Neutropenia In Cancer Patients Research Articles

Myeloid-derived suppressor cells (MDSCs) in patients with solid tumors: considerations for granulocyte colony-stimulating factor treatment.

Myeloid-derived suppressor cells (MDSCs) have been shown to contribute to tumor escape from host immune surveillance and to cancer progression by production of tumor-promoting soluble factors. Granulocyte colony-stimulating factor (G-CSF) is a principle cytokine controlling granulocyte number. Recombinant human G-CSF (rhG-CSF) has become the main therapeutic agent for the treatment of neutropenia and prophylaxis of febrile neutropenia in cancer patients. However, we show here that rhG-CSF triggers accumulation of granulocytic and monocytic subsets. Consequently, we discuss the pharmacological use of granulopoiesis stimulating factors not only in the context of febrile neutropenia but also from the perspective of MDSC-dependent and MDSC-independent mechanisms of immunosuppression and cancer angiogenesis.

The role of granulocyte macrophage colony stimulating factor (GM-CSF) in radiation-induced tumor cell migration.

Recently it has been observed in preclinical models that that radiation enhances the recruitment of circulating tumor cells to primary tumors, and results in tumor regrowth after treatment. This process may have implications for clinical radiotherapy, which improves control of a number of tumor types but which, despite continued dose escalation and aggressive fractionation, is unable to fully prevent local recurrences. By irradiating a single tumor within an animal bearing multiple lesions, we observed an increase in tumor cell migration to irradiated and unirradiated sites, suggesting a systemic component to this process. Previous work has identified the cytokine GM-CSF, produced by tumor cells following irradiation, as a key effector of this process. We evaluated the ability of systemic injections of a PEGylated form of GM-CSF to stimulate tumor cell migration. While increases in invasion and migration were observed for tumor cells in a transwell assay, we found that daily injections of PEG-GM-CSF to tumor-bearing animals did not increase migration of cells to tumors, despite the anticipated changes in circulating levels of granulocytes and monocytes produced by this treatment. Combination of PEG-GM-CSF treatment with radiation also did not increase tumor cell migration. These findings suggest that clinical use of GM-CSF to treat neutropenia in cancer patients will not have negative effects on the aggressiveness of residual cancer cells. However, further work is needed to characterize the mechanism by which GM-CSF facilitates systemic recruitment of trafficking tumor cells to tumors.

Comparing granulocyte colony–stimulating factor filgrastim and pegfilgrastim to its biosimilars in terms of efficacy and safety: A meta-analysis of randomised clinical trials in breast cancer patients

BackgroundGranulocyte colony–stimulating factors (G-CSFs) are widely used to prevent neutropenia in cancer patients undergoing myelosuppressive chemotherapy. Several biosimilar medicines of G-CSF are now available, with their development involving a step-wise series of comparisons to demonstrate similarity to reference biologics. Randomised clinical trials (RCTs) are considered confirmatory, and for G-CSF biosimilars, patients with breast cancer (BC) undergoing myelosuppressive chemotherapy are the most sensitive population in which to confirm similarity. This meta-analysis aimed to compare the clinical efficacy and safety of approved or proposed G-CSF biosimilars (filgrastim or pegfilgrastim) with reference G-CSF in patients with BC. MethodsA Medline literature search up to March 2017 identified RCTs comparing biosimilar G-CSF to reference in BC patients. The primary efficacy end-point was mean difference in duration of severe neutropenia (DSN). Secondary efficacy end-points were differences in depth of absolute neutrophil count (ANC) nadir, time to ANC recovery and incidence of febrile neutropenia. Safety analyses included calculation of risk ratios for bone pain events, myalgia events and serious adverse events. Random effect models were fitted to obtain the pooled estimates of the mean difference for continuous outcomes and the risk ratio for dichotomous outcomes and their corresponding 95% confidence intervals (CIs). FindingsEight eligible RCTs were included in this meta-analysis. Overall difference in DSN between reference and biosimilar medicines was not statistically significant (0·06 d [95% CI −0·05, 0·17]). The analysis of secondary efficacy end-points showed no significant differences between reference biologics and biosimilar medicines, as well as the analysis of bone pain events, myalgia events and serious adverse events. InterpretationThis meta-analysis showed no significant differences in clinical efficacy and safety between biosimilar and reference G-CSF in BC patients.

