Granulocyte Colony-stimulating Factors Treatment Research Articles

How Can Oncology Nurses and Advanced Practice Providers Reduce the Burden of Chemotherapy-Induced Febrile Neutropenia in the US?

Background: Neutropenia and febrile neutropenia (FN) are serious complications of myelosuppressive chemotherapy and present a considerable burden to patients with cancer. Febrile neutropenia is associated with increased risks of infection and hospitalization, a particular concern during the coronavirus disease 2019 (COVID-19) pandemic. Oncology nurses and advanced practice providers (APPs; including nurse practitioners, physician assistants, advanced practice nurses, and pharmacists) play a vital role in the management of patients with cancer and the prevention of infections. Objectives: The objectives of this article are to summarize the burden of chemotherapy-related neutropenia and FN in patients with cancer in the US and to evaluate the role of oncology nurses and APPs in preventing and managing FN. Methods: This article provides a narrative review of US studies reporting on the burden of FN, FN during COVID-19, adherence to guidelines for the use of prophylactic granulocyte colony-stimulating factors (G-CSFs), the involvement of oncology nurses in FN prevention, management, and patient quality of life, and inappropriate and/or incomplete G-CSF treatment. Findings: Despite advances in supportive care for patients with cancer receiving myelosuppressive chemotherapy, neutropenia and FN present a considerable burden to patients, particularly during the COVID-19 pandemic. Oncology nurses and APPs play a vital role in the appropriate and timely delivery of supportive care, which can improve patient outcomes and minimize treatment costs.

Real-world evaluation of supportive care using an electronic health record text-mining tool: G-CSF use in breast cancer patients

PurposeChemotherapy-induced febrile neutropenia (FN) is a life-threatening and chemotherapy dose-limiting adverse event. FN can be prevented with granulocyte-colony stimulating factors (G-CSFs). Guidelines recommend primary G-CSF use for patients receiving either high (> 20%) FN risk (HR) chemotherapy, or intermediate (10–20%) FN risk (IR) chemotherapy if the overall risk with additional patient-related risk factors exceeds 20%. In this study, we applied an EHR text-mining tool for real-world G-CSF treatment evaluation in breast cancer patients.MethodsBreast cancer patients receiving IR or HR chemotherapy treatments between January 2015 and February 2021 at LUMC, the Netherlands, were included. We retrospectively collected data from EHR with a text-mining tool and assessed G-CSF use, risk factors, and the FN and neutropenia (grades 3–4) and incidence.ResultsA total of 190 female patients were included, who received 77 HR and 113 IR treatments. In 88.3% of the HR regimens, G-CSF was administered; 7.3% of these patients developed FN vs. 33.3% without G-CSF. Although most IR regimen patients had ≥ 2 risk factors, only 4% received G-CSF, of which none developed neutropenia. However, without G-CSF, 11.9% developed FN and 31.2% severe neutropenia.ConclusionsOur text-mining study shows high G-CSF use among HR regimen patients, and low use among IR regimen patients, although most had ≥ 2 risk factors. Therefore, current practice is not completely in accordance with the guidelines. This shows the need for increased awareness and clarity regarding risk factors. Also, text-mining can effectively be implemented for the evaluation of patient care.

A Study to Assess the Management of Febrile Neutropenia in Oncology Patients in a Tertiary Care Hospital

