Duration Of Febrile Neutropenia Research Articles

Efficacy and safety of PEG-rhG-CSF versus rhG-CSF in preventing granulocytopenia in sarcoma patients receiving doxorubicin combined with ifosfamide: A prospective, randomized, non-inferiority phase II study.

e24173 Background: Prophylactic use of rhG-CSF is routinely recommended in patients with a high risk of febrile neutropenia (FN) after chemotherapy. Currently, rhG-CSF is mostly used in clinical practice. However, PEG-rhG-CSF tends to be a substitute due to its convenience and long-acting effect. Regarding concerns about its efficacy and safety, whether PEG-rhG-CSF could be prophylactically used after these regimens with a high risk of FN is still in doubt. Doxorubicin combined with ifosfamide is commonly applied in sarcoma patients and is one of the most serious myelosuppressive chemotherapy regimens in solid tumors. We compared the efficacy and safety of PEG-rhG-CSF with rhG-CSF in the prevention of severe granulocytopenia and FN, in patients receiving this representative regimen. Methods: This was a single-center, prospective, randomized, crossover, non-inferiority phase II trial. Patients with sarcoma suitable for doxorubicin combined with ifosfamide treatment were enrolled. All patients received 2 cycles of chemotherapy and were randomly assigned to either the AOB group (PEG-rhG-CSF used in 1st cycle and rhG-CSF in 2nd cycle) or BOA group (rhG-CSF used in 1st cycle and PEG-rhG-CSF in 2nd cycle). Blood monitoring every other day until ANC ≥ 2×109/L in two consecutive tests. The primary endpoints were the frequency and duration of grade 4 granulocytopenia after prophylactic use of PEG-rhG-CSF and rhG-CSF respectively, the secondary endpoints were the frequency and duration of febrile neutropenia, and proportion of antibiotic use. Results: From Jan 1, 2018 to Aug 31, 2021, 70 patients were enrolled, 35 each in AOB and BOA. There were no statistical differences in the incidence and duration of grade 4 granulocytopenia (85.7% vs. 77.0%, p = 0.1; 1.34d vs. 1.41d, p = 0.70), the proportion and duration of febrile neutropenia (12.8% vs. 8.2%, p = 0.77; 0.6d vs. 0.8d, p = 0.74), and the proportion of antibiotics used (19.1% vs. 14.9%, p = 0.79) when comparing PEG-rhG-CSF vs. rhG-CSF in prophylactical use. The incidence of grade 4 granulocytopenia in both groups was comparable in 1st cycle (90.9% vs. 96.0%, p = 0.47), but in 2nd cycle it was significantly lower in AOB than that in BOA (54.5% vs. 88.0%, p = 0.01). The lowest value of ANC was higher in AOB in 2nd cycle (0.32G/L vs. 0.12G/L, p = 0.03). Conclusions: This study demonstrated PEG-rhG-CSF could prevent granulocytopenia and FN in sarcoma patients receiving doxorubicin combined with ifosfamide, with comparable efficacy and toxicities as rhG-CSF. Considering the convenience in use and patient compliance, PEG-rhG-CSF could be an effective and reasonable alternative to rhG-CSF. Clinical trial information: ChiCTR1900021945 .

Effectiveness of biosimilar pegfilgrastim in patients with multiple myeloma after high-dose melphalan and autologous stem cell transplantation

Multiple myeloma (MM) is the main indication for autologous stem cell transplantation (ASCT). Novel supportive therapies (e.g., granulocyte colony-stimulating factor) have significantly improved post-ASCT-related mortality; however, data on biosimilar pegfilgrastim-bmez (BIO/PEG) in this setting is lacking. This prospective cohort study compared Italian patients with MM who received BIO/PEG post-ASCT with data collected retrospectively from historical control groups from the same center who received either filgrastim-sndz (BIO/G-CSF) or pegfilgrastim (PEG; originator). The primary endpoint was time to neutrophil engraftment (three consecutive days with an absolute neutrophil count ≥ 0.5 × 109/L). Secondary endpoints included incidence and duration of febrile neutropenia (FN). Of the 231 patients included, 73 were treated with PEG, 102 with BIO/G-CSF, and 56 with BIO/PEG. Median age was 60 years and 57.1% were male. Neutrophil engraftment was reached after a median of 10 days in the BIO/PEG and PEG groups and 11 days in the BIO/G-CSF group. Among patients who achieved neutrophil engraftment earlier than this (i.e., day 9), 58% (29/50) were on PEG; of those who achieved it later (i.e., day 11), 80.8% (59/73) were on BIO/G-CSF. FN incidence was higher with BIO/G-CSF (61.4%) versus PEG (52.1%) or BIO/PEG (37.5%) (p = 0.02 among groups). Patients on BIO/PEG had less frequent grade 2–3 diarrhea (5.5%) compared with BIO/G-CSF (22.5%) or PEG (21.9%); grade 2–3 mucositis was most frequent in the BIO/G-CSF group. In conclusion, pegfilgrastim and its biosimilar displayed an advantageous efficacy and safety profile compared with biosimilar filgrastim in patients with MM post-ASCT.

The effect of pre-conditioning immunoglobulin and absolute lymphocyte count on the outcomes of allogeneic hematopoietic cell transplantation

IntroductionThe prevention of mortality and morbidity related to the increasingly used allogeneic hematopoietic cell transplantation (allo-HCT), along with the effects of pre- and post-transplant immune status on transplant outcomes, have become the focus of the studies conducted on this subject in recent years. In parallel, this study was designed to investigate the effects of pre-conditioning immunoglobulin (pre-conditioning-Ig) and pre-conditioning absolute lymphocyte count (pre-conditioning-ALC) levels on transplant outcomes. MethodsThis study was designed as a retrospective, observational and cross-sectional study. The objective of the study is to investigate the effects of pre-conditioning-Ig and ALC levels primarily on the rate of patients with febrile neutropenia (FEN) and the duration of FEN and length of hospital stay (LoS), and secondarily on acute graft-versus-host disease (aGVHD), cytomegalovirus (CMV) viremia, and mortality in the acute leukemia patients who underwent allo-HCT. ResultsA total of 104 acute leukemia patients, of whom 55 had acute lymphoblastic leukemia (ALL) and 49 had acute myeloid leukemia (AML), were included in the study. Compared to the AML group, the median pre-conditioning-IgG, IgA, and IgM levels were found to be significantly lower in the ALL group (11.3 vs. 6.6, p < 0.001; 1.8 vs. 0.9, p < 0.001; and 0.7 vs. 0.4, p < 0.001; respectively). But, there was no significant difference between the groups in pre-conditioning-Ig and ALC levels and transplant outcomes. However, subgroup analysis revealed that high pre-conditioning-ALC levels were significantly correlated with aGVHD levels (Odds Ratio: 1.02; p = 0.034) and low pre-conditioning-IgM levels were significantly correlated with increased mortality rate (Hazard Ratio: 0.08; p = 0.042) in AML patients. ConclusionThe significant difference determined between the ALL and AML groups in pre-conditioning-Ig levels was not reflected on the effects of pre-conditioning-Ig and ALC levels on transplant outcomes. However, we observed that pre-conditioning-IgM and ALC levels have an impact on transplant outcomes in AML patients.