509P - Assessment of chemotherapy induced febrile neutropenia in cancer patients: A prospective observational study in South India

509P - Assessment of chemotherapy induced febrile neutropenia in cancer patients: A prospective observational study in South India

Comparative Diagnostic Performance of the Granulocyte and Neutrophil Counts

ObjectivesUse of point-of-care testing is increasing, however many haematology analysers can only determine granulocyte count without further differentiation into neutrophils, eosinophils and basophils. Since the diagnosis of life-threatening neutropenia in cancer patients requires a distinct neutrophil count, this study aimed to determine the comparative performance between the neutrophil and granulocyte count. Design and methodsA database of 508 646 venous full blood count results measured on a laboratory reference analyser was mined from a large oncology unit. The relationship between granulocyte and neutrophil counts was assessed. Multinomial logistic regression was used to classify results into neutropenia grades using an equivalent granulocyte count. ResultsGranulocyte to neutrophil count correlation was 0.997. The accuracy for classification into neutropenia grades using the derived equivalent granulocyte count ranges was 96.4%. Identification of results with a neutrophil count <1.5×109 cells/L using an equivalent granulocyte count of <1.69×109 cells/L resulted in sensitivity, specificity, positive and negative predictive values of 98.0%, 99.5%, 97.8% and 99.5%, respectively. ConclusionsThese results describe the relationship between granulocyte and neutrophil counts, measured on a laboratory analyser, in a large population of patients with malignancies and receiving anti-cancer therapies. However, this relationship must be established using a point of care testing system with a three-part differential count before considering the possibility that a granulocyte count can guide clinical decisions in the absence of a definitive neutrophil count, to reduce the frequency and severity of neutropenic complications in patients receiving cancer treatments.

Abstract 1347: In vivo efficacy of eflapegrastim in rats with chemotherapy-induced neutropenia

Abstract Introduction: Eflapegrastim (SPI-2012, HM10460A) is a novel, long-acting recombinant human granulocyte colony-stimulating factor (rhG-CSF). Eflapegrastim consists of an rhG-CSF conjugated to a recombinant E. coli derived Fc fragment of IgG4 via a polyethylene glycol linker. Eflapegrastim is in clinical development for the treatment of chemotherapy-induced neutropenia in cancer patients. The purpose of this study was to evaluate and compare the efficacy of eflapegrastim, pegfilgrastim and filgrastim in rats with chemotherapy-induced neutropenia. Methods: Rats were treated with 50 mg/kg of cyclophosphamide (CPA) intraperitoneally to induce neutropenia. Pegfilgrastim was administered subcutaneously as a single dose of 100 µg/kg on Day 1 and filgrastim was administered subcutaneously at a dose of 20 µg/kg daily for five days on days 1 to 5. Eflapegrastim was administered subcutaneously as a single dose on day 1, at doses ranging from 32 µg /kg to 322 µg/kg (or 8.8 µg/kg to 88 µg/kg as G-CSF equivalent). Blood samples were collected for 8 days after drug administration for the measurement of neutrophil counts and the Duration of Severe Neutropenia (DSN). Results: The DSN in neutropenic rats treated with eflapegrastim was compared with the DSN in neutropenic rats treated with pegfilgrastim or filgrastim. The DSN was 0.2 days when eflapegrastim was administered as a single dose at 88 µg/kg (as G-CSF equivalent) 24 hours after administering CPA. In contrast, the DSN was 3.04 days with filgrastim administered at a dose of 20 µg/kg for 5 days from Day 1 to Day 5 and 2.8 days with pegfilgrastim administered as a single dose of 100 µg/kg 24 hours after administering CPA. At the lowest eflapegrastim dose of 8.8 µg/kg that was about 1/10 of G-CSF equivalent dose for pegfilgrastim, the DSN in eflapegrastim treated rats was 2.94 days. Thus, eflapegrastim was found to be more potent in shortening the DSN with a lower G-CSF equivalent dose when compared to either pegfilgrastim or filgrastim. Conclusion: Eflapegrastim was about 10 times more potent than pegfilgrastim at G-CSF equivalent doses in this neutropenic rat model Citation Format: Young Hoon Kim, InYoung Choi, Prasad Kolli, Guru Reddy. In vivo efficacy of eflapegrastim in rats with chemotherapy-induced neutropenia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1347. doi:10.1158/1538-7445.AM2017-1347

UGT1A1*6 polymorphisms are correlated with irinotecan-induced neutropenia: a systematic review and meta-analysis.

