility of triggering a vascular toxicity and try to identify patients at increased risk for this side effect.

Lay abstract Background: Several case reports suggest that a type of drug called granulocyte colony-stimulating factor (G-CSFs) may, in rare cases, produce serious side effects, such as vasculitis. Materials & methods: A systematic search was conducted to describe this unusual side effect. Results: Fifty-seven patients were analyzed. The most prevalent cancer type in which this side effect was observed was breast cancer (47%). Only 47% of patients were treated with steroids. The main symptoms, such as fever, chest/epigastric pain and general malaise, are nonspecific and cannot be used to diagnose the side effect; laboratory findings are suggestive of inflammation. Conclusion: Accurate assessment of what causes this adverse event is extremely important. Although the benefit of G-CSF treatment outweighs the potential damage, oncologists should consider the possibility of triggering vascular toxicity and try to identify patients at increased risk.

Economic Analysis on Adoption of Biosimilar Granulocyte Colony-Stimulating Factors in Patients With Nonmyeloid Cancer at Risk of Febrile Neutropenia Within the Oncology Care Model Framework.

PURPOSE: Value-based programs, such as the Oncology Care Model (OCM), seek to improve care for patients undergoing chemotherapy, while reducing total costs. The purpose of this study is to quantify the impact of adopting biosimilar granulocyte colony-stimulating factors (G-CSFs) for febrile neutropenia (FN) primary prophylaxis (PP) from a US practice perspective. METHODS: A 1-year economic analysis on real-world direct drug costs and health care resource utilization was conducted in a hypothetical cohort of 500 patients with nonmyeloid cancer receiving chemotherapy. The first model simulated total cost savings of biosimilar versus reference G-CSFs over six cycles of chemotherapy. The second model evaluated cost and outcome implications of expanding the use of biosimilar G-CSFs to an additional 10% of patients at intermediate FN risk. RESULTS: Based on real-world evidence over 1 year, a total of 121 of 500 patients received G-CSF prophylaxis resulting in cost savings that ranged from $0.54M US dollars (USD) (short-acting, eg, filgrastim) to $1.68M USD (long-acting, eg, pegfilgrastim) when switching from reference to biosimilar G-CSFs. Expanding the use of biosimilar G-CSFs allowed an additional 24 patients to receive prophylaxis of FN, leading to cost savings of $0.03M USD or $1.19M USD, with a reduction of $0.08M USD in FN-related resource utilization cost. The per-patient per-year cost saving for long-acting G-CSFs was about $3,000 USD. CONCLUSION: The implementation of biosimilar versus reference G-CSFs to OCM-participating practices results in a reduction of costs and facilitates achieving OCM metrics by improving patients' outcomes while expanding biosimilar G-CSFs access to patients at intermediate risk of chemotherapy-induced FN.

Comparing the efficacy and side-effects of PDLASTA® (Pegfilgrastim) with PDGRASTIM® (Filgrastim) in breast cancer patients: a non-inferiority randomized clinical trial.

BACKGROUND: The objective of this study was to compare the efficacy and side effects of a single dose (Pegfilgrastim or PDL) or repeated six daily injections (Filgrastim or PDG) during chemotherapy courses in breast cancer patients in a non-inferiority clinical trial. METHODS: In this randomized clinical trial, 80 patients were recruited and allocated randomly to two equal arms. In one group, a single subcutaneous dose of PDL was injected the day after receiving the chemotherapy regimen in each cycle. The second arm received a subcutaneous injection of PDG for six consecutive days in each cycle of treatment. The side effects of GCF treatment and its effect on blood parameters were compared in each cycle and during eight cycles of chemotherapy. RESULTS: Hematologic parameters showed no significant differences in any of the treatment courses between the two study groups. The comparison of WBC (p = 0.527), Hgb (p = 0.075), Platelet (p = 0.819), Neutrophil (p = 0.575), Lymphocyte (p = 705) and ANC (p = 0.675) changes during the eight courses of treatment also revealed no statistically significant difference between the two study groups. Side effects including headache, injection site reaction and muscle pain had a lower frequency in patients receiving PDL drugs. CONCLUSION: It seems that PDL is non-inferior in efficacy and also less toxic than PDG. Since PDL can be administered in a single dose and is also less costly, it can be regarded as a cost-effective drug for the treatment of chemotherapy-induced neutropenia. TRIAL REGISTRATION: IRCT20190504043465N1 , May 2019.

Oral Step-Down Therapy With Levofloxacin for Febrile Neutropenia in Children With Cancer.

BACKGROUND: Although febrile neutropenia (FN) is a frequent complication in children with cancer receiving chemotherapy, there remains significant variability in selection of route (intravenous [IV] vs oral) and length of therapy. We implemented a guideline with a goal to change practice from using IV antibiotics after hospital discharge to the use of step-down oral therapy with levofloxacin for most children with FN until absolute neutrophil count > 500. The objectives of this study were to determine the impact of this guideline on home IV antibiotic use, and to evaluate the safety of implementation of this guideline. METHODS: We performed a quasi-experimental, pre-post study of discharge FN treatment at a stand-alone children's hospital in patients without bacteremia discharged between January 2013 and October 2018. In January 2015, a multidisciplinary team created a guideline to switch most children with FN to oral levofloxacin, which was formally implemented as of September 2017. Discharges during the postintervention period (after September 2017) were compared to discharges in the preintervention period (between January 2013 and December 2014). RESULTS: In adjusted multivariable regression analyses, the postimplementation period was associated with a decrease in home IV antibiotics (adjusted risk ratio [aRR], 0.07 [95% confidence interval {CI}, .03-.13]) and fewer IV antibiotic initiations within 24 hours of a new healthcare encounter up to 7 days after discharge (aRR, 0.39 [95% CI, .17-.93]) compared to the preintervention time period. CONCLUSIONS: Step-down oral levofloxacin for children with FN who are afebrile with an ANC ≤ 500 at discharge is feasible and resulted in similar clinical outcomes compared to home IV antibiotics.

