A comparison of eflapegrastim to pegfilgrastim in the management of chemotherapy-induced neutropenia in patients with early-stage breast cancer undergoing cytotoxic chemotherapy (RECOVER): A Phase 3 study.
Cobb Patrick Wayne,Moon Yong Wha,Mezei Klára,Láng István,Bhat Gajanan,Chawla Shanta,Hasal Steven J,Schwartzberg Lee S
Eflapegrastim (Rolontis ) is a novel, long-acting hematopoietic growth factor consisting of a recombinant human granulocyte-colony stimulating factor (rhG-CSF) analog conjugated to a human IgG4 Fc fragment via a short polyethylene glycol linker. We report results from a second pivotal, randomized, open-label, Phase 3 study comparing the efficacy and safety of eflapegrastim to pegfilgrastim for reducing the risk of chemotherapy-induced neutropenia. Patients with Stage I to IIIA early-stage breast cancer (ESBC) were randomized 1:1 to fixed-dose eflapegrastim 13.2 mg (3.6 mg G-CSF) or pegfilgrastim (6 mg G-CSF) administered one day after standard docetaxel/cyclophosphamide (TC) therapy for four cycles. The primary objective was to demonstrate noninferiority (NI) of eflapegrastim compared to pegfilgrastim in mean duration of severe neutropenia (DSN; Grade 4) in Cycle 1. A total of 237 eligible patients were randomized 1:1 to receive either eflapegrastim (n = 118) or pegfilgrastim (n = 119). Cycle 1 severe neutropenia was observed in 20.3% (n = 24) of patients receiving eflapegrastim and 23.5% (n = 28) receiving pegfilgrastim. The DSN of eflapegrastim in Cycle 1 was noninferior to pegfilgrastim with a mean difference of -0.074 days (NI P-value < .0001). Noninferiority was maintained throughout the four treatment cycles (P < .0001 in all cycles). Other efficacy endpoints results were comparable between treatment arms, and adverse events, irrespective of causality and grade, were comparable between treatment arms. The results demonstrate noninferior efficacy and comparable safety for eflapegrastim, at a lower G-CSF dose, vs pegfilgrastim. The potential for the increased potency of eflapegrastim to deliver improved clinical benefit warrants further clinical study.
Pharmacokinetic and Pharmacodynamic Equivalence of Pegfilgrastim-cbqv and Pegfilgrastim in Healthy Subjects.
Finck Barbara,Tang Helen,Civoli Francesca,Hodge Jennifer,O'Kelly Hillary,Vexler Vladimir
Advances in therapy
INTRODUCTION:Pegfilgrastim-cbqv was developed as a biosimilar of pegfilgrastim, a pegylated form of recombinant human granulocyte colony-stimulating factor approved for decreasing febrile neutropenia-associated infection in patients receiving myelosuppressive drugs. This multicenter, randomized, single-blind, partial-reference-replicated, three-sequence crossover study assessed pharmacokinetic and pharmacodynamic bioequivalence of pegfilgrastim-cbqv and pegfilgrastim in healthy subjects. METHODS:One hundred twenty-two subjects were randomized to one of three treatment sequences; each included one dose of pegfilgrastim-cbqv and two doses of pegfilgrastim separated by ≥ 28 days. The primary pharmacokinetic end points were area under the curve (AUC) from 0 to infinity (AUC) and maximum concentration (C). The primary pharmacodynamic end points were maximum absolute neutrophil count (ANC) and ANC AUC from time 0 to the last measurable observation (ANC AUC). Pharmacokinetic and pharmacodynamic bioequivalences were demonstrated if the 90% CI for the geometric mean ratio (GMR) of pegfilgrastim-cbqv to pegfilgrastim was within 80-125% for the primary end points. RESULTS:Pharmacokinetic bioequivalence criteria were met for C (GMR 105.0; 90% CI 95.5-115.4) and AUC (GMR 97.5; 90% CI 88.6-107.2). Pharmacodynamic bioequivalence criteria were met for ANC (GMR 99.6; 90% CI 96.2-103.2) and ANC AUC (GMR 96.7; 90% CI 92.2-101.4). Adverse events occurred in 76.0%, 76.6%, and 73.1% of subjects for pegfilgrastim-cbqv, first pegfilgrastim, and second pegfilgrastim dosing periods across treatment sequences, respectively. Investigators found no drug-related serious adverse events. CONCLUSION:This study established pharmacokinetic and pharmacodynamic bioequivalence of pegfilgrastim-cbqv to pegfilgrastim. The treatments displayed similar safety profiles, including immunogenicity, with no unexpected safety findings. CLINICAL TRIALS REGISTRATION:ClinicalTrials.gov, NCT02650973, February 2016.