Irinotecan (IRI) chemotherapy toxicities can be severe, and may result in treatment delay, morbidity and in some rare cases death. Neutropenia is a life-threatening side effect of irinotecan, and UDP glucuronosyltransferases (UGTs) gene polymorphisms could predict the side effects in cancer patients and then reduce IRI-induced toxicity by preventative treatment or a decrease in dose. Both UGT1A1*6 and *28 were reliably demonstrated to be risk factors for IRI-induced neutropenia, with tests for both polymorphisms potentially being particularly useful in Asian cancer patients. However, some researchers reported that UGT1A1*6 could predict IRI-induced toxicities in Asian populations, controversial conclusions still remained. Thus, the association between UGT1A1*6 polymorphisms and IRI-induced severe toxicity in cancer patients is still needed to be explored. Therefore, this study aims to investigate the association between UGT1A1*6 polymorphisms and IRI-related severe neutropenia in cancer patients on a large scale. A total of 12 studies that included 746 wild genotype (G/G) cases and 394 variant genotype (G/A and A/A) cases were included on the basis of inclusion criteria. Then we assessed the methodologies quality; odds ratio (OR), risk difference (RD) and 95% confidence intervals (95% CI) were used to assess the strength of association. Overall, an increased risk of severe neutropenia in cancer patients with UGT1A1*6 polymorphisms was found. Patients with recessive models (GA+AA vs. GG) of UGT1A1*6 showed an increased risk (OR 2.03, 95% CI 1.54-2.68; RD=0.11, P<0.001). Specifically, the heterozygous variant of UGT1A1*6 showed an increased risk (OR 1.83, 95% CI 1.36-2.46; RD=0.09, P<0.001), and homozygous mutation showed also high risk (OR 2.95, 95% CI 1.83-4.75; RD=0.18, P<0.001) for severe neutropenia. Subgroup meta-analysis revealed that for patients harboring both heterozygous and homozygous variants, cancer types, low dose of IRI and the duration of treatment also presented comparably increased risk in suffering severe neutropenia. As for country, in China and Japan, there was a statistically increased severe neutropenia with variant genotype of UGT1A1*6 (China: GA+AA vs. GG, OR 1.83, 95% CI 1.28-2.59; RD=0.08, P=0.001; Japan: GA+AA vs. GG, OR 2.39, 95% CI 1.45-3.92; RD=0.15, P=0.001). In conclusion, in this meta-analysis, the UGT1A1*6 polymorphisms were associated with an increased risk of IRI-induced neutropenia in cancer patients, and increased incidences of severe neutropenia could be correlated with diverse regions, cancer type, low dose of IRI and the duration of treatment.

Abstract P5-11-07: Pharmacokinetics of eflapegrastim in a phase 2 open-label dose-ranging study in breast cancer patients receiving TC regimen

Abstract Background: Eflapegrastim (SPI-2012/HM10460A) is a novel, long acting recombinant human granulocyte colony-stimulating factor (rhG-CSF). Eflapegrastim consists of an rhG-CSF conjugated to the recombinant E coli derived Fc fragment of IgG4 via a polyethylene glycol linker. Eflapegrastim is in clinical development for the treatment of chemotherapy induced neutropenia in cancer patients. Methods: Pharmacokinetics (PK) of eflapegrastim was investigated in an open label, dose-ranging Phase 2 study in breast cancer patients receiving docetaxel + cyclophosphamide (TC) chemotherapy. The study consisted of 4 arms. Patients in Arms 1 through 3 received subcutaneous doses of 45, 135, or 270 µg /kg of eflapegrastim and patients in Arm 4 received 6 mg pegfilgrastim (Neulasta®) on Day 2 of each 21-day chemotherapy cycle. Serum samples were collected from a subset of eflapegrastim patients at pre-specified time-points and analyzed for eflapegrastim by a validated enzyme-linked immunosorption assay (ELISA). Pharmacokinetic analyses were conducted on serum concentration-time profiles after dosing in Cycle 1. The serum concentrations for samples collected in Cycle 3 were compared with the corresponding concentrations in Cycle 1. Pharmacokinetic analyses were not conducted for pegfilgrastim patients. Results: The PK profile of eflapegrastim was investigated in 11 patients, including 3 patients in the 45 µg/kg treatment arm, 4 patients in the 135 µg/kg treatment arm, and 4 patients in the 270 µg/kg treatment arm. Following single eflapegrastim doses of 45, 135, or 270 µg/kg, peak serum concentrations increased in a dose proportional manner. The summary of pharmacokinetics of eflapegrastim is presented in the Table below. Pharmacokinetic Parameters of Eflapegrastim in Patients Following Single Subcutaneous Doses in Cycle 1ParameterEflapegrastim 45 μg/kg/Eflapegrastim 135μg/kgEflapegrastim 270 μg/kgCmax, ng/mLN = 3; Mean = 7.00; SD = 6.08N = 4; Mean = 247; SD = 276N =3; Mean = 299; SD = 329Tmax, haN =2; Mean = 58.7; SD = 46.9 - 70.5N = 4; Mean =9.00; SD = 8 - 48.1N = 3; Mean = 24.00; SD = 24 - 24.1AUC0-312, ng•hr/mLN = 0; Mean = NC; SD = NCN = 2; Mean = 16000; SD = 5850N = 3; Mean = 22900; SD = 25100t1/2, hbN = 0; Mean = NC; SD = NCN = 2; Mean = 81.0; SD = 88.4N = 1; Mean = 31.5; SD = NCAUC = area under the concentration-time curve; Cmax = maximum serum concentration; h = hour; NC = not calculated; SD = standard deviation; t1/2 = half-life; Tmax = time to maximum serum concentration; a) Expressed as median and range; b) Expressed as harmonic mean and pseudo SD The maximum serum concentrations of eflapegrastim in Cycle 3 increased with the dose of eflapegrastim. The serum concentrations of eflapegrastim in Cycle 3 were generally lower than those in Cycle 1, but the profile was similar to Cycle 1. Conclusions: The Cmax and AUC(0-312) of eflapegrastim increased in a dose proportional manner following subcutaneous administration. The half-life of eflapegrastim ranged from 31.5 to 81.0 hours, which is consistent with the half-life of other long-acting myeloid growth factors. Citation Format: Vacirca JL, Papai Z, Horvath Z, Makharadze R, Reddy G, Song T, Koli P, Schwartzberg LS. Pharmacokinetics of eflapegrastim in a phase 2 open-label dose-ranging study in breast cancer patients receiving TC regimen [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-11-07.