Background: The cytotoxic chemotherapy is the mainstay treatment of cancer and it is usually complicated with infections. Appropriate antibiotics and other supportive medications must be started immediately as bacterial infections may progress with the absence of granulocytes. Improved outcomes can be seen with empirical administration of broad-spectrum antibiotics and they remain as the standard of care. Patients with intermediate-risk for Febrile Nuetropenia (FN) (10%-20%) need to be evaluated for additional patient risk factors, after assessment, patients who present with at least one of the risk factors for FN is recommended for treatment with a G-CSF. Methodology: Our study was a retrospective cohort single centered observational study carried out randomly in 104 patients in the oncology department of Lourdes hospital, Cochin Data of the patients were collected from Mediware system, medical records and Statistical software SPSS were used for analysis of the data. Results: In our study febrile neutropenia was managed using antimicrobials, of which antibiotics and antifungals prescribed were 12.09% and 1.97% respectively and with granulocyte-colony stimulating factors (G-CSFs) (6.15%). Principally used empirical monotherapy was meropenem sulbactum / meropenem (n = 48) which was followed by piperacillin tazobactum (n=18) and cefoperazone sulbactum (n=15) This study had a leading prescription of Cyclophosphamide containing chemotherapy regimens which led to neutropenia. Breast cancer patients accounts the majority of febrile neutropenic episodes despite of receiving GCSF prophylaxis. The most common type of cancer patients who are suffering from neutropenia were breast cancer. The compliance with National Comprehensive Cancer Network (NCCN) guidelines were analyzed in that we can see 84.6% patients had partial compliance and 14.4% patients had full compliance. Conclusion: A total of 66 patients received both antibiotics and G-CSF treatment however 13 patients and 25 patients were managed only with G-CSF and antibiotic therapy respectively. This study had a leading prescription of Cyclophosphamide containing chemotherapy regimens which led to neutropenia. These regimens were used mainly in breast cancer patients. Breast cancer patients accounts the majority of febrile neutropenic episodes despite of receiving GCSF prophylaxis. The most common type of cancer patients who are suffering from neutropenia were breast cancer. The NCCN guidelines, majority of patients showed partial compliance(86.6%) and about (14.4%) showed full compliance.

Budget Saving Potential of Pegfilgrastim Biosimilar for the Treatment of Chemotherapy-Induced Febrile Neutropenia, in Italy

INTRODUCTION: Current Italian guidelines recommend prophylaxis with granulocyte colony-stimulating factors (G-CSFs) to reduce the risk of chemotherapy-induced febrile neutropenia (FN). The availability of G-CSF biosimilars represents an opportunity for savings in the Italian National Healthcare Service (NHS) delivery of care.OBJECTIVE: To assess the cost saving potential associated with the introduction of pegfilgrastim biosimilars to local formularies, compared to the current G-CSF standard practice in Italy.METHODS: A budget impact model was developed to compare the current standard practice of long-acting (LA) and short-acting (SA) G-CSFs use, with a future scenario in which the market share of LA G-CSFs grows due to the more advantageous administration schedule and price of pegfilgrastim biosimilar. The analysis included G-CSF treatment schedules, drug acquisition costs and costs of patient management including hospitalization and ambulatory care.RESULTS: The introduction of pegfilgrastim biosimilar resulted in cumulative 3-year cost savings of € 59,650 and € 41,539 for FN prophylaxis in a potential cohort of 1000 patients with solid tumors and lymphomas, respectively.CONCLUSIONS: The results indicate that the introduction of pegfilgrastim biosimilar is potentially associated with substantial cost savings for the Italian healthcare system.

Should We Expand the Use of Granulocyte-Colony Stimulating Factors (G-CSF) during the COVID-19 Pandemic?

Cancer patients are considered more susceptible to the SARS-CoV-2 infection. Higher rates of respiratory failure and death were reported in cancer patients and COVID-19, compared with the general population. Among other measures deemed to protect this vulnerable subcategory, both ASCO and ESMO recommended the extension of G-CSF use, to include prophylactic administration in all patients receiving regimens with 10%-20% risk of febrile neutropenia (FN) and also in regimens with risk of FN <10%, if patients were considered with poor bone marrow reserve due to comorbidities or advanced age. However, accumulating data reported in several recent publications suggested a direct involvement of the high neutrophil count, due to G-CSF stimulation, in the development of the adult respiratory distress syndrome (ARDS), the hallmark of the severe COVID-19 disease. In addition, some recent evidences suggest that G-CSF may hamper the efficacy of the mRNA vaccine. This paper reviews the most important data reporting higher rates of respiratory failures and death associated with G-CSF treatment in cancer patients and SARS-CoV-2 infection. Therefore, we consider that the current recommendation of expanding the G-CSF use in cancer patients during the COVID-19 pandemic should be reconsidered. The most important protective measures for cancer patients remain specific vaccination and a rigorous compliance with the general protective measures, whereas the G-CSF should be administrated as traditionally recommended by the current guidelines.