G-CSF and G-CSFR Modulate CD4 and CD8 T Cell Responses to Promote Colon Tumor Growth and Are Potential Therapeutic Targets.
Karagiannidis Ioannis,Jerman Stephanie J,Jacenik Damian,Phinney Brandon B,Yao Ruoxin,Prossnitz Eric R,Beswick Ellen J
Frontiers in immunology
Cytokines are known to shape the tumor microenvironment and although progress has been made in understanding their role in carcinogenesis, much remains to learn regarding their role in tumor growth and progression. We have identified granulocyte colony-stimulating factor (G-CSF) as one such cytokine, showing that G-CSF is linked with metastasis in human gastrointestinal tumors and neutralizing G-CSF in a mouse model of colitis-associated cancer is protective. Here, we set out to identify the role of G-CSF and its receptor, G-CSFR, in CD4 and CD8 T cell responses in the tumor microenvironment. MC38 colon cancer cells were injected into WT, G-CSFR mice, or Rag2 mice. Flow cytometry, Real Time PCR and Multiplex cytokine array analysis were used for T cell phenotype analysis. Adoptive transfer of WT or G-CSFR CD4 of CD8 T cells were performed. Mouse tumor size, cytokine expression, T cell phenotype, and cytotoxic activity were analyzed. We established that in G-CSFR mice, tumor growth of MC38 colon cancer cells is significantly decreased. T cell phenotype and cytokine production were also altered, as both and approaches revealed that the G-CSF/G-CSFR stimulate IL-10-producing, FoxP3-expressing CD4 and CD8 T cells, whereas G-CSFR T cells exhibit increased IFNγ and IL-17A production, leading to increased cytotoxic activity in the tumor microenvironment. Furthermore, peritumoral injection of recombinant IFNγ or IL-17A inhibited colon and pancreas tumor growth compared to controls. Taken together, our data reveal an unknown mechanism by which G-CSF, through its receptor G-CSFR, promotes an inhibitory Treg phenotype that limits tumor immune responses and furthermore suggest that targeting this cytokine/receptor axis could represent a novel therapeutic approach for gastrointestinal, and likely other tumors with high expression of these factors.
[Cost-effectiveness of primary prophylaxis with PEG-rhG-CSF in early-stage breast cancer patients receiving chemotherapy in China].
Xia W,Wang S S,Hu H,Zhao F L,Xu F,Hong R X,Jiang K K,Yuan Z Y,Shi Y X,Zhao K,Huang J J,Xue C,Bi X W,Lu Q Y,An X,Zhang J M
Zhonghua zhong liu za zhi [Chinese journal of oncology]
To evaluate the cost effectiveness of primary prophylaxis (PP) with pegylated recombinant human granulocyte colony stimulating factor (PEG-rhG-CSF), PP with recombinant human granulocyte colony stimulating factor (rhG-CSF) and no prophylaxis in women with early-stage breast cancer in China. Two phase Markov models were constructed for a hypothetical cohort of patients aged 45 with stage Ⅱ breast cancer. The first phase modelled costs and outcomes of 4 cycles docetaxel combined with cyclophosphamide [TC×4, febrile neutropenia (FN) risk>20%] chemotherapy, which assumptions based on literature reviews, including FN rates [base-case (deterministic sensitivity analysis range), 0.29 (0.24-0.35)] and related events [FN case-fatality, 3.4 (2.7-4.1)]. Second phase modelled the long term survival which was link with the relative dose intensity (RDI) [mortality hazard ratio () of RDI < 85% vs ≥85%, 1.45 (1.00-2.32)]. Clinical effectiveness, therapeutic costs, and economic utilities were estimated from peer-reviewed publications and expert opinions in case of unavailability of published evidences. Compared to rhG-CSF PP and no prophylaxis, the cost of PEG-rhG-CSF PP increased to 5 208.19 RMB and 5 222.73 RMB, respectively. The quality-adjusted life-years (QALYs) enhanced to 0.066 and 0.297, respectively. Accordingly, the incremental cost effectiveness ratios (ICERs) are 79 146.3 RMB and 17 558.77 RMB per QALY, which were both below the willingness to pay (WTP) threshold of three times GDP per capita (18, 000 RMB) recommended by the WHO. Sensitivity analysis suggested that the more clinically effective the primary prophylaxis with PEG-rhG-CSF is, the more cost-effective primary prophylaxis with PEG-rhG-CSF will be. And the lower the mortality of RDI<85% vs ≥85% is, the more cost-effective primary prophylaxis with PEG-rhG-CSF will be. Although the cost of PP PEG-rhG-CSF is higher, considering the additional benefits, the administrating of PP PEG-rhG-CSF is likely to be a cost-effective alternative to PP rhG-CSF and no prophylaxis in patients with early stage breast cancer whose FN risks are more than 20% in China.