Abstract P5-11-08: Immunogenicity of eflapegrastim in a phase 2 open-label dose-ranging study of eflapegrastim in breast cancer patients receiving TC regimen

Abstract Background: Eflapegrastim (SPI-2012/HM10460A) is a novel, long-acting recombinant human granulocyte colony-stimulating factor (rhG-CSF). Eflapegrastim consists of an rhG-CSF conjugated to a recombinant E. coli derived Fc fragment of IgG4 via a polyethylene glycol linker. Eflapegrastim is in clinical development for the treatment of chemotherapy induced neutropenia in cancer patients. Methods: Immunogenicity of eflapegrastim was investigated in an open label, dose-ranging Phase 2 study in breast cancer patients receiving docetaxel + cyclophosphamide (TC) chemotherapy. The study consisted of 4 arms. Patients in Arms 1 through 3 received subcutaneous doses of 45, 135, or 270 µg/kg eflapegrastim and Arm 4 received 6 mg pegfilgrastim (Neulasta®) on Day 2 of each 21-day chemotherapy cycle. Blood samples for immunogenicity analysis were collected before the start of each chemotherapy cycle (Day 1) and at the End-of-Study Visit. Samples were tested in a screening assay for Anti-Drug Antibodies (ADA) to eflapegrastim by a validated enzyme linked immunosorption assay (ELISA). Positive samples from the screening assay were further tested in a confirmatory assay for antibodies binding to eflapegrastim or G-CSF. Samples found positive in the confirmatory assay were further tested in a validated cell based neutralizing antibody assay. Results: Serum samples from 143 patients in the study were tested for ADA to eflapegrastim and G-CSF. Preexisting antibodies binding to eflapegrastim or G-CSF were detected in 9 out of 143 (6.3%) patients. One out of the 27 patients (3.7%) in the Pegfilgrastim Arm who was negative prior to dosing was positive for ADA in the G-CSF confirmatory assay. Two out of 100 patients (2.0%) treated with eflapegrastim, who were negative prior to dosing, demonstrated treatment-induced formation of ADA in the G-CSF confirmatory assay. However, the responses in these patients were transient (ie, not consistently positive at all the sampling times) and the assay response values were low and only slightly above the plate-specific cut points. None of the patients tested were positive for G-CSF neutralizing antibodies. A formal assessment of the impact of serum ADA on the PK of eflapegrastim was not performed since PK was examined in only a limited number of patients and all of those patients were negative for ADA both at study initiation and post-dose. Conclusion: No neutralizing antibodies against eflapegrastim or G-CSF were detected in patients administered eflapegrastim in this study. Citation Format: Vacirca JL, Papai Z, Agajanian R, Horvath Z, Makharadze R, Ibrahim E, Koli P, Reddy G, Tedesco KL, McGregor K, Schwartzberg LS. Immunogenicity of eflapegrastim in a phase 2 open-label dose-ranging study of eflapegrastim in breast cancer patients receiving TC regimen [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-11-08.