Management of fever and neutropenia in the adult patient with acute myeloid leukemia.

INTRODUCTION: Febrile neutropenia represents one of the most common treatment-associated complications in the management of acute myeloid leukemia (AML) and is considered an oncologic emergency. Rapid and detailed workup as well as the initiation of empiric broad-spectrum antibiotic therapy are critical to avoid sepsis and to reduce mortality. Although a definitive source of infection is frequently not identified, the severely immunosuppressed status of the AML patient undergoing cytotoxic therapy results in a high risk for a wide array of bacterial, fungal, and viral etiologies. AREAS COVERED: The authors herein review the diagnostic and therapeutic approach to the neutropenic leukemia patient based on the current knowledge. Special consideration is given to the rapidly changing therapeutic landscape in AML, creating new challenges in the management of infectious complications. EXPERT OPINION: Multidrug-resistant organisms pose a major challenge in the management of neutropenic fever patients with hematologic malignancies - including AML. Future directions to improve outcomes demand innovative treatment approaches as well as advances in biomarker research to facilitate diagnosis and disease monitoring. Recent achievements in AML-targeted therapy led to an increased incidence of differentiation syndrome, a potentially life-threatening side effect that frequently resembles clinical infection and requires prompt recognition and aggressive intervention.

Effect of lipegfilgrastim administration as prophylaxis of chemotherapy-induced neutropenia on dose modification and incidence of neutropenic events: real-world evidence from a non-interventional study in Belgium and Luxembourg.

Objectives: This study evaluated the effect of lipegfilgrastim, a glycopegylated granulocyte-colony stimulating factor, used as primary (PP) or secondary prophylaxis (SP) on chemotherapy (CT) treatment modifications, as well as the incidence of CT-induced neutropenic events in adult patients receiving cytotoxic CT with or without biological therapy (BT) for solid and hematological tumors, in routine clinical practice. Other objectives were to characterize the population of lipegfilgrastim-treated cancer patients and safety assessment. Methods: This phase 4, prospective, observational study was conducted at 15 centers from Belgium and Luxembourg, between 2015 and 2017. Results: Of 139 patients, 82.7% had breast cancer and 54.7% were treated with dose-dense regimens. Most received lipegfilgrastim as PP (82.0%) and were at high-risk of febrile neutropenia (FN) (68.3%). FN and grade III/IV neutropenia were reported for 7.9% and 22.3% patients. Among 123 evaluated patients, CT/BT dose modifications were recorded for 33.3% (PP) and 52.4% (SP) of patients receiving lipegfilgrastim; dose reductions, followed by dose delays, were more frequent than omissions. Among 45 patients with dose modifications, FN was reported for 8.8% and 9.1% patients and grade IV neutropenia for 17.6% and 18.2% of patients when lipegfilgrastim was applied for PP and SP, respectively. Adverse events related to lipegfilgrastim occurred for 55 (39.6%) patients; bone pain and back pain were more frequent. Lipegfilgrastim-related serious adverse events were reported for 9 (6.5%) patients. Conclusion: Use of lipegfilgrastim in real-world settings resulted in limited CT dose modifications and low incidences of neutropenic events, with no new safety concerns arising.

Renal proximal tubulopathy in an HIV-infected patient treated with tenofovir alafenamide and gentamicin: a case report.

BACKGROUND: The nucleotide reverse transcriptase inhibitor Tenofovir Alafenamide (TAF) is a novel pro-drug of tenofovir (TFV) and possesses a superior renal safety profile compared with tenofovir disoproxil fumerate (TDF). Due to unique pharmacokinetic characteristics, treatment with TAF is not associated with significant renal proximal tubular accumulation of TFV. TAF is associated with a lower risk of acute kidney injury, chronic kidney disease, proteinuria and renal proximal tubular dysfunction than treatment with TDF. No cases of Fanconi syndrome have been reported in clinical trials of TAF. It is unknown whether treatment with TAF can lead to accumulation of TFV in proximal tubular cells and cause nephrotoxicity under certain clinical circumstances. CASE PRESENTATION: Here we report the case of a patient on stable TAF-based antiretroviral therapy with for HIV-1 infection who developed proximal tubulopathy when treated with gentamicin for febrile neutropenia in the context of relapsed Hodgkin lymphoma. Eighteen days after commencing chemotherapy for relapsed Hodgkin lymphoma the patient presented to hospital with fevers, hypotension and neutropenia. The patient was commenced on piperacillin, tazobactam and gentamicin. Within 24 h the patient developed marked hypokalaemia and hypophosphataemia requiring intravenous replacement therapy. There was proteinuria, glycosuria and evidence of marked urinary electrolyte wasting, consistent with acute proximal tubular dysfunction. Eleven days after the gentamicin was stopped the serum biochemistry normalised. The urinary electrolyte wasting and proteinuria had improved, and the glycosuria had resolved. CONCLUSION: This is the first case report to describe acute renal proximal tubulopathy in an HIV-infected patient treated with TAF and gentamicin. As the number of patients prescribed TAF outside the clinical trial setting increases, so too does the potential for previously unreported drug interactions and adverse events. Clinicians need to be aware of potential unreported adverse drug reactions as the use of TAF becomes increasingly common in clinical practice.