Safety and efficacy of administering reduced doses of pegylated recombinant human granulocyte-colony stimulating factors in patients treated with cisplatin and etoposide for small cell carcinoma: A retrospective study.
Liu Chang,Hao Ying,Wang Lei,Meng Fanlu,Wen Fuyu,Zhong Diansheng
BACKGROUND:The aim of this study was to discuss the safety and efficacy of administering reduced doses (3 mg) of pegylated recombinant human granulocyte-colony stimulating factor (PEG-rhG-CSF) at approximately 24 h or up to three days following treatment with etoposide and cisplatin (EP). METHODS:A total of 104 cycles from 31 patients were divided into a PEG-rhG-CSF prophylaxis group (PP-Group) and a control group (No-PP-Group). The PP-Group received a reduced dose of 3 mg of PEG-rhG-CSF within a minimum of 15 h and a maximum of 72 h following EP chemotherapy, while the rest did not receive any G-CSF prophylaxis (No-PP-Group). For both groups, complete blood counts, incidence of febrile neutropenia (FN), grade III or IV neutropenia, and the use of antibiotics to treat neutropenia were recorded. RESULTS:There was statistically no significant difference in the incidence of FN (0% vs. 1.4%, p = 1), antibiotic use due to neutropenia (0% vs. 2.7%, p = 0.881), estimated lowest mean marginal (EM) platelet (106.56 × 10 /L vs. 127.70 × 10 /L, p = 0.056) and hemoglobin (110.48 g/L vs. 110.14 g/L, p = 0.906) levels between the two groups. However, when compared with the No-PP-group, the white blood cell count in the PP-group was significantly higher (EM means: 4.95 × 10 /L vs. 2.80 × 10 /L, p < 0.01), while the incidence of grade III or IV neutropenia was significantly lower (9.1% vs. 68.1%, p < 0.01). CONCLUSIONS:The administration of a low dose (3 mg) of PEG-rhG-CSF within approximately 24 h or up to three days following EP treatment is safe and effective at reducing the risk of neutropenia. These findings bring a more flexible administration interval between PEG-rhG-CSF and EP treatment.
Pegfilgrastim versus filgrastim after high-dose chemotherapy and autologous peripheral blood stem cell support.
Castagna L,Bramanti S,Levis A,Michieli M G,Anastasia A,Mazza R,Giordano L,Sarina B,Todisco E,Gregorini A I,Santoro A
Annals of oncology : official journal of the European Society for Medical Oncology
BACKGROUND:American Society of Clinical Oncology guidelines recommend the use of growth factor after high-dose chemotherapy (HDC) and peripheral blood stem cell (PBSC) support. This randomized trial aims to demonstrate the noninferiority of pegfilgrastim (PEG) compared with filgrastim (FIL) after HDC. PATIENTS AND METHODS:Eighty patients were assigned to FIL at a daily dose of 5 mug/kg or a single fixed dose of PEG (6 mg) 1 day after PBSC. The primary end point was the duration of neutropenia both in terms of absolute neutrophil count (ANC) <0.5 x 10(9)/l and of days to reach an ANC >0.5 x 10(9)/l. RESULTS:The mean duration of neutropenia was 6 and 6.2 days and the mean time to reach an ANC >0.5 x 10(9)/l was 11.5 and 10.8 in the FIL and PEG group, respectively. No differences were observed in the mean time to reach an ANC >1.0 x 10(9)/l (12.2 versus 12.0 days) in the incidence of fever (62% versus 56%) and of documented infections (31% versus 25%). The mean duration of antibiotic therapy was 5.7 and 4.0 days in FIL and PEG group, respectively. CONCLUSION:PEG is not inferior to FIL in hematological reconstitution and represents an effective alternative after HDC and PBSC.
G-CSF and its receptor in myeloid malignancy.
Beekman Renée,Touw Ivo P
Granulocyte colony-stimulating factor (G-CSF) has been used in the clinic for more than 2 decades to treat congenital and acquired neutropenias and to reduce febrile neutropenia before or during courses of intensive cytoreductive therapy. In addition, healthy stem cell donors receive short-term treatment with G-CSF for mobilization of hematopoietic stem cells. G-CSF has also been applied in priming strategies designed to enhance the sensitivity of leukemia stem cells to cytotoxic agents, in protocols aimed to induce their differentiation and accompanying growth arrest and cell death, and in severe aplastic anemia and myelodysplastic syndrome (MDS) to alleviate anemia. The potential adverse effects of G-CSF administration, particularly the risk of malignant transformation, have fueled ongoing debates, some of which can only be settled in follow-up studies extending over several decades. This specifically applies to children with severe congenital neutropenia who receive lifelong treatment with G-CSF and in which the high susceptibility to develop MDS and acute myeloid leukemia (AML) has now become a major clinical concern. Here, we will highlight some of the controversies and challenges regarding the clinical application of G-CSF and discuss a possible role of G-CSF in malignant transformation, particularly in patients with neutropenia harboring mutations in the gene encoding the G-CSF receptor.