PCN85 - Cost-Minimization Analysis of Lipegfilgrastim in Prophylaxis Of Febrile Neutropenia in Cancer Patients

To conduct cost-minimization analysis of lipegfilgrastim compared with pegfilgrastim, filgrastim, lenograstim in prophylaxis of febrile neutropenia (FN) in cancer patients in Russia for 1-year period. A cost-minimization model was developed in Excel 2013 to simulate the costs for 1-year period. The total number of patients with FN in Russia according to the statistics equals 110556. The following costs were taken into account: costs for the treatment course with granulocyte colony-stimulating factor drugs (including ones for administration of the drugs), costs for the treatment of a FN event, expenses for management of adverse events associated with administration of granulocyte colony-stimulating factor drugs. The average tender prices for the study drugs were used as the source of data on prices for G-CSFs. The number of administrations and bottles per administration were calculated in accordance with Prescribing Information for the drugs. According to the Program of state guarantees for provision of free medical care the costs of each FN event is 119,808 rubles. Adverse events management was calculated according to the data on the incidence of adverse events from the Prescribing information documents and tariffs of Federal Compulsory Medical Insurance Fund. According to the cost-minimization analysis, the least costly was prophylaxis with lipegfilgrastim (211484 rubles/3200 $) by the end of the 1st year per 1 patient. Costs in pegfilgrastim group resulted in 314986 rubles/4766 $, in filgrastim group (11 days of treatment) – 264620 rubles/4004 $, in lenograstim group (11 days of treatment) – 690798 rubles/10452 $. Current rate taken as for 15.06.2016 is 1$ = 66,09 RUB. The prophylaxis with lipegfilgrastim is a cost saving option compared with G-CSF registered for prophylaxis of febrile neutropenia in cancer patients in Russia for 1-year period.

Cost-effectiveness of screening for DPYD polymorphisms to prevent neutropenia in cancer patients treated with fluoropyrimidines.

To compare the cost of screening for three mutations in the dihydropyrimidine dehydrogenase gene and the costs of treating severe fluoropyrimidine-induced neutropenia. The polymorphisms rs3918290 (DPYD*2A), rs67376798 (DPYD 2846A>T) and rs55886062 (1679T>G, DPYD*13) were genotyped using real-time PCR, TaqMan probes and a rapid cell lysis to provide PCR-ready DNA. We found that genotyping 1000 patients in our center cost €6400 and that the mean cost of treating severe neutropenia was €3044. Therefore, if severe fluoropyrimidine-induced neutropenia is reduced by genotyping the three DPYD variations in at least 2.21 cases per 1000 treated patients, then DPYD genotyping will prove cost effective. We demonstrated that real-time DPYD genotyping using TaqMan probes is cost effective in all fluoropyrimidine-based treatments.

Hospitalisations pour neutropénie fébrile chimio-induite en France en 2010–2011 : impact clinique et caractéristiques des patients à partir des données de la base PMSI

Febrile neutropenia (FN) is a severe complication of chemotherapy in terms of morbidity and mortality. Using data from the PMSI database, the objective of this work was to estimate the clinical burden caused by hospitalization for FN in France, assessed by number of patients, number of stays and hospital mortality. Using the PMSI database (which includes all hospitalizations occurring annually in France), an algorithm was used to select newly-diagnosed patients treated by chemotherapy in 2010/2011 who were hospitalized for FN within the 30 days following each administration of chemotherapy during their first year of treatment. The number, characteristics and comorbidities of patients were described, as well as the number and length of stay and mortality in hospitalized patients. In 2010-11, 10,229 patients were hospitalized for FN, representing a hospitalization rate of 7.4% in newly-diagnosed patients receiving chemotherapy. A total of 13,559 stays were identified, with an average duration of 6.3±8.7 days (median=4 days). A total of 720 deaths occurred during the hospital stays, corresponding to a mortality rate of 7%. Among patients hospitalized for FN, there were 14% of patients with diabetes, 8% with heart failure, 34% with hypertension and 41% with at least one of these three comorbidities. With 10,299 hospitalized patients and 13,559 stays in 2010-11, the clinical burden induced by febrile neutropenia in cancer patients treated with chemotherapy is considerable.

Risk factors for febrile neutropenia in cancer patients treated with chemotherapy.

6559Background: Several risk factors for febrile neutropenia (FN) have been identified in previous studies (eg, chemotherapy [chemo] dose intensity, advanced age, and comorbidities). The possible b...