A Phase 3 Double-Blind, Randomized, Placebo Controlled Study to Evaluate the Efficacy and Safety of AB-205 Plus Standard of Care (SOC) Versus Placebo Plus Standard of Care in Adults with Lymphoma Undergoing High-Dose Therapy and Autologous Hematopoietic Cell Transplantation (E-CELERATE) (NCT05181540) - Trials in Progress

Myeloablative conditioning or high-dose therapy followed by autologous hematopoietic cell transplantation (HDT-AHCT) is a standard of care (SOC) and potentially curative consolidation therapy for eligible patients diagnosed with aggressive lymphoma. Although effective in chemosensitive patients, HDT-AHCT is associated with severe regimen-related toxicities (SRRTs) that affect quality of life and may increase mortality risk (Olivieri et al., BBMT 2018). SRRTs occur due to the off-target cytotoxicity of HDT that involves damage to the microvasculature and the vascular stem cell niches of multiple organs. SRRTs predominantly affect organs with high cell turnover causing severe complications such as diffuse gastrointestinal (GI) mucositis (oral/GI SRRT) and delayed hematopoietic recovery. Rates and severity of toxicities increase with age, relevant to the demographics of the aging lymphoma population. Importantly, patients identify oral/GI SRRT as one of the most severe adverse effects experienced with HDT-AHCT (Stiff et al., BMT 2001). Notwithstanding, there are limited treatment strategies aimed at preventing SRRTs. AB-205 is an experimental, engineered cell therapy that consists of allogeneic, human umbilical vein endothelial cells transduced with the pro-survival E4ORF1+ gene (E-CEL® cells). The proposed mechanism of action is paracrine in nature consisting of cell expression of reparative angiocrine factors which are thought to accelerate the repair injuries from off-target cytotoxicity of myeloablative conditioning. In a previously presented Phase 1/2 study [NCT03925935] in HCT-eligible patients with lymphoma, AB-205 was well tolerated and resulted in a 9% incidence of early oral/GI SRRT [defined as Grade ≥3 mucositis (M), nausea (N), vomiting (V) or diarrhea (D) in systemic lymphoma subjects conditioned with BEAM and BEAM-alternates (Phase 1/2 data is locked and analysis is in progress). This oral/GI SRRT incidence compared highly favorably to an incidence rate of 41% resulting from a contemporary, retrospective observational study conducted at two phase 1/2 sites (done concurrently during the conduct of the phase 1/2 study). Accordingly, a phase 3, randomized, double-blind, placebo-controlled multi-center study (E-CELERATE) has been initiated to further investigate the efficacy and safety of AB-205 in reducing (preventing) severe toxicities and complications related to off-target cytotoxicity of myeloablative HDT. Approximately 140 patients will be enrolled across 25 sites in the United States. Key inclusion criteria: Age ≥ 40; diagnosis of Hodgkin or non-Hodgkin lymphoma who are candidates for HDT-AHCT with one of the following myeloablative conditioning regimens: carmustine, etoposide, cytarabine, melphalan (BEAM); bendamustine, etoposide, cytarabine, melphalan (BeEAM); achieved complete response (CR) or partial response (PR) prior to planned HDT; ECOG ≤ 2; serum bilirubin ≤ 2 mg/dL; AST, ALT, and alkaline phosphatase < 3 × ULN. Key exclusion criteria: Prior HCT; primary CNS lymphoma; systemic lymphoma with secondary CNS involvement at time of relapse prior to planned HDT-AHCT; active malignancy other than the one for which the subject is undergoing HDT-AHCT; subjects with a known history of HIV. Endpoints: The primary endpoint is complete response defined as the absence of oral/GI SRRT (NCI CTCAE Grade ≥ 3 M, N, V, or D from the time of HDT through Day +21 post-HCT). Secondary endpoints include the duration of oral/GI SRRT; patient-reported symptom burden per MD Anderson Symptom Inventory; duration of febrile neutropenia; time to neutrophil engraftment; incidence of Grade ≥ 3 non-hematologic treatment emergent AEs; absence of SRRT; and survival endpoints: non-relapse mortality, progression free survival and overall survival. Eligible patients will be randomized 1:1 to receive SOC supportive care prophylaxis + AB-205 or placebo intravenously (IV) given on Day 0 within 4 hours of AHCT. 20×106 cells/kg AB-205 IV or an analogous volume of placebo IV will be administered. Randomization will be stratified by lymphoma type (HL/NHL), hematopoietic cell transplantation-comorbidity index, disease status prior to HDT (CR/PR). Daily assessments of oral/GI SRRT will occur from start of HDT to Day +21 post AHCT (Figure 1). Current status: Active recruitment and enrollment ongoing [NCT05181540]. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Febrile Neutropenia Duration Is Associated with the Severity of Gut Microbiota Dysbiosis in Pediatric Allogeneic Hematopoietic Stem Cell Transplantation Recipients.