Randomized comparison of pegfilgrastim day 4 versus day 2 for the prevention of chemotherapy-induced leukocytopenia.
Zwick C,Hartmann F,Zeynalova S,Pöschel V,Nickenig C,Reiser M,Lengfelder E,Peter N,Schlimok G,Schubert J,Schmitz N,Loeffler M,Pfreundschuh M,
Annals of oncology : official journal of the European Society for Medical Oncology
BACKGROUND:To study the effects of deferring pegfilgrastim until day 4 on the reduction of chemotherapy-induced leukocytopenia. PATIENTS AND METHODS:Patients of age 61-80 years with aggressive lymphoma were randomly assigned to receive 6 mg pegfilgrastim on day 2 or 4 of a 2-week chemotherapy regimen (R-CHOP-14). RESULTS:Two hundred and ninety-two and 313 chemotherapy cycles were evaluable in 103 patients. Post-nadir pegfilgrastim serum levels were higher after day 4 than after day 2 application. This was associated with an attenuated leukocyte nadir after day 4 pegfilgrastim and there were fewer days with leukocytes <2 × 10(3)/mm(3) compared with day 2 pegfilgrastim. Grade 3 and 4 leukocytopenias (70% versus 43.3%; P < 0.001) and grade 4-only leukocytopenias (47% versus 20.5%; P < 0.001) were more frequent after day 2 pegfilgrastim. There were more chemotherapy cycles with grade 3 and 4 infections after day 2 than day 4 pegfilgrastim (9.4% versus 6.0%; P = 0.118). Interventional antibiotics were given more often after day 2 than after day 4 pegfilgrastim (30.7% versus 21.9% of cycles; P = 0.008). There were five deaths during leukocytopenia after day 2 and none after day 4 pegfilgrastim (P = 0.027). CONCLUSIONS:Administration of pegfilgrastim on day 4 was more effective in reducing severe leukocytopenias and resulted in fewer deaths during leukocytopenia. Pegfilgrastim should be given on day 4 to better exploit its myeloprotective potential.
Testing G-CSF responsiveness predicts the individual susceptibility to infection and consecutive treatment in recipients of high-dose chemotherapy.
Straka Christian,Sandherr Michael,Salwender Hans,Wandt Hannes,Metzner Bernd,Hübel Kai,Silling Gerda,Hentrich Marcus,Franke Daniel,Schwerdtfeger Rainer,Freund Mathias,Sezer Orhan,Giagounidis Alexander,Ehninger Gerhard,Grimminger Wolfgang,Engert Andreas,Schlimok Günter,Scheid Christof,Hellmann Peter,Heinisch Harald,Einsele Hermann,Hinke Axel,Emmerich Bertold
The individual risk of infection and requirements for medical treatment after high-dose chemotherapy have been unpredictable. In this prospective, multicenter, open-label study we investigated the potential of granulocyte colony-stimulating factor (G-CSF) responsiveness as a predictor. A total of 168 patients with multiple myeloma or lymphoma received a single dose of subcutaneous G-CSF (lenograstim, 263 μg) after high-dose chemotherapy. Highly variable leukocyte peaks were measured and grouped as low (quartile 1; leukocytes 100-10 100/μL), medium (quartile 2; leukocytes > 10 100-18 300/μL), and high (quartiles 3/4; leukocytes > 18 300-44 800/μL). G-CSF responsiveness (low vs medium vs high) was inversely correlated with febrile neutropenia (77% vs 60% vs 48%; P = .0037); the rate of infection, including fever of unknown origin (91% vs 67% vs 54%; P < .0001); days with intravenous antibiotics (9 vs 6 vs 5; P < .0001); and antifungal therapy (P = .042). In multivariate analysis, G-CSF responsiveness remained the only factor significantly associated with infection (P = .016). In addition, G-CSF responsiveness was inversely correlated with grade 3/4 oral mucositis (67% vs 33% vs 23%; P < .0001). G-CSF responsiveness appears as a signature of the myeloid marrow reserve predicting defense against neutropenic infection after intensive chemotherapy. This study is registered at http://www.clinicaltrials.gov as NCT01085058.