Assessing febrile neutropenia outcomes in patients receiving primary versus secondary prophylactic G-CSF treatment therapy with intermediate neutropenic risk chemotherapy regimens.

Prophylaxis with granulocyte colony-stimulating factors (G-CSFs) reduce the severity and duration of chemotherapy-induced neutropenia. Currently, the use of G-CSF prophylactic treatment to prevent neutropenia and its complications varies widely in clinical practice with no standardization for intermediate-risk chemotherapy regimens. The purpose of this study was to assess neutropenic outcomes in patients receiving intermediate-risk chemotherapy regimens who receive primary versus secondary prophylactic G-CSFs. This is a retrospective, multicenter cohort study of patients who received intermediate risk chemotherapy regimens and at least one dose of G-CSF therapy. 121 patients were included and were divided into primary (n = 76) or secondary prophylaxis (n = 45) groups. The primary outcome for this study was the incidence of neutropenic episodes per course of treatment. The secondary outcomes included the percentage of patients who experienced delays in chemotherapy doses, the number of chemotherapy dose reductions, and the number of subsequent treatment delays. The incidence of neutropenic episodes over the course of therapy was 0.42 episodes in the primary group compared to 1.52 episodes in the secondary group (p < 0.05). 10.5% of patients in the primary group versus 54.3% of patients in the secondary group experienced chemotherapy dose delays (p < 0.05). There were no statistically significant differences in chemotherapy dose reductions or in the average number of FN risk factors between groups. This retrospective, cohort study determined that patients receiving intermediate risk chemotherapy regimens should receive primary prophylaxis, regardless of risk factors in order to decrease episodes of neutropenia and chemotherapy dose delays.

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.

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.

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.

Similar Incidence Of Febrile Neutropenia With Same-Day Versus Subsequent Day G-CSF Administration In Non-Hodgkin Lymphoma Patients Receiving R-CHOP Chemotherapy

▪ BackgroundThe chemotherapy regimen of Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (R-CHOP) every 21 days remains a standard first line treatment for many subtypes of B-cell non-Hodgkin lymphoma (NHL). R-CHOP chemotherapy carries a significant risk of febrile neutropenia (FN). FN is a potentially life threatening complication which typically requires hospital admission and empiric administration of broad spectrum antibiotics. FN can also cause delays and dose reductions with treatment, which are associated with poorer outcomes. Granulocyte colony stimulating factors (G-CSF) are indicated for primary prophylaxis with high risk patients to ameliorate this serious complication of treatment. Prescribing guidelines recommend that G-CSF's not be given until 24 hours after receiving chemotherapy. However, due to logistical issues of outpatient insurance coverage, travel, and patient convenience, it is not always practical to delay G-CSF administration until the day after chemotherapy. Therefore, some patients at our institution received G-CSF on the same day as chemotherapy. Patients and MethodsWe identified 113 lymphoma patients treated with R-CHOP who also received G-CSF primary prophylaxis at our institution from 6/21/04-1/12/12. G-CSF primary prophylaxis with daily filgrastim or a single dose of pegfilgrastim was administered within the first six days of starting R-CHOP, categorized as either same day (D1) or later (D2+). We retrospectively analyzed FN incidence and associated outcomes in patients receiving growth factor as primary prophylaxis administered the same day compared with >24 hours after chemotherapy. FN was estimated using the cumulative incidence method and compared between groups with the Pepe-Mori test. Cox analysis was used to identify prognostic factors for survival and relapse-free survival. ResultsIn our study, 113 patients received R-CHOP and G-CSF as primary prophylaxis (31 D1, 82 D2+). FN occurred in 8 out of 31 D1 patients (25.8%), and in 21 out of 82 patients in the D2+ group (25.6%). FN incidence did not differ between the two groups (P=0.91). No significant differences in relapse-free or overall survival were observed. Risk factors associated with mortality in multivariable analysis included development of FN (hazard ratio 4.33, 95% CI 1.88-10.0, P<0.001) and receiving R-CHOP while hospitalized as an inpatient (hazard ratio 7.16, 95% CI 3.08-16.6, P<0.001). ConclusionsAmong patients receiving G-CSF as primary prophylaxis with R-CHOP, we observed no difference in FN between G-CSF administered the same day and D2+. Not surprisingly, the development of FN and receiving R-CHOP while hospitalized, were both found to be significant risk factors associated with mortality. Previous prospective studies showed more severe and prolonged level of neutropenia, with higher rates of FN with same day versus next day administration in a small cohort of R-CHOP treated NHL patients (Burris et al, 2010). In our retrospective study, we were not able to evaluate neutrophil levels at multiple time points throughout each cycle, and longer follow-up is necessary to evaluate other long-term endpoints of potential interest, such as the incidence of secondary myeloid malignancies after same-day versus next-day G-CSF treatment. For patients who require G-CSF support, next day administration remains the recommended schedule. However, same day administration may be a reasonable alternative if access to care and patient compliance are concerns. Disclosures:Hill:Celgene: Honoraria, Research Funding.