Simple SummaryFebrile neutropenia is a common complication in pediatric patients undergoing allogeneic hematopoietic stem cell transplantation. Its genesis is often attributed to infections; however, a specific cause frequently cannot be defined. We hypothesize that the composition of the intestinal flora may contribute to the genesis of the neutropenic fever. We analyzed the microbial composition of stool samples from pediatric patients from three European centers and assessed the relationship with the duration of the fever during neutropenia. We found that a more stable composition of the microbiota during the transplantation course is associated with a shorter duration of fever. Moreover, patients with a higher duration of fever presented higher levels of Collinsella, Megasphaera, Prevotella, Roseburia, Eggerthella and Akkermansia in the stool.Febrile neutropenia (FN) is a common complication in pediatric patients receiving allogeneic hematopoietic stem cell transplantation (HSCT). Frequently, a precise cause cannot be identified, and many factors can contribute to its genesis. Gut microbiota (GM) has been recently linked to many transplant-related complications, and may also play a role in the pathogenesis of FN. Here, we conducted a longitudinal study in pediatric patients receiving HSCT from three centers in Europe profiling their GM during the transplant course, particularly at FN onset. We found that a more stable GM configuration over time is associated with a shorter duration of fever. Moreover, patients with longer lasting fever exhibited higher pre-HSCT levels of Collinsella, Megasphaera, Prevotella and Roseburia and increased proportions of Eggerthella and Akkermansia at the engraftment. These results suggest a possible association of the GM with the genesis and course of FN. Data seem consistent with previous reports on the relationship of a so-called “healthy” GM and the reduction of transplant complications. To our knowledge, this is the first report in the pediatric HSCT setting. Future studies are warranted to define the underling biological mechanisms and possible clinical implications.

C-Reactive Protein Monitoring and Clinical Presentation of Fever as Predictive Factors of Prolonged Febrile Neutropenia and Blood Culture Positivity after Autologous Hematopoietic Stem Cell Transplantation-Single-Center Real-Life Experience.

Background: Febrile neutropenia (FN) is a medical emergency that requires urgent evaluation, timely administration of empiric broad-spectrum antibiotics and careful monitoring in order to optimize the patient’s outcome, especially in the setting of both allogeneic and autologous hematopoietic stem cell transplant (ASCT). Methods: In this real-life retrospective study, a total of 49 consecutive episodes of FN were evaluated in 40 adult patients affected by either multiple myeloma (thirty-eight) or lymphoma (eleven), following ASCT, with nine patients having fever in both of the tandem transplantations. Results: Febrile neutropenia occurred a median of 7 days from ASCT. Median duration of FN was 2 days, with 25% of population that had fever for at least four days. Ten patients had at least one fever spike superior to 39 °C, while the median number of daily fever spikes was two. Twenty patients had positive blood cultures with XDR germs, namely Pseudomonas aeruginosa and Klebsiella pneumoniae, present in seven cases. ROC analysis of peak C-reactive protein (CRP) values was conducted based on blood culture positivity and a value of 12 mg/dL resulted significant. Onset of prolonged fever with a duration greater than 3 days was associated with the presence of both a peak number of three or more daily fever spikes (p = 0.02) and a body temperature greater than 39 °C (p = 0.04) based on odds ratio (OR). Blood culture positivity and peak CRP values greater than 12 mg/dL were also associated with prolonged fever duration, p = 0.04, and p = 0.03, respectively. The probability of blood culture positivity was also greater in association with fever greater than 39 °C (p = 0.04). Furthermore, peak CRP values below the cut-off showed less probability of positive blood culture (p = 0.02). Conclusions: In our study, clinical characteristics of fever along with peak CRP levels were associated with a higher probability of both prolonged fever duration and positive blood culture, needing extended antibiotic therapy.

Cost-effectiveness of primary prophylaxis of febrile neutropenia with pegfilgrastim in docetaxel, cisplatin and 5-fluorouracil therapy for esophageal cancer.

Objective: The efficacy of docetaxel, cisplatin, and 5-fluorouracil (DCF) therapy in treating esophageal cancer has been reported. However, febrile neutropenia (FN) is a potentially serious adverse event of DCF therapy with an incidence of 10 to 40%. Pegfilgrastim, a granulocyte colony-stimulating factor (G-CSF), has been shown to have a primary prophylactic role in FN. However, it has been suggested that excessive use of expensive G-CSF should be avoided. Therefore, we performed a cost-utility analysis of primary prophylaxis with pegfilgrastim. Design: Cost-effectiveness analysis using decision tree modelling. Methods: We used a decision tree analysis model based on the report of primary prophylaxis with pegfilgrastim. Based on a previous study, the FN incidence rate was set at 40.0% (95% confidence interval (CI): 11.9-68.1) for the pegfilgrastim group and 43.5% (95%CI: 21.6-65.4) for the no pegfilgrastim group. The FN treatment cost was US$726.63, and the duration of FN was 3.65±1.20 days. The utility value of patients who received DCF therapy was 0.643, and the change in utility value at FN onset was -0.15. Expected cost, quality-adjusted life year (QALY), and incremental cost-effectiveness ratio (ICER) were calculated, and cost-utility analysis was performed. Results: The ICER of pegfilgrastim was 184,976.75 USD/QALY. As a result of sensitivity analysis, the utility of FN had the greatest impact on the cost-effectiveness analysis, followed by the drug cost of pegfilgrastim. Conclusion: Primary prophylaxis of FN with pegfilgrastim might not be cost-effectiveness. In determining whether to administer pegfilgrastim it is necessary to consider patient factors, not just the incidence of FN.

Budget Impact Analysis of Switching Chemotherapy Patients Using Granulocyte Colony-Stimulating Factors (G-CSFs) from Pegfilgrastim to Short-Acting G-CSFs in the United States