G-CSF supplementation with chemotherapy can promote revascularization and subsequent tumor regrowth: prevention by a CXCR4 antagonist.
Voloshin Tali,Gingis-Velitski Svetlana,Bril Rotem,Benayoun Liat,Munster Michal,Milsom Chloe,Man Shan,Kerbel Robert S,Shaked Yuval
Recombinant granulocyte colony-stimulating factor (G-CSF) is used to accelerate recovery from chemotherapy-induced myelosuppression. G-CSF has been recently shown to stimulate angiogenesis mediated by several types of bone marrow-derived cell populations. To investigate whether G-CSF may alter tumor response to therapy, we studied Lewis lung and EMT/6 breast carcinomas in mice treated with paclitaxel (PTX) chemotherapy in combination with G-CSF. We compared the results obtained to mice treated with PTX and AMD3100, a small-molecule drug antagonist of CXCR4 which, like G-CSF, can be used to mobilize hematopoietic cells. We show that PTX combined with G-CSF treatment facilitates revascularization, leading to an improvement in blood perfusion in LLC tumors, and a decrease in hypoxia in EMT/6 tumors, thus enhancing tumor growth in comparison to PTX or PTX and AMD3100 therapies. We found that hemangiocytes but not Gr-1(+) CD11b(+) cells colonize EMT/6 tumors after treatment with PTX and G-CSF, but not PTX and AMD3100, and therefore may contribute to angiogenesis. However, increases in hemangiocyte colonization were not observed in LLC PTX and G-CSF-treated tumors, suggesting distinct mechanisms of tumor revascularization after G-CSF. Overall, our observations suggest that despite its known considerable clinical benefits, G-CSF might contribute to tumor revascularization by various mechanisms, and diminish the antitumor activity of chemotherapy, an effect that can be prevented by AMD3100.
Uptake and economic impact of first-cycle colony-stimulating factor use during adjuvant treatment of breast cancer.
Hershman Dawn L,Wilde Elizabeth T,Wright Jason D,Buono Donna L,Kalinsky Kevin,Malin Jennifer L,Neugut Alfred I
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
PURPOSE:In 2002, pegfilgrastim was approved by the US Food and Drug Administration and the benefits of dose-dense breast cancer chemotherapy, especially for hormone receptor (HR) -negative tumors, were reported. We examined first-cycle colony-stimulating factor use (FC-CSF) before and after 2002 and estimated US expenditures for dose-dense chemotherapy. METHODS:We identified patients in Surveillance, Epidemiology, and End Results-Medicare greater than 65 years old with stages I to III breast cancer who had greater than one chemotherapy claim within 6 months of diagnosis(1998 to 2005) and classified patients with an average cycle length less than 21 days as having received dose-dense chemotherapy. The associations of patient, tumor, and physician-related factors with the receipt of any colony-stimulating factor (CSF) and FC-CSF use were analyzed by using generalized estimating equations. CSF costs were estimated for patients who were undergoing dose-dense chemotherapy. RESULTS:Among the 10,773 patients identified, 5,266 patients (48.9%) had a CSF claim. CSF use was stable between 1998 and 2002 and increased from 36.8% to 73.7% between 2002 and 2005, FC-CSF use increased from 13.2% to 67.9%, and pegfilgrastim use increased from 4.1% to 83.6%. In a multivariable analysis, CSF use was associated with age and chemotherapy type and negatively associated with black/Hispanic race, rural residence, and shorter chemotherapy duration. FC-CSF use was associated with high socioeconomic status but not with age or race/ethnicity. The US annual CSF expenditure for women with HR-positive tumors treated with dose-dense chemotherapy is estimated to be $38.8 million. CONCLUSION:A rapid increase in FC-CSF use occurred over a short period of time, which was likely a result of the reported benefits of dose-dense chemotherapy and the ease of pegfilgrastim administration. Because of the increasing evidence that elderly HR-positive patients do not benefit from dose-dense chemotherapy, limiting pegfilgrastim use would combat the increasing costs of cancer care.
Prevention of pegfilgrastim-induced bone pain: a phase III double-blind placebo-controlled randomized clinical trial of the university of rochester cancer center clinical community oncology program research base.