Oral Ezatiostat HCl (Telintra), a Glutathione Analog Prodrug GSTP1-1 Inhibitor, for Treatment of Patients with Myeloid Growth Factor-Resistant Idiopathic Chronic Neutropenia (ICN)

AbstractAbstract 4394 Introduction:Idiopathic chronic neutropenia (ICN) is a group of diseases characterized by low circulating neutrophils, recurrent fevers, mucosal inflammation, and systemic infections. The risk of complications is inversely proportional to the absolute neutrophil count (ANC), with the most severe occurring with ANC of < 0.5 × 109/L. Most patients respond to daily s.c. administration of granulocyte colony stimulating factors (G-CSF); however, some patients do not respond. Patients undergoing G-CSF therapy also often have bone and muscle pain, thrombocytopenia and splenomegaly, complicating therapy. Ezatiostat, a glutathione S-transferase (GST) inhibitor that activates Jun kinase, promoting growth and maturation of hematopoietic progenitors, is an investigational agent in development for treatment of ICN. This report describes 4 patients with longstanding ICN who responded to ezatiostat, all of whom prior to treatment had frequent hospitalizations for sepsis, prolonged courses of antibiotics and poor response to myeloid growth factors. Methods:Patients (pts) with severe ICN and inadequate ANC response to G-CSF were enrolled in this phase 2 trial. After initial starting dose of 2000 mg in divided doses twice daily (b.i.d.) dose-equilibration over 4 weeks, pts were treated with ezatiostat daily for 3 weeks followed by 1 week off. Treatment was given until lack of ANC response or unacceptable toxicity. Clinical benefit was determined by ANC response, infection-free periods, antibiotic use and hospitalizations for infections. Results:Four female pts, age range 23–63, with median ANC of 200 (50–400) were enrolled. Patient 1 is 62 y.o. with longstanding history of infections and treatment with G-CSF. Before entering study, she had recurrent ear, labial, left thigh, pulmonary and sinus infections despite growth factor treatment, to which she had severe reactions. Baseline white blood cell (WBC)/ANC ratio was 2.2/0.7. WBC/ANC improved with ezatiostat for 4 mo to 3.62/1.71 and infections resolved. Patient 2, a 63 y.o. with ICN for 26 years, had a median baseline WBC/ANC on G-CSF treatment of 3.1/.180 and a history of multiple hospital admissions for sepsis, non-healing perineal and decubitus ulcers, and recurrent high fevers within 4 days of cessation of parenteral antibiotics, necessitating resumption. Post-ezatiostat treatment median ANC was 3.1 (range 1.6–3.75) with a persistent infection-free period of over 22 mo with no hospitalizations or antibiotic therapy required. Patient 3, a 23 y.o. with ICN since age 10, initially responded to G-CSF but stopped responding despite injections b.i.d., and ANC never rose above 1000. Her last hospitalization was for methicillin-resistant staphylococcus aureus skin infection, upper respiratory infection with cervical adenopathy, and oral ulcers. She had infections every 3 months and baseline WBC/ANC of 1.4/0.13. She had minimal response over 4 mo of observation, with highest values 2.65/0.92 and median ANC of 0.40, but had no further bacterial infection or use of G-CSF. Patient 4, a 39 y.o. with ICN of 10 years’ duration, had severe bone pain with G-CSF and responses were brief (1–2days). Previously, she had hospital admissions and emergency room visits 4–5 times a year and was ill 2–3 times a week with recurrent urinary tract infections, pneumonias (4–5 times per year), oral ulcers, sinus and gastrointestinal infections, furuncles, and infection after dental work. Baseline WBC/ANC was 1.23/0.20. Currently, her WBC/ANC is 1.50/0.26. While ANC did not increase, infection rate decreased and she had no ER visits or admissions for over 5 mo. She responded to a single 300 mcg dose of of G-CSF with an ANC of 1.0 for a week, suggesting re-sensitization to G-CSF. Most common ezatiostat-related adverse events were grade 1 nausea, abnormal urine/stool odor, and dysgeusia. Conclusions:Ezatiostat, a novel GSTP1-1 inhibitor and jun kinase modulator as treatment of patients with ICN and grade 4 neutropenia not responsive to myeloid growth factors, results in a durable ANC response and clinically significant reductions in serious infections. Results suggest a potential role for ezatiostat as an oral therapy alternative or adjunct to G-CSF in the treatment of ICN in patients who are not responsive to G-CSF. Response to this targeted therapy may also give insight into the pathophysiology of ICN and further study is warranted. Disclosures:Lyons:Telik, Inc.: Research Funding. Wilks:Telik, Inc.: Research Funding. Friedman:Telik, Inc.: Research Funding. Young:Telik, Inc.: Employment, Equity Ownership. Brown:Telik, Inc.: Employment, Equity Ownership.