Introduction: Neutropenia is a common complication in patients receiving myelosuppressive chemotherapy for nonmyeloid malignancies. Severe and febrile neutropenia (FN) are associated with prolonged hospitalization, serious infections and broad-spectrum antibiotic use, decreased quality of life, and increased medical costs and mortality. G-CSFs are often administered to reduce incidence, severity, and duration of FN in chemotherapy patients. While pegfilgrastim is dosed once per chemotherapy cycle (14-day efficacy), data suggest the average duration of short-acting G-CSF use is considerably shorter than 14 days. This analysis estimated the budget impact of increasing utilization of short-acting G-CSFs (filgrastim [Neupogen®], tbo-filgrastim [Granix®, a filgrastim follow-on biologic], and filgrastim-sndz [Zarxio®, a filgrastim biosimilar]) while decreasing utilization of long-acting pegfilgrastim (Neulasta®) products for patients with nonmyeloid malignancies treated with myelosuppressive chemotherapy from a US payer perspective.Methods: An interactive budget impact model was developed to estimate changes in drug and administration costs associated with a projected 10% reduction in pegfilgrastim market share (an estimated 7.6% of the total G-CSF market) and an equal increase split evenly across short-acting product lines (approximately 1/3 allocated to 300-mcg products and 2/3 allocated to 480-mg products within product lines) for patients with nonmyeloid malignancies treated with myelosuppressive chemotherapy within a 1-million-member health plan. Patient self-administration at home was assumed for 40% of patients receiving short-acting G-CSFs and 10% of patients receiving long-acting agents, with the remaining administered by health care provider (HCP) in an office or other outpatient setting. Patients receiving short-acting G-CSFs were assumed to require 10 doses per chemotherapy cycle, with long-acting agents given once per cycle. Self-administered products were purchased via the patient's pharmacy benefit at an assumed Tier 3 formulary status with a patient copay of $57 per prescription. HCP-administered products were assumed to be primarily (85%) purchased through the patient's medical benefit and provided on site, while a small proportion of patients (15%) were assumed to purchase G-CSFs through their pharmacy benefit to be HCP administered; in both cases, administration costs for injections were included, and with pharmacy benefit adjudication, a patient drug cost-share was applied ($57 per prescription). Base-case data were derived from publicly available resources. The budget impact was calculated using a 1-year time horizon, along with the difference in effective per-member per-year (PMPY) cost between current and proposed scenarios; univariate sensitivity analyses were conducted.Results: The effective annual per-patient plan drug costs ranged from $12,288 to $30,772 for short-acting G-CSFs and from $27,013 to $33,698 for pegfilgrastim (depending on dose and adjudication channel per product). The estimated total effective annual plan cost prior to the utilization shift was $425,518,352 (PMPY = $425.53) and was $419,985,093 (PMPY = $419.99) following the shift. The home administration budget increased by $5,793,056, while the HCP administration budget decreased by $11,326,314, for an overall annual cost savings of $5,533,259 (PMPY = $5.54). Per-patient savings for tbo-filgrastim and filgrastim-sndz ranged from 16.1% to 54.5%, depending on dose and adjudication channel. The model was most sensitive to changes in pegfilgrastim acquisition cost and the patient's medical benefit cost-share.Conclusions: Budget impact analyses examine the financial impact associated with the introduction of new treatments or shifting existing treatment patterns to help decision makers determine how best to allocate resources. Without considering additional impacts of health plan contracted rates and manufacturer rebates, the annual plan per-patient drug cost for tbo-filgrastim and filgrastim-sndz formulations were substantially less expensive than pegfilgrastim for an average treatment cycle. This analysis estimated an annual US health plan cost savings of over $5.5 million or more than $5.50 PMPY following an overall 7.6% utilization shift from long-acting to short-acting G-CSFs. DisclosuresJames:Teva Pharmaceuticals: Consultancy. Trautman:Teva Pharmaceuticals: Consultancy. Szabo:Teva Pharmaceuticals: Employment. Tang:Teva Pharmaceuticals: Employment.

Immunogenicity Assessment of Tbo-Filgrastim in Cancer Patients Receiving Chemotherapy

Introduction: Neutropenia is the primary cause of chemotherapy (CT) delays, interruptions, and dose reductions, potentially compromising patient outcomes, including survival and complete response rates. Granulocyte colony-stimulating factors (G-CSFs), which support the proliferation, differentiation, and activation of hematopoietic cells, reduce the incidence, severity, and duration of febrile neutropenia in CT patients. Tbo-filgrastim (Granix®) with a non-glycosylated methionyl group is a short-acting version of G-CSF approved since 2012 under a biologic license application in the United States. Recombinant proteins may induce an immune reaction. Generation of antidrug antibodies (ADAs) may have serious consequences, including anaphylaxis resulting from hypersensitivity, neutralization of endogenous counterparts by cross-reactive neutralizing antibodies (NAbs), and reduction of drug efficacy. The objective of this analysis is to evaluate the immunogenicity of tbo-filgrastim, including the presence of the binding antibodies and neutralizing antibodies against tbo-filgrastim and its endogenous counterpart (native G-CSF), in patients receiving CT for solid and hematologic malignancies.Methods: Blood samples were collected during three independent phase 3 clinical studies that compared the efficacy and safety of tbo-filgrastim with filgrastim and/or placebo, administered 1 day after CT for 5 to 14 days. A 3-tier approach (screening, confirmation, and titer assay) was implemented to evaluate binding ADAs for tbo-filgrastim using a validated homogeneous enzyme-linked immunosorbent assay. Neutralizing activity was assessed for the confirmed-positive ADA test samples using a validated cell-based proliferation assay based on the ability of NAbs from the test samples to inhibit tbo-filgrastim or glycosylated G-CSF-stimulated proliferation of NFS-60 cells in vitro . Clinical measures were examined for all patients with confirmed-positive samples of ADAs for a possible correlation between the presence of ADAs and the potential clinical impact of immunogenicity.Results: A total of 436 patients with cancer who received the drug were assessed for immunogenicity of tbo-filgrastim, including 213 patients with breast cancer, 160 patients with lung cancer, and 63 patients with non-Hodgkin lymphoma (NHL). From breast cancer patients, only 3 patients, each having one positive sample, were confirmed positive for ADAs with low titer; none of these samples showed cross-reactivity to endogenous (glycosylated) G-CSF or neutralizing antibody activity. From lung cancer patients, only 3 patients, each having one positive sample, were confirmed positive for ADAs with low titer; none of these ADA-positive samples cross-reacted with endogenous G-CSF, and one pre-dose sample showed NAb activity in cycle 1 before tbo-filgrastim treatment. From NHL patients, only 1 patient was confirmed positive for ADAs on cycle 3. This patient had only one positive post-dose sample. The ADA titer was too low to be determined; however, no cross-reactivity or NAb activity was associated with this NHL sample. Overall, the immunogenicity incidence was 1.6% (7/436) in all cancer patients tested. None of the patients with a confirmed-positive ADA sample had evidence of hypersensitive or anaphylactic reactions or loss of efficacy.Conclusions: Incidence of immunogenicity or treatment-emergent ADAs in patients receiving CT and tbo-filgrastim was low across all three cancer populations, and all positive samples had low-titer ADAs. None of positive samples had cross-reactive ADAs to the endogenous G-CSF. Except for one pre-dose sample that showed neutralizing activity towards tbo-filgrastim, no neutralizing activities were found in other positive samples towards tbo-filgrastim or endogenous G-CSF. None of the patients with a positive ADA sample had clinically relevant immunogenicity-related symptoms during the conduct of the study. DisclosuresZou:Teva Pharmaceuticals: Employment, Equity Ownership. Buchner:Teva ratiopharm: Employment, Equity Ownership. Field:Teva Pharmaceuticals: Employment. Barash:Teva Pharmaceuticals: Employment, Equity Ownership. Liu:Teva Pharmaceuticals: Employment, Equity Ownership.