Фармакоэкономический анализ применения препаратов гранулоцитарных колониестимулирующих факторов в профилактике фебрильной нейтропении у пациентов с онкологическими заболеваниями в условиях здравоохранения Российской Федерации

Фармакоэкономический анализ применения препаратов гранулоцитарных колониестимулирующих факторов в профилактике фебрильной нейтропении у пациентов с онкологическими заболеваниями в условиях здравоохранения Российской Федерации

Clinical research in febrile neutropenia in cancer patients: Past achievements and perspectives for the future

Clinical research in febrile neutropenia in cancer patients: Past achievements and perspectives for the future

Phase Ib Studies of Benegrastim in Chinese Women with Breast Cancer Receiving Myelotoxic Chemotherapy

▪Neutropenia is common in patients receiving myelotoxic chemotherapy. BenegrastimTM(F-627), a recombinant human G-CSF dimer, is an once-per-cycle therapy for prophylactic neutropenia in cancer patients after chemotherapy. Two phase I dose finding studies of benegrastim were conducted in Chinese women with stage I-IV breast cancer receiving myelotoxic chemotherapy. The aims of the studies were to evaluate the safety profile and pharmacokinetics (PK) and pharmacodynamics (PD) properties of benegrastim.In the first study, a total of 18 patients were enrolled to receive 3 sequential dose levels of benegrastim at 80, 240 and 360 µg/kg (n=6). The patients received epirubicin/cyclophosphamide (EC) chemotherapy on day one. Benegrastim was administered to patients on day 3 by SC injection once per chemotherapy cycle for up to 4 cycles. In the second study, 15 patients were sequentially assigned to 240 µg/kg (n=7) and 320 µg/kg (n=8) of benegrastim. These patients received doxorubicin, docetaxel and cyclophosphamide (TAC) on day one, benegrastim was administered on day 2 by SC injection for up to 6 cycles. The PK/PD properties of benegrastim were evaluated in cycle one and cycle three.Benegrastim was well tolerated in both clinical studies. The treatment emergent adverse events related to benegrastim were back pain, arthralgia, musculoskeletal pain, and rash, commonly seen in rhG-CSF therapy. The PK/PD result in patients receiving TAC in the first chemotherapy cycle is shown in Fig 1. Dose-dependent benegrastim exposure and ANC increase were demonstrated in these two clinical trials. In breast cancer patients receiving EC or TAC, benegrastim showed a non-linear pharmacokinetics. Benegrastim shortened the duration of neutropenia post chemotherapy in a dose dependent manner. In conclusion, benegrastim may provide an alternative approach to manage neutropenia, especially, severe neutropenia in patients after chemotherapy. [Display omitted] DisclosuresCao:Generon (Shanghai) Corporation Ltd.: Research Funding. Yuan:Generon (Shanghai) Corporation Ltd.: Research Funding. Huang:Generon (Shanghai) Corporation Ltd.: Employment. Ji:Generon (Shanghai) Corporation Ltd.: Research Funding. Peng:Generon (Shanghai) Corporation Ltd.: Research Funding. Yan:Generon (Shanghai) Corporation Ltd.: Employment. Tang:Generon (Shanghai) Corporation Ltd.: Employment.

Risk of chemotherapy-induced febrile neutropenia in cancer patients receiving pegfilgrastim prophylaxis: does timing of administration matter?

PurposeContrary to the approved indication for pegfilgrastim prophylaxis, some patients receive it on the same day as the last administration of chemotherapy in clinical practice, which could adversely impact risk of febrile neutropenia (FN). An evaluation of the timing of pegfilgrastim prophylaxis and FN risk was undertaken.MethodsA retrospective cohort design and data from two US private health care claims repositories were employed. Study population comprised adults who received intermediate/high-risk chemotherapy regimens for solid tumors or non-Hodgkin’s lymphoma (NHL) and received pegfilgrastim prophylaxis in ≥1 cycle; all cycles with pegfilgrastim were pooled for analyses. Odds ratios (OR) for FN during the cycle were estimated for patients who received pegfilgrastim on the same day (day 1) as the last administration of chemotherapy versus days 2–4 from chemotherapy completion.ResultsThe study population included 45,592 patients who received pegfilgrastim in 179,152 cycles (n = 37,095 in cycle 1); in 12 % of cycles, patients received pegfilgrastim on the same day as chemotherapy. Odds of FN were higher for patients receiving pegfilgrastim prophylaxis on the same day as chemotherapy versus days 2–4 from chemotherapy in cycle 1 (OR = 1.6, 95 % CI = 1.3–1.9, p < 0.001) and all cycles (OR = 1.5, 95 % CI = 1.3–1.6, p < 0.001).ConclusionsIn this large-scale evaluation of adults who received intermediate/high-risk regimens for solid tumors or NHL in US clinical practice, FN incidence was found to be significantly higher among those who received pegfilgrastim prophylaxis on the same day as chemotherapy completion versus days 2–4 from chemotherapy completion, underscoring the importance of adhering to the indicated administration schedule.Electronic supplementary materialThe online version of this article (doi:10.1007/s00520-015-3036-7) contains supplementary material, which is available to authorized users.