Effects of prophylactic hematopoietic colony stimulating factors on stem cell transplantations: Meta-analysis

Hematopoietic growth factors are often given for prevention of febrile neutropenia (FN), infections, and other complications by hastening neutrophil recovery in the treatment of malignancies after high dose chemotherapy (HDCT). Although several meta-analyses have already demonstrated beneficial effects of prophylactic granulocyte colony-stimulating factors (G-CSF) administration, the effects of G-CSF have not been confirmed in cancer patients receiving stem cell transplantation (SCT) after HDCT. Therefore, we performed a statistical combination of controlled clinical trials to investigate the efficacy of prophylactic use of G-CSF in preventing the neutropenic complications associated with SCT following HDCT in cancer patients. We searched PubMed to identify potentially relevant references and finally selected seven randomized controlled trials that met all of the eligibility criteria. Our meta-analysis demonstrated that prophylactic G-CSF reduced the risk of documented infections and time to hematologic recovery manifested by days to absolute neutrophil count (ANC) ≥ 0.5 × 10(9)/L, days to ANC ≥ 1.0 × 10(9)/L, and days to platelets ≥ 20 × 10(9)/L in SCT patients with cancer following HDCT. The G-CSF treated group also showed a decrease in the length of hospital stay. However, there was no difference between G-CSF treatment group and placebo group in regard to all-cause mortality, infection-related mortality, grade 2∼4 acute graft-versus-host-disease, and episode of fever.

Cost comparison of outpatient treatment with granulocyte colony-stimulating factors (G-CSF) in Germany

Granulocyte colony-stimulating factors (G-CSF), are available for prevention of neutropenia and reduction of its complications in cytostatic chemotherapy. The purpose of this analysis was to determine the consumption rates for various G-CSF and to compare outpatient medication costs per patient and treatment cycle. Prescription data of statutory health insurance members in Germany (IMS®LRx database) with G-CSF prescriptions between January 2008 and July 2010 were evaluated. A period of observation of at least 6 months prior to and after the G-CSF prescription was required. Prescription data of 8,726 patients treated with original filgrastim, 4,240 with biosimilar filgrastim, 6,456 with lenograstim, and 9,939 with pegfilgrastim were analyzed. The regression model showed statistically significant costreducing effects per cycle for treatment with lenograstim compared with non-lenograstim (-0.47 vs. original filgrastim; -0.15 vs. biosimilar filgrastim; -1.04 vs. pegfilgrastim; each p < 0.0001). This result has been adjusted for patient age, gender, number of injections, and prescribing specialist group. Treatment with the original preparation lenograstim is significantly cheaper compared to the other two original drugs and biosimilar. The costs of G-CSF treatment with the original preparation lenograstim and the filgrastim biosimilars are in a similar range, but with a significantly lower cost for lenograstim. Compared to their reference product the biosimilars thus show a cost advantage.