Comparative Cost-Efficiency Analysis of Granulocyte Colony-Stimulating Factors for Use in Chemotherapy Patients in the United States

Introduction: Granulocyte colony-stimulating factors (G-CSFs), when used to reduce the incidence, severity, and duration of febrile neutropenia (FN) in chemotherapy patients, may subsequently reduce direct medical costs associated with FN by reducing rates of hospitalization, serious infections, and the use of broad-spectrum antibiotics. While the cost per chemotherapy cycle for short-acting G-CSFs (ie, filgrastim [Neupogen®], filgrastim-sndz [Zarxio®], and tbo-filgrastim [Granix®]) depends on the frequency and number of doses administered and dose used (ie, 300 mcg or 480 mcg), the cost for the long-acting G-CSF pegfilgrastim (Neulasta® 6 mg) is relatively consistent, as it is dosed once per chemotherapy cycle and is effective for 14 days. Given this difference, the extent and duration required for short-acting G-CSF treatment determine the cost-efficiency of these agents relative to pegfilgrastim, when considering similar efficacy and safety across products. This cost-efficiency analysis evaluated the effective daily cost of G-CSFs per chemotherapy cycle, from a US payer perspective.Methods: An interactive model was developed to simulate the relative cost for one chemotherapy cycle from 1 to 14 days for all currently marketed G-CSF products indicated to decrease the incidence or reduce the duration of FN in patients with non-myeloid malignancies treated with myelosuppressive chemotherapy. All agents were assumed to be provided at the health care provider (HCP) office, purchased through the patient's medical benefit, and administered by the HCP. An administration cost for each injection was included. Base-case data were derived from publicly available resources. Daily cost for short-acting G-CSFs was calculated using single dose drug acquisition cost and one administration fee per day, while daily cost for pegfilgrastim was calculated using the drug acquisition cost for one injection plus one administration cost. Additionally, the acquisition cost for short-acting agents was weighted according to the national utilization for low- (300 mcg) vs high-dose (480 mcg) products.Results: The cost of tbo-filgrastim treatment ranged from $312.96 (1 dose) to $4381.47 (14 doses), the cost of filgrastim-sndz treatment ranged from $351.30 to $4918.23, and the cost of filgrastim treatment ranged from $475.24 to $6653.33, compared with $4527.93 for one injection of pegfilgrastim. Tbo-filgrastim is cost-efficient compared with pegfilgrastim through 14 doses. Pegfilgrastim becomes cost-efficient compared with filgrastim-sndz at 13 doses and with filgrastim at 10 doses.Conclusion: Real-world data suggest that short-acting G-CSF products are used fewer than 14 days per chemotherapy cycle in clinical practice, while one dose of pegfilgrastim is efficacious for 14 days. Using acquisition costs plus administration costs for the injections, without considering the additional impact of health plan-contracted rates and manufacturer rebates for the drugs themselves, tbo-filgrastim is cost-efficient for a complete 14-day chemotherapy cycle compared with pegfilgrastim, while filgrastim-sndz and filgrastim are cost-efficient compared with pegfilgrastim through 12 doses and 9 doses, respectively. That is, short-acting products are more cost-efficient than pegfilgrastim in any chemotherapy cycle if fewer than 10 doses are needed. This finding assumes equal efficacy and safety among G-CSFs, and that all other chemotherapy-related patient characteristics are otherwise equal, including clinical appropriateness of prescribed duration of short-acting G-CSFs. G-CSFs reduce FN-associated direct medical costs and may differ in their ability to further reduce total direct medical costs of care for chemotherapy-treated patients when daily cost is considered in conjunction with necessary days of therapy. [Display omitted] DisclosuresJames:Teva Pharmaceuticals: Consultancy. Trautman:Teva Pharmaceuticals: Consultancy. Szabo:Teva Pharmaceuticals: Employment. Tang:Teva Pharmaceuticals: Employment.

Neutrophil recovery with or without G-CSF in non M3 AML patient with DA 3+7 protocol

Background: Induction of acute myeloid leukaemia is associated with a high incidence of treatment related mortality mostly due to neutropenia related infections. This study primarily analyses the duration of neutrophil recovery with or without G-CSF during induction with DA 3+7 in non M3 AML patients. This study also evaluates role of G-CSF in duration febrile neutropenia, hospital stay, total blood products transfusion, total number of used injectable antibiotics and remission status. Methods: It was a Quasi Experimental - Non-Randomized Controlled Trail. There were two groups a) Case = Patients receiving G-CSF b) Control= Patients not receiving G-CSF. Sampling was purposive sampling. Results: 50 patients in two group, G-CSF group (n=25) and Control group (No G-CSF) (n=25) participated in this study. Among them 54% was female and 46% was male. Median age of the participants was 28 years. Neutrophil recovery duration in G-CSF group Vs Control group showed 22.64 Vs 24.64 days (p value 0.003). Duration of febrile neutropenia in G-CSF group Vs Control group showed 11.24 Vs 13.56 days (p value 0.038). Duration of hospital stay in G-CSF group Vs Control group showed 23.64 Vs 25.76 days (p value 0.002). Total number of blood and blood product transfusion in G-CSF group Vs Control group showed 3.80 Vs 3.88 (p value 0.597). Total number of injectable antibiotics in G-CSF group Vs Control group showed 2.72 Vs 3.12 days (p value 0.169). In G-CSF group 22 (88%) and in Control group 23 (92%) were in complete remission (p value 0.637). Conclusions: G-CSF significantly reduces the duration of neutropenia (p value 0.003), febrile neutropenia (p value 0.038) and hospital stay (p value 0.002) after induction with DA 3+7. This may cause reduction in treatment cost and sepsis related mortality. G-CSF can’t significantly reduce use of blood products (p value 0.597) and injectable antibiotics (p value 0.169) after induction with DA 3+7. G-CSF does not affect morphological remission status (p value 0.637) after induction with DA 3+7.