A Phase II, Randomized, Multi-Centre, Open-Label, Active-Controlled, Dose-Finding Trial of F-627 (benefilgrastim) in Women with Breast Cancer Receiving Myelotoxic Chemotherapy

▪Neutropenia is common in patients receiving myelotoxic chemotherapy. Benefilgrastim, an rhG-CSF dimer (rhG-CSF-FC fusion protein), is a once-per-cycle therapy for prophylactic neutrophil support. In this Phase II trial, 230 women with stage I-IV breast cancer are to be treated for 4 chemotherapy cycles with either docetaxel/cyclophosphamide (TC) or doxorubicin/docetaxel/cyclophosphamide (TAC) chemotherapy, with each cycle lasting approximately 21 days. Patients will be randomized to receive either benefilgrastim or pegfilgrastim (Neulasta; 6 mg fixed dose) one day after chemotherapy during each cycle, as a subcutaneous injection. Dose levels of benefilgrastim examined are 80 µg/kg (TC patients only), and 240 and 320 µg/kg (TC and TAC patients). The primary endpoint is the duration of grade 3/4 neutropenia in chemotherapy cycle 1. As of August 1, 2014, 232 patients have completed chemotherapy cycle 1; safety and efficacy were analyzed for these enrolled patients.For the TC chemotherapy regimen, a total of 141 patients were randomized (ratio = 1:1:1:1) into 4 arms (80, 240, and 320 µg/kg benefilgrastim or 6 mg pegfilgrastim). In the TAC chemotherapy regimen, a total of 91 patients were randomized (ratio = 1:1:1) into 3 arms (240 and 320 µg/kg benefilgrastim or 6 mg pegfilgrastim). The incidence of grade 3/4 and grade 4 neutropenia and their mean durations in cycle 1 are provided in Table 1. There were higher incidences of grade 3/4 and grade 4 neutropenia in the TAC regimen compared to the TC regimen.The safety profiles of benefilgrastim and pegfilgrastim were similar. A total of 10 SAEs were reported in 6 patients with the majority (7 SAEs in 4 patients) occurring in those receiving pegfilgrastim. The most commonly observed treatment emergent adverse events (>10% of total TC + TAC patients) were: alopecia, nausea, asthenia, neutropenia, bone pain, and fatigue. The rates were similar amongst treatment regimens and treatment groups.In summary, a single subcutaneous injection of benefilgrastim 240 or 320 µg/kg provided neutrophil support to patients treated with both the TC and TAC chemotherapy regimens. The safety profile of benefilgrastim was comparable to that of pegfilgrastim during multiple chemotherapy cycles. The results suggest a potential use of benefilgrastim for the management of severe neutropenia in cancer patients undergoing high dose chemotherapy.Abstract 1584. Table 1:Preliminary ResultsTC RegimenTAC RegimenBenefilgrastimPegfilgrastim 6 mg (N=35)BenefilgrastimPegfilgrastim 6 mg (N=29)80 µg/kg (N=35)240 µg/kg (N=37)320 µg/kg (N=34)240 µg/kg (N=29)320 µg/kg (N=30)Grade 3/4 neutropenia n/N (%)10/35 (28.6)10/37 (27.0)7/34 (20.6)7/35 (20.0)17/25 (68.0)19/26 (73.1)17/24 (70.8)Duration (days) Mean (SD) 95% CI2.4 (2.07) 1.2, 3.62.2 (0.79) 1.7, 2.71.9 (0.38) 1.6, 2.11.4 (0.79) 0.9, 2.02.8 (1.67) 2.1, 3.52.6 (1.07) 2.2, 3.12.2 (0.73) 1.9, 2.5Grade 4 neutropenia n/N (%)4/35 (11.4)7/37 (18.9)6/34 (17.6)3/35 (8.6)14/25 (56.0)17/26 (65.4)15/24 (62.5)Duration (days) Mean (SD) 95% CI2.0 (1.15) 0.6, 3.42.1 (0.90) 1.5, 2.81.2 (0.41) 0.8, 1.51.0 (0.00) 1.0, 1.01.9 (1.33) 1.3, 2.62.0 (0.87) 1.6, 2.41.5 (0.64) 1.2, 1.8SAEs n (%) # SAEs0 01 (2.7) 10 02 (5.7) 30 01 (3.3) 22 (6.9) 4CI=confidence interval; SAE=serious adverse event; SD=standard deviation DisclosuresGlaspy:Generon (Shanghai) Corporation Ltd.: Research Funding. Tang:Generon (Shanghai) Corporation Ltd.: Employment. Rutty:Everest Clinical Research Services Inc.: Employment; Generon (Shanghai) Corporation Ltd.: Consultancy; Schering Corporation: Consultancy; Roche: Consultancy; Methylgene: Consultancy; Steba Biotech SA: Consultancy; Aderans Research Institute Inc: Consultancy; Stem Cell Theraputics: Consultancy; Genentech: Consultancy; Pearly Therapeutics: Consultancy; Sundise Chinese Medicine Technology Development Corp: Consultancy; Endocyte, Inc: Consultancy; Hutchison Medipharma: Consultancy; Nutrition Science Partners Limited: Consultancy. Yan:Generon (Shanghai) Corporation Ltd.: Employment.