Neutropenia inducida por fármacos antineoplásicos: utilización de los factores estimulantes de colonias de granulocitos

Neutropenia is a frequent adverse event of the pharmacologic treatment of cancer. Morbidity and mortality-associated neutropenia can be successfully treated and prevented with granulocyte-colony stimulating factors (G-CSF). European and American Guidelines recommend their prophylactic use when the expected percentage of febrile neutropenia exceeds 20 % or there are concomitant risk factors. Afebrile neutropenia is not considered to benefit from G-CSF treatment. Other approved indications include stem cell mobilization, and an adequate delivery of dose-intense and dose-dense chemotherapy regimens.

Acute myeloid leukaemia or myelodysplastic syndrome following use of granulocyte colony-stimulating factors during breast cancer adjuvant chemotherapy

It is still controversial whether granulocyte colony-stimulating factors (G-CSF) per se increases the risk of secondary acute myeloid leukaemia (AML) or myelodysplastic syndrome (MDS) or whether the requirements for its use cause an increased risk of AML/MDS. In fact, the apparent effects of G-CSF may be caused by the high doses of epirubicin and cyclophosphamide received by the patients included in the treatment arms to which G-CSF was assigned [1]. In the manuscript by Hershman et al. [2], of the 906 women with stages I–III breast cancer, who were treated with G-CSF concurrently with adjuvant chemotherapy, 16 (1.77%) developed AML/MDS. The hazard rate ratio for AML or MDS among those treated with G-CSF or granulocyte–macrophage colony-stimulating factor compared with those who were not was 2.14. One of the issues concerning this observational study is that no information was available about the cumulative dose and duration of G-CSF treatment [3]. Smith et al. [4] found a positive association between the use and the dose of G-CSF and the risk of secondary acute leukaemia (sAL) in patients receiving standard anthracycline and dose-intensified cyclophosphamide. Eighteen of the 22 patients enrolled in B-25 trial and diagnosed with AML/MDS received G-CSF doses in excess of the median dose administered to all patients (242 lg/kg). Controlling for treatment arm, patient age, and operation, the estimated risk of AML/MDS for patients receiving more than the median dose of G-CSF, relative to those receiving the median dose or less, was 3.58 (P = 0.02). On the other hand, in the study by Praga et al. [5], the patients allocated to receive G-CSF according to protocol received median cumulative doses of epirubicin and cyclophosphamide significantly (P = 0.0001) higher than the corresponding median cumulative doses in patients not mandated to receive G-CSF. According to Wilking et al. [6], the major pitfall with the tailored and dose-escalated FEC arm (5-fluorouracil, epirubicin, cyclophosphamide) was the increased risk for secondary AML or MDS. All patients received prophylactic filgrastim (5 lg/kg daily subcutaneously) on days 2–14. The dose of epirubicin in the tailored FEC was much higher than in the standard FEC followed by marrow-supported high-dose therapy (780 vs. 181 mg/m, respectively). By contrast, Crump et al. [7] found no case of sAL among patients given epirubicin-based adjuvant chemotherapy plus G-CSF and Citron et al. [8] reported no correlation between the use of G-CSF and the incidence of sAL among patients randomized to standard or dose-dense chemotherapy. In our experience [9], the crude incidence of sAL after adjuvant high dose epirubicin plus cyclophosphamide with G-CSF support was 0.41%. Future analyses should investigate the possible role of G-CSF cumulative dose and duration of exposure in causing leukaemia in patients treated with adjuvant epirubicin and cyclophosphamide.