A breakthrough in treatment of cancer patients with grade 4/profound febrile neutropenia.

e14513 Background: febrile neutropenia (FN) remains one of the most serious side effects of chemotherapy treatment, which is life-threatening. Late consequence of FN is dose reduction and delaying of therapies. Actual guidelines allows granulocyte-colony-stimulating factors (G-CSF) in management of profound FN in addition to antibiotics and supportive care Methods: it is an original prospective study, approved by local ethics comitee, which included 73 patients with confirmed malignancy, treated in our Institute with chemotherapy, who developed febrile neutropenia (FN) and were hospitalised. Patients with myeloablative chemotherapy and bone marrow transplantation support, severe renal impairment, abnormal liver function or with a history of allergic reactions to the antibiotics were excluded from the study. There were recorded 96 episodes of grade 4 FN (1-3 episodes / patients). Each of one was hospitalised according to institutional guideline but with a dose of G-CSF of 16 µg/Kg/day i.v. continous infusion Results: median age of included patients was 59 years, with approximately 48 % male and 52% female, whithout significance in terms of recovery from FN (p = 1.00). 30% of the patients had prophilactic G-CSF administrated, but not significant for recovery from aplasia for included patients (p = 0.34). Median chemotherapy line responsible for FN was 2, and median cycle which produced FN was 3. Median level of neutrophiles (PMN) 450/mm3 and leucocytes (WBC) 1875/ mm3 at time of FN, 10 patients being in profound FN (PMN &lt; 100/mm3). Median time to recovery was 25.5 hours for 72 included patients, with 1 patient dead whithout recovery. Predictive factors for shortened recovery were lower levels of reactive protein C (p &lt; 0.001) and procalcitonine (p = 0.002) and higher WBC (p = 0.006) and PMN (p &lt; 0.001) at time of administration of responsible chemotherapy regimen for FN. The earlier cycle responsible, between a line of chemotherapy, for FN, the better chance for patient to have shortened duration of FN (p &lt; 0.0001). Conclusions: continous i.v. administration of G-CSF could represents a very effective alternative for patients with profound febrile neutropenia, with the shortest ever reported interval for neutrophiles recovery

Impact of malnutrition on febrile neutropenia in children with acute lymphoblastic leukemia during induction phase chemotherapy

Background Acute lymphoblastic leukemia (ALL) is the most common malignancy in children and adolescents. Febrile Neutropenia (FN) is a medical emergency on ALL that often leads to death. Nutrition status assessment on ALL patient is important because malnutrition can reduce the tolerance of chemotherapy, increase incidence of infection and decrease survival rate.&#x0D; Objectives To assess malnutrition as a risk factor for FN in children with ALL.&#x0D; Methods This case-control study was performed at Sardjito Hospital, Yogyakarta on patients aged 1 month to 18 years diagnosed with ALL and undergoing induction phase chemotherapy between January 2013 and December 2015. The case and control subjects were children with and without FN, respectively. Febrile neutropenia was confirmed by patients temperature above 38ºC at one measurement and a peripheral neutrophil count of less than 1,000/mm3. Malnutrition was defined as body weight-for-height was between -2 and &lt;-3 standard deviation. Subjects were included using simple random sampling.&#x0D; Result Bivariate analysis showed a significant correlation between malnutrition and FN (OR 2.62; 95%CI 1.07 to 6.45; P=0.03). However, there was no inverse correlation between socioeconomic status and FN (OR 1.1; 95%CI 0.42 to 2.41; P=0.83). There was no correlation between nutritional status and duration of FN (P= 0.48). &#x0D; Conclusion Malnutrition is a risk factor for FN in children with acute lymphoblastic leukemia.

Patient-Administered Biologic and Biosimilar Filgrastim May Offer More Affordable Options for Patients with Nonmyeloid Malignancies Receiving Chemotherapy in the United States: A Budget Impact Analysis from the Payer Perspective.

Granulocyte colony-stimulating factors (G-CSFs) are often administered to reduce the incidence, severity, and duration of febrile neutropenia (FN) in chemotherapy patients. Tbo-filgrastim and filgrastim-sndz represent a follow-on biologic and a biosimilar version, respectively, of the short-acting G-CSF filgrastim with comparable efficacy and safety. To estimate the budget impact of increasing use of patient-(home-) administered tbo-filgrastim and filgrastim-sndz from a U.S. payer perspective. An interactive budget impact model was developed to estimate the changes in drug cost associated with projected increases in the market share of tbo-filgrastim from 5% to 10% and of filgrastim-sndz from 10% to 12% (with a corresponding decrease in filgrastim market share from 85% to 78%) for a 1 million-member health plan among patients with nonmyeloid malignancies receiving chemotherapy with a high risk of FN. Patient self-administration at home was assumed for 20% of patients receiving short-acting G-CSF treatment; all products were purchased through the patient's pharmacy benefit and were assumed to have tier 3 formulary status with a patient copay of $54 per prescription. Base-case data were derived from publicly available resources. The total plan budget impact was calculated using a 1-year time horizon, along with the differences in per member per month and per member per year (PMPY) costs between the current and future scenarios. The effective annual per-patient drug cost to the plan totaled between $16,961 and $27,199, depending on dosage and packaging, for tbo-filgrastim; between $16,216 and $26,015 for filgrastim-sndz; and between $19,134 and $30,663 for filgrastim. The estimated total annual plan cost associated with patient-administered short-acting G-CSFs was $53,298,217 (PMPY = $53.30) in the current scenario and $52,828,832 (PMPY = $52.82) in the future scenario. Cost savings totaled $469,385 (PMPY = $0.48). The model was most sensitive to changes in the percentage of patients self-administering G-CSF at home and to the wholesale acquisition cost for filgrastim. The effective annual plan per-patient drug costs for tbo-filgrastim and filgrastim-sndz were 11% and 15% lower than filgrastim, respectively. The present analysis estimated an annual U.S. health plan cost savings approaching $0.5 million following increases in market shares of approximately 5% for tbo-filgrastim and 2% for filgrastim-sndz. This study was sponsored by Teva Branded Pharmaceutical Products R & D, which participated in the study design, data interpretation and analysis, the writing of the report, and the decision to submit. Aventine Consulting received consulting fees from Teva Pharmaceuticals and developed the cost model and provided data analysis support. Trautman and James are employed by Aventine Consulting. Szabo and Tang are employed by Teva Pharmaceuticals.