Kirshner Jeffrey J,Heckler Charles E,Janelsins Michelle C,Dakhil Shaker R,Hopkins Judith O,Coles Charlotte,Morrow Gary R
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
PURPOSE:Pegfilgrastim-induced bone pain is a significant clinical problem that may result in discontinuation of pegfilgrastim and lead to less effective chemotherapy dosing. Interventions for pegfilgrastim-induced bone pain are needed. PATIENTS AND METHODS:The University of Rochester Cancer Center Clinical Community Oncology Program Research Base randomly assigned 510 patients at 17 sites to receive either naproxen (500 mg two times per day) or placebo on the day of pegfilgrastim administration, continuing for 5 to 8 days after pegfilgrastim. Patients recorded pain severity (using a scale of 0 to 10) and duration in daily diaries. The primary outcome measure was the area under the curve (AUC) for pain for days 1 through 5. Secondary outcome measures included the identification of risk factors for the development of pain and response to naproxen. RESULTS:Patients' mean age was 55.6 years and 86% were female. Sixty-eight percent of patients had breast cancer and 10% had lung cancer. Pain reached its peak at 3 days for both groups. The mean AUC for pain was 7.71 for the placebo group and 6.04 for the naproxen group (P = .037). Naproxen reduced maximum pain from 3.40 to 2.59 (P = .005). Naproxen also reduced overall pain incidence from 71.3% to 61.1% (P = .020) and duration from 2.40 to 1.92 days (P = .009). The reduction in severe pain (> 5 on a scale of 1 to 10) from 27.0% to 19.2% was also significant (P = .048). Risk factors could not be identified to predict incidence, severity, or ability to prevent pegfilgrastim-induced bone pain. CONCLUSION:Our phase III randomized placebo-controlled clinical trial demonstrated that naproxen at a dose of 500 mg twice per day is effective in reducing the incidence and severity of pegfilgrastim-induced bone pain.
Primary granulocyte colony-stimulating factor prophylaxis during the first two cycles only or throughout all chemotherapy cycles in patients with breast cancer at risk for febrile neutropenia.
Aarts Maureen J,Peters Frank P,Mandigers Caroline M,Dercksen M Wouter,Stouthard Jacqueline M,Nortier Hans J,van Laarhoven Hanneke W,van Warmerdam Laurence J,van de Wouw Agnes J,Jacobs Esther M,Mattijssen Vera,van der Rijt Carin C,Smilde Tineke J,van der Velden Annette W,Temizkan Mehmet,Batman Erdogan,Muller Erik W,van Gastel Saskia M,Borm George F,Tjan-Heijnen Vivianne C G
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
PURPOSE:Early breast cancer is commonly treated with anthracyclines and taxanes. However, combining these drugs increases the risk of myelotoxicity and may require granulocyte colony-stimulating factor (G-CSF) support. The highest incidence of febrile neutropenia (FN) and largest benefit of G-CSF during the first cycles of chemotherapy lead to questions about the effectiveness of continued use of G-CSF throughout later cycles of chemotherapy. PATIENTS AND METHODS:In a multicenter study, patients with breast cancer who were considered fit enough to receive 3-weekly polychemotherapy, but also had > 20% risk for FN, were randomly assigned to primary G-CSF prophylaxis during the first two chemotherapy cycles only (experimental arm) or to primary G-CSF prophylaxis throughout all chemotherapy cycles (standard arm). The noninferiority hypothesis was that the incidence of FN would be maximally 7.5% higher in the experimental compared with the standard arm. RESULTS:After inclusion of 167 eligible patients, the independent data monitoring committee advised premature study closure. Of 84 patients randomly assigned to G-CSF throughout all chemotherapy cycles, eight (10%) experienced an episode of FN. In contrast, of 83 patients randomly assigned to G-CSF during the first two cycles only, 30 (36%) had an FN episode (95% CI, 0.13 to 0.54), with a peak incidence of 24% in the third cycle (ie, first cycle without G-CSF prophylaxis). CONCLUSION:In patients with early breast cancer at high risk for FN, continued use of primary G-CSF prophylaxis during all chemotherapy cycles is of clinical relevance and thus cannot be abandoned.
Prophylaxis of infectious complications with colony-stimulating factors in adult cancer patients undergoing chemotherapy-evidence-based guidelines from the Infectious Diseases Working Party AGIHO of the German Society for Haematology and Medical Oncology (DGHO).
Vehreschild J J,Böhme A,Cornely O A,Kahl C,Karthaus M,Kreuzer K-A,Maschmeyer G,Mousset S,Ossendorf V,Penack O,Vehreschild M J G T,Bohlius J
Annals of oncology : official journal of the European Society for Medical Oncology
BACKGROUND:Current evidence on myelopoietic growth factors is difficult to overview for the practicing haematologist/oncologist. International guidelines are sometimes conflicting, exclude certain patient groups, or cannot directly be applied to the German health system. This guideline by the Infectious Diseases Working Party (AGIHO) of the German Society of Haematology and Medical Oncology (DGHO) gives evidence-based recommendations for the use of G-CSF, pegylated G-CSF, and biosimilars to prevent infectious complications in cancer patients undergoing chemotherapy, including those with haematological malignancies. METHODS:We systematically searched and evaluated current evidence. An expert panel discussed the results and recommendations. We then compared our recommendations to current international guidelines. RESULTS:We summarised the data from eligible studies in evidence tables, developed recommendations for different entities and risk groups. CONCLUSION:Comprehensive literature search and expert panel consensus confirmed many key recommendations given by international guidelines. Evidence for growth factors during acute myeloid leukaemia induction chemotherapy and pegfilgrastim use in haematological malignancies was rated lower compared with other guidelines.