History of chronic comorbidity and risk of chemotherapy-induced febrile neutropenia in cancer patients not receiving G-CSF prophylaxis.

Chemotherapy-induced febrile neutropenia (FN) is a clinically important complication that affects patient outcome by delaying chemotherapy doses or reducing dose intensity. Risk of FN depends on chemotherapy- and patient-level factors. We sought to determine the effects of chronic comorbidities on risk of FN. We conducted a cohort study to examine the association between a variety of chronic comorbidities and risk of FN in patients diagnosed with six types of cancer (non-Hodgkin lymphoma and breast, colorectal, lung, ovary, and gastric cancer) from 2000 to 2009 who were treated with chemotherapy at Kaiser Permanente Southern California, a large managed care organization. We excluded those patients who received primary prophylactic granulocyte colony-stimulating factor. History of comorbidities and FN events were identified using electronic medical records. Cox models adjusting for propensity score, stratified by cancer type, were used to determine the association between comorbid conditions and FN. Models that additionally adjusted for cancer stage, baseline neutrophil count, chemotherapy regimen, and dose reduction were also evaluated. A total of 19 160 patients with mean age of 60 years were included; 963 (5.0%) developed FN in the first chemotherapy cycle. Chronic obstructive pulmonary disease [hazard ratio (HR) = 1.30 (1.07-1.57)], congestive heart failure [HR = 1.43 (1.00-1.98)], HIV infection [HR = 3.40 (1.90-5.63)], autoimmune disease [HR = 2.01 (1.10-3.33)], peptic ulcer disease [HR = 1.57 (1.05-2.26)], renal disease [HR = 1.60 (1.21-2.09)], and thyroid disorder [HR = 1.32 (1.06-1.64)] were all associated with a significantly increased FN risk. These results provide evidence that history of several chronic comorbidities increases risk of FN, which should be considered when managing patients during chemotherapy.

Enhanced heterologous expression of biologically active human granulocyte colony stimulating factor in transgenic tobacco BY-2 cells by localization to endoplasmic reticulum.

Tobacco Bright Yellow-2 (BY-2) cells, one of the best characterized cell lines is an attractive expression system for heterologous protein expression. However, the expression of foreign proteins is currently hampered by their low yield, which is partially the result of proteolytic degradation. Human granulocyte colony stimulating factor (hG-CSF) is a hematopoietic cytokine. Recombinant hG-CSF is successfully being used for the treatment of chemotherapy-induced neutropenia in cancer patients. Here, we describe a simple strategy for producing biologically active hG-CSF in tobacco BY-2 cells, localized in the apoplast of BY-2 cells, as well as targeted to the endoplasmic reticulum (ER). ER targeting significantly enhanced recombinant production which scaled to 17.89 mg/l from 4.19 mg/l when expressed in the apoplasts. Southern blotting confirmed the stable integration of hG-CSF in the BY-2 nuclear genome, and the expression of hG-CSF was analysed by Western blotting. Total soluble protein containing hG-CSF isolated from positive calli showed proliferative potential when tested on HL-60 cell lines by MTT assay. We also report the potential of a Fluorescence-activated cell sorting approach for an efficient sorting of the hG-CSF-expressing cell lines, which will enable the generation of homogenous high-producing cell lines.