Therapeutic Use of Granulocyte Colony-Stimulating Factors for Established Febrile Neutropenia

The prophylactic use of granulocyte colony-stimulating factors (G-CSFs) reduces the severity and duration of neutropenia and reduces the incidence of febrile neutropenia after cancer chemotherapy. However, the use of G-CSFs, particularly filgrastim, to treat established neutropenia remains controversial. A recent meta-analysis of randomised controlled trials (RCTs) evaluating G-CSF treatment for established febrile neutropenia demonstrated a reduction in prolonged hospitalisations. Because more than one-third of patients in the analysis were hospitalised for at least 10 days, this finding has broad pharmacoeconomic and clinical significance. This analysis presents the potential cost implications of G-CSF treatment for established neutropenia among hospitalised patients. Direct medical costs ($US, year 2003 values) related to hospitalisation for established neutropenia were modelled using a hospital perspective and according to two treatment options: (i) no use of G-CSF during the neutropenic episode (control); and (ii) addition of daily G-CSF until neutrophil recovery. Within each option, we modelled the probability of a long stay (>or=10 days) and patient survival. The model used three data sets: discharge data from a consortium of academic medical institutions, drug cost data (filgrastim) from Federal payers, and estimates of G-CSF efficacy derived from a meta-analysis of RCTs of treatment in patients with established febrile neutropenia. The lowest expected total cost was predicted for both treatment options; sensitivity analyses and Monte Carlo simulations were used to evaluate the robustness of the model. The G-CSF arm produced the lowest expected cost, and predicted net estimated savings of $US1046 per neutropenic episode compared with the control strategy. G-CSF was less expensive than the control for most reasonable estimates of cost per day and all lengths of stay (LOS) >or=10 days. G-CSF was the least costly strategy for 73.5% of 10,000 Monte Carlo iterations, while the no-G-CSF control strategy predicted savings in 26.5% of iterations. This pharmacoeconomic model suggests that therapeutic use of G-CSF should be considered for patients with established neutropenia in order to reduce overall hospital cost. G-CSF treatment may offer substantial potential savings for hospitalised patients with established neutropenia over a wide range of model assumptions. Therapeutic G-CSF use among patients hospitalised for established neutropenia may complement the recommended prophylactic use of these agents for the prevention of neutropenic episodes.

Frequency of Febrile Neutropenia in Breast Cancer Patients Receiving Epirubicin and Docetaxel/Paclitaxel with Colony-Stimulating Growth Factors: A Comparison of Filgrastim or Lenograstim with Pegfilgrastim

Objective: Recombinant granulocyte colony-stimulating factors (G-CSF) have been shown to be effective in reducing the risk of infections associated with antitumour chemotherapy. This report describes a single-centre experience of the efficacy of pegfilgrastim compared with filgrastim or lenograstim in reducing the incidence of febrile neutropenia in patients receiving combination chemotherapy with taxane and epirubicin in a neoadjuvant and adjuvant setting. Methods: A total of 118 patients with breast cancer were treated with either epirubicin 75 mg/m² and docetaxel 75 mg/m² or epirubicin 90 mg/m² and paclitaxel 200 mg/m² every 3 weeks; 88 received G-CSF support with daily filgrastim or lenograstim and 30 with pegfilgrastim once per cycle. Results: Eight patients (9.1%) with prophylactic filgrastim or lenograstim support developed febrile neutropenia, as well as 1 patient (3.3%) in the pegfilgrastim group (p = 0.445). Febrile neutropenia occurred in 13 (2.7%) of 476 filgrastim or lenograstim supported chemotherapy cycles and in 2 (1.2%) of 172 cycles with pegfilgrastim support (p = 0.376). The frequency of chemotherapy delays and dose reductions was not significantly different between the two G-CSF treatment groups. Conclusion: These data show a trend towards superiority of pegfilgrastim over filgrastim or lenograstim in reducing the frequency of febrile neutropenia in patients treated with taxane and epirubicin chemotherapy regimens for breast cancer.