Cost effectiveness of primary pegfilgrastim prophylaxis in patients with breast cancer at risk of febrile neutropenia.
Aarts Maureen J,Grutters Janneke P,Peters Frank P,Mandigers Caroline M,Dercksen M Wouter,Stouthard Jacqueline M,Nortier Hans J,van Laarhoven Hanneke W,van Warmerdam Laurence J,van de Wouw Agnes J,Jacobs Esther M,Mattijssen Vera,van der Rijt Carin C,Smilde Tineke J,van der Velden Annette W,Temizkan Mehmet,Batman Erdogan,Muller Erik W,van Gastel Saskia M,Joore Manuela A,Borm George F,Tjan-Heijnen Vivianne C
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
PURPOSE:Guidelines advise primary granulocyte colony-stimulating factor (G-CSF) prophylaxis during chemotherapy if risk of febrile neutropenia (FN) is more than 20%, but this comes with considerable costs. We investigated the incremental costs and effects between two treatment strategies of primary pegfilgrastim prophylaxis. METHODS:Our economic evaluation used a health care perspective and was based on a randomized study in patients with breast cancer with increased risk of FN, comparing primary G-CSF prophylaxis throughout all chemotherapy cycles (G-CSF 1-6 cycles) with prophylaxis during the first two cycles only (G-CSF 1-2 cycles). Primary outcome was cost effectiveness expressed as costs per patient with episodes of FN prevented. RESULTS:The incidence of FN increased from 10% in the G-CSF 1 to 6 cycles study arm (eight of 84 patients) to 36% in the G-CSF 1 to 2 cycles study arm (30 of 83 patients), whereas the mean total costs decreased from € 20,658 (95% CI, € 20,049 to € 21,247) to € 17,168 (95% CI € 16,239 to € 18,029) per patient, respectively. Chemotherapy and G-CSF determined 80% of the total costs. As expected, FN-related costs were higher in the G-CSF 1 to 2 cycles arm. The incremental cost effectiveness ratio for the G-CSF 1 to 6 cycles arm compared with the G-CSF 1 to 2 cycles arm was € 13,112 per patient with episodes of FN prevented. CONCLUSION:We conclude that G-CSF prophylaxis throughout all chemotherapy cycles is more effective, but more costly, compared with prophylaxis limited to the first two cycles. Whether G-CSF prophylaxis throughout all chemotherapy cycles is considered cost effective depends on the willingness to pay per patient with episodes of FN prevented.
The effect of filgrastim or pegfilgrastim on survival outcomes of patients with cancer receiving myelosuppressive chemotherapy.
Lyman G H,Reiner M,Morrow P K,Crawford J
Annals of oncology : official journal of the European Society for Medical Oncology
BACKGROUND:Primary prophylaxis with granulocyte colony-stimulating factor (G-CSF) is associated with higher chemotherapy relative dose intensity, which may lead to improved outcomes; however, the association between G-CSF primary prophylaxis and overall survival (OS) is not well characterized. This study assessed the effect of G-CSF primary prophylaxis on patient outcomes in randomized, controlled, registrational clinical trials of filgrastim and pegfilgrastim. PATIENTS AND METHODS:Three placebo-controlled and two non-inferiority clinical trials of filgrastim and/or pegfilgrastim in patients receiving myelosuppressive chemotherapy for lung, breast, or colorectal cancer were included. The median OS, 6- and 12-month survival rates, and hazard ratios [HRs; unadjusted Cox model with 95% confidence intervals (CIs)] were estimated for patients receiving ≥1 dose of filgrastim, pegfilgrastim, or placebo. Comparisons were based on a log-rank test. A fixed-effect meta-analysis assessed the effect of primary prophylaxis with filgrastim/pegfilgrastim on OS in the placebo-controlled trials. RESULTS:In patients with lung cancer receiving filgrastim versus placebo, the median OS was 14.1 versus 11.1 months (HR, 0.81; 95% CI 0.48-1.35; P = 0.412); in patients who crossed over to filgrastim from placebo after cycle 1, the median OS was 16.9 months (HR, 0.75; 95% CI 0.43-1.28; P = 0.286). The median OS was inestimable in at least one treatment arm in the other studies because of the small number of OS events. Where estimable, 6- and 12-month survival rates were generally greater among patients receiving filgrastim/pegfilgrastim versus placebo. In the meta-analysis of placebo-controlled studies comparing G-CSF primary prophylaxis with placebo in the as-treated analysis sets, the HR (95% CI) for OS was 0.77 (0.58-1.03). CONCLUSIONS:In this retrospective analysis, OS point estimates were greater among patients receiving filgrastim versus placebo, but the differences were not statistically significant. Further studies evaluating patient outcomes with G-CSF prophylaxis are warranted. CLINICAL TRIAL REGISTRATION:NCT00035594, NCT00094809.