Pegfilgrastim: More Cost Effective and Equally Efficacious Option as Compared to Filgrastim in Autologous Stem Cell Transplant.

Use of growth factor after high-dose chemotherapy (HDC) and autologous peripheral blood stem cell (PBSC) support is current standard in reducing days of neutropenia. This retrospective study aims to compare the efficacy of two standard growth factors, pegfilgrastim (PEG) and filgrastim (FIL) after HDC. We collected data on 195 consecutive adult patients who received an autotransplant (myeloma, lymphoma and others) between January 2004 and December 2014 at two tertiary care centres. The primary end point was the duration of neutropenia in terms of days to reach an ANC > 0.5 × 109/L. Filgrastim was given to 110 patients and PEG was given to 85 patients. Time to engraftment, defined as the time to reach an ANC of 0.5 × 109/L on 2 consecutive days after the day of auto-SCT, was 12.6days with FIL compared with 12.1days with PEG group (p = 0.126). When comparing the total days of severe neutropenia (WBC < 0.1 × 109/L), there were 5.5days of severe neutropenia with FIL compared with 5.8days with PEG group (p = 0.7). The duration of febrile neutropenia was an average of 5.3days with FIL and 4.6days with PEG (p = 0.029). The total number of antibiotic days was shorter for the patients who received PEG, being 11.08days with PEG and 12.1days with FIL (p = 0.184).The average cost savings per person in terms of number of days of hospitalization and number of days of total parental nutrition was 582 Rs (p = 0.512) and 6003 Rs (p = 0.018) respectively in favour of PEG arm. PEG is similar to FIL in hematological reconstitution, however it is more cost effective alternative after HDC and PBSC.

Epstein-Barr virus and cytomegalovirus infections and their clinical relevance in Egyptian leukemic pediatric patients

BackgroundEpstein-Barr virus (EBV) and human cytomegalovirus (CMV) infections are environmental risk factors affecting the outcome of cancer due to an impairment in the cell-mediated immunity. Therefore, this study aimed to detect the frequency of EBV and CMV DNA and their association with clinical characteristics and outcome of pediatric leukemic patients.MethodsSamples of 50 immunocompromised pediatric leukemic patients and 30 apparently healthy children were subjected to the amplification of EBV DNA by one version of PCR targeting the Bam H1 W region of the genomic region of EBV, and the amplification of CMV DNA by targeting the CMV UL97 genomic region by a second round PCR. All investigations were performed on WBCs and sera. Results were correlated with the clinical and laboratory characteristics of the disease, and with overall survival.ResultsEBV and CMV DNA were detected in 20 and 54% of leukemic patients, respectively. Nine out of ten patients with EBV DNA (90%) were positive for CMV DNA in their sera. The presence of EBV DNA or CMV DNA was associated with neutropenia and a low total leukocyte count (TLC) (p = 0.02, 0.03, respectively). The presence of severe CMV disease, longer duration of febrile neutropenia, neutropenia, lymphopenia, thrombocytopenia and the presence of EBV DNA in patients’ sera were significantly associated with worse overall survival.ConclusionThe detection of CMV disease and EBV DNA is relatively common in leukemic children and is significantly associated with a decline in the overall survival.

Budget Impact Analysis of Treating Chemotherapy Patients with Health Care Provider-Administered Tbo-Filgrastim, Filgrastim-Sndz, and Filgrastim in the United States

Introduction: Granulocyte colony-stimulating factors (G-CSFs) are often administered to reduce the incidence, severity, and duration of febrile neutropenia in chemotherapy patients. Tbo-filgrastim and filgrastim-sndz are short-acting G-CSFs with comparable efficacy and safety to that of filgrastim. The present analysis estimated the budget impact of increasing utilization of health care provider (HCP)-administered tbo-filgrastim and filgrastim-sndz on patients with nonmyeloid malignancies treated with myelosuppressive chemotherapy from a US payer perspective.Methods: An interactive budget impact model was developed to estimate the changes in drug and administration costs for a 1 million member health plan. Administration by an HCP (within a clinic or other outpatient setting) was assumed for 80% of patients receiving short-acting G-CSF treatment, with the majority (85%) of products adjudicated through the patient’s medical benefit/provided by the HCP and the remaining 15% purchased through the patient’s pharmacy benefit. For medical benefit adjudication, the model projected increases in the market share of tbo-filgrastim from 37% to 42% and filgrastim-sndz from 2% to 4% (with a decrease in filgrastim market share from 61% to 54%). For pharmacy benefit adjudication, the model projected increases in the market share of tbo-filgrastim from <1% to 2% and filgrastim-sndz from 5% to 7% (with a decrease in filgrastim market share from 95% to 91%). Base case data were derived from publicly available resources. The overall plan budget impact was calculated using a 1-year time horizon, along with the difference in per-member per-year (PMPY) cost between the current and future scenarios; one-way sensitivity analyses were conducted.Results: The effective annual plan per-patient drug cost totaled between $11,904 and $27,199, depending on dose, presentation, and benefit adjudication, for tbo-filgrastim, between $15,418 and $26,015 for filgrastim-sndz, and between $15,573 and $30,663 for filgrastim. The estimated overall annual plan cost associated with HCP-administered short-acting G-CSFs was $177,151,918 (PMPY = $177.15) in the current scenario and $175,230,445 (PMPY = $175.23) in the future scenario. Cost savings totaled $1,921,473 (PMPY = $1.92). The model was most sensitive to changes in the overall proportion of patients with HCP-administered G-CSFs and to HCP filgrastim acquisition cost.Conclusions: Budget impact analyses examine the financial impact associated with the introduction of new treatments or shifting existing treatment patterns in order to help decision makers determine how best to allocate resources. The majority of HCP-administered G-CSF is adjudicated through the medical benefit, where the effective annual plan per-patient drug cost was lowest for tbo-filgrastim (24% lower cost than filgrastim). For the remainder of HCP-administered G-CSF adjudicated through the pharmacy benefit, the effective annual plan per-patient drug cost was lowest for filgrastim-sndz (15% lower cost than filgrastim). The present analysis estimated an annual US health plan cost savings approaching $2 million overall or almost $2.00 PMPY following an increase of market share by approximately 5% for tbo-filgrastim and 2% for filgrastim-sndz. DisclosuresTrautman:Teva Pharmaceuticals, Inc.: Consultancy. Szabo:Patient Centered Outcomes Research (PCORI): Consultancy; Teva Pharmaceuticals, Inc.: Employment; Eli Lilly & Company; Zoetis: Equity Ownership. Lo-Coco:Teva, Novartis, Baxalta, Pfizer: Consultancy; Teva, Lundbeck: Honoraria, Speakers Bureau. James:Teva Pharmaceuticals, Inc.: Consultancy. Gabriel:Teva Pharmaceuticals, Inc.: Employment. Pathak:Teva Pharmaceuticals: Employment, Equity Ownership. Tang:Teva Pharmaceuticals, Inc.: Employment.

Budget Impact Analysis of Treating Chemotherapy Patients with Patient-Administered Tbo-Filgrastim, Filgrastim-Sndz, and Filgrastim in the United States

Introduction: Neutropenia is a common complication in patients receiving myelosuppressive chemotherapy for nonmyeloid malignancies. Severe and febrile neutropenia are associated with prolonged hospitalization, serious infections and the use of broad-spectrum antibiotics, increased medical costs, and increased mortality. Granulocyte colony-stimulating factors (G-CSFs) are often administered to reduce the incidence, severity, and duration of febrile neutropenia in chemotherapy patients. The present analysis estimated the budget impact of increasing utilization of patient (home)-administered tbo-filgrastim and filgrastim-sndz in patients with nonmyeloid malignancies treated with myelosuppressive chemotherapy from a US payer perspective.Methods: An interactive budget impact model was developed to estimate the changes in drug costs associated with projected increases in the market share of tbo-filgrastim from 5% to 10% and filgrastim-sndz from 10% to 12% (with a corresponding decrease in filgrastim market share from 85% to 78%) for a 1 million-member health plan. Patient self-administration at home was assumed for 20% of patients receiving short-acting G-CSF treatment; all products were purchased through the patient's pharmacy benefit and were assumed to have Tier 3 formulary status with a patient co-pay of $54 per prescription. Base-case data were derived from publicly available resources. The overall plan budget impact was calculated using a 1-year time horizon, along with the difference in per-member per-year (PMPY) cost between the current and future scenarios; one-way sensitivity analyses were conducted.Results: The effective annual plan per-patient drug cost totaled between $16,961 and $27,199, depending on dose and presentation, for tbo-filgrastim, between $16,216 and $26,015 for filgrastim-sndz, and between $19,134 and $30,663 for filgrastim. The estimated overall annual plan cost associated with short-acting G-CSFs was $53,298,217 (PMPY = $53.30) in the current scenario and $52,828,832 (PMPY = $52.82) in the future scenario. Estimated cost savings totaled $469,385 (PMPY = $0.48). The model was most sensitive to changes in the overall proportion of patients self-administering G-CSFs at home and to the wholesale acquisition cost for filgrastim.Conclusions: The effective annual plan per-patient drug cost for tbo-filgrastim and filgrastim-sndz was lower by 11% and 15%, respectively, as compared with filgrastim. The present analysis estimated an annual US health plan cost savings approaching $0.5 million overall or $0.50 PMPY following an increase of market share by approximately 5% for tbo-filgrastim and 2% for filgrastim-sndz. DisclosuresTrautman:Teva Pharmaceuticals, Inc.: Consultancy. Szabo:Eli Lilly & Company; Zoetis: Equity Ownership; Teva Pharmaceuticals, Inc.: Employment; Patient Centered Outcomes Research (PCORI): Consultancy. Lo-Coco:Teva, Lundbeck: Honoraria, Speakers Bureau; Teva, Novartis, Baxalta, Pfizer: Consultancy. James:Teva Pharmaceuticals, Inc.: Consultancy. Gabriel:Teva Pharmaceuticals, Inc.: Employment. Pathak:Teva Pharmaceuticals: Employment, Equity Ownership. Tang:Teva Pharmaceuticals, Inc.: Employment.

Efficacy of deferred dosing of granulocyte colony-stimulating factor in autologous hematopoietic transplantation for multiple myeloma

Routine administration of G-CSF following autologous hematopoietic SCT (ASCT) expedites ANC recovery and reduces hospitalization by 1–2 days; it has no impact on febrile neutropenia, infections, morbidity, mortality, event-free survival or OS. To determine whether delayed G-CSF dosage could result in equivalent ANC recovery and thereby improve cost effectiveness, we deferred the administration of G-CSF until WBC recovery had begun. A total of 117 patients with multiple myeloma received ASCT from January 2005 to September 2012. Of these, 52 were in the conventional dosing group (CGD) and received G-CSF from Day +7 for a median of five doses. In the deferred dosing group (DGD), 65 patients received G-CSF from median day 14 post transplant for a median of zero doses. There was no difference between groups in the incidence or duration of febrile neutropenia, duration of ⩾grade III mucositis, weight gain, rash, engraftment syndrome or early death (100 days). The DGD group had a significantly longer time to neutrophil engraftment than the CGD group (15 days vs 12 days; P<0.0001), a longer period of severe neutropenia (<100/μL; 8 days vs 6 days; P<0.0001), longer treatment with intravenous antibiotics (7 days vs 5 days; P=0.016) and longer hospital stay (19 days vs 17 days; P=<0.0001). Although the cost of G-CSF was lower in the DGD group (mean $308 vs $2467), the additional hospitalization raised the median total cost of ASCT in this group by 17%. There was, however, no adverse effect of deferred dosing on the rate of febrile neuropenic episodes or Day 100 survival, so that deferred dosing of G-CSF may be suitable for patients receiving ASCT as outpatients, for whom longer hospital stay would not be an offsetting cost.

Myeloid Growth Factors

Febrile neutropenia, a common side effect of myelosuppressive chemotherapy in patients with cancer, can result in prolonged hospitalization and broad-spectrum antibiotic use, often prompting treatment delays or dose reductions of drug regimens. Prophylactic use of myeloid growth factors (mainly the colony-stimulating factors filgrastim and pegfilgrastim) in patients of heightened risk can reduce the severity and duration of febrile neutropenia. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Myeloid Growth Factors provide recommendations on the use of these agents mainly in the oncology setting based on clinical evidence and expert consensus. This version includes revisions surrounding the issue of timing of pegfilgrastim administration. It also includes new sections on tbo-filgrastim, a recently approved agent that is biologically similar to filgrastim, and the role of myeloid growth factors in the hematopoietic cell transplant setting.