Optimal use of recombinant granulocyte colony-stimulating factor with chemotherapy for solid tumors.
Danova Marco,Barni Sandro,Del Mastro Lucia,Danesi Romano,Pappagallo Giovanni L
Expert review of anticancer therapy
Neutropenia is a frequent complication of anticancer chemotherapy (CT) often associated with life-threatening infections, hospitalization, dose reduction and/or delay in the administration of CT. Administration of recombinant granulocyte colony-stimulating factor (rG-CSF) reduces the duration and the degree of CT-neutropenia. rG-CSF that stimulates both neutropoiesis and neutrophil function, has become an integral part of supportive care during cytotoxic CT, to prevent febrile neutropenia (FN), particularly in patients with a risk of FN ≥ 20%. International guidelines have standardized conditions for rG-CSF administration, however, some 'gray zones' still exist around optimal timing and tailoring of this therapy. We report here the results of a research project aimed to extend the consensus on the optimal use of rG-CSF in association with CT in patient with solid tumours. We also propose a recently developed pharmacodynamic model, based on the biological effects of CT and rG -CSF on bone marrow compartments that clearly indicates within the prophylactic rather than therapeutic setting the better way of rG-CSF administration.
Recombinant human granulocyte colony-stimulating factor in the management of cancer patients: five years on.
Bronchud M H
Recombinant human granulocyte colony-stimulating factor (G-CSF) has been used worldwide in cancer patients for over 1 year, and (only 5 years from the first publication on the clinical use of this growth factor) experience is rapidly accumulating in many oncological situations. Several randomized studies have confirmed its value in allowing the optimal delivery of chemotherapy without undue dose reductions or dose delays, while at the same time reducing the overall risks of febrile neutropenia associated with the use of cytotoxic chemotherapy. Its virtual lack of significant side effects, its selectivity of action, its rapid effect on neutrophil kinetics (reducing both the maturation and release times of bone marrow neutrophils to 1-2 days rather than the normal 4-5 days), and the reproducible augmentation of neutrophil production in several neoplastic and nonneoplastic situations, as well as the activation of myeloid cell functions, have made G-CSF the growth factor of choice in most cancer units. Some of the published information regarding its current and potential use in the management of oncological patients is summarized here.
Therapy for neutropenia in hairy cell leukemia with recombinant human granulocyte colony-stimulating factor.
Glaspy J A,Baldwin G C,Robertson P A,Souza L,Vincent M,Ambersley J,Golde D W
Annals of internal medicine
STUDY OBJECTIVE:To determine whether recombinant human granulocyte colony-stimulating factor (G-CSF) is effective in increasing neutrophil counts in patients with hairy cell leukemia and neutropenia. DESIGN:Open label, phase I/II study of G-CSF, given by daily subcutaneous injection for up to 7 weeks. SETTING:Outpatient oncology clinic of a university medical center. PATIENTS:A consecutive sample of four patients with hairy cell leukemia complicated by severe neutropenia. Three patients completed the study; one patient was removed after 2 weeks of therapy. INTERVENTIONS:Granulocyte colony-stimulating factor was given by daily subcutaneous injection. Each patient began therapy with 1 microgram/kg body weight.d; after 1 week the dose was increased to 3 micrograms/kg.d, and 1 week later to 6 micrograms/kg.d. Therapy was continued for 5 to 6 weeks. Patients were taught self-injection, and administered treatment at home. MEASUREMENTS AND MAIN RESULTS:In three patients, an increase in absolute neutrophil counts from less than 0.9 X 10(9)/L to greater than 4.0 X 10(9)/L was noted within 2 weeks of beginning G-CSF therapy. In two patients, infections resolved during therapy. One patient developed acute neutrophilic dermatosis (the Sweet syndrome) while receiving 3 micrograms/kg.d of G-CSF, and drug therapy was discontinued. CONCLUSIONS:Granulocyte colony-stimulating factor may increase neutrophil counts within 2 weeks in patients with hairy cell leukemia and neutropenia. This therapy may be a useful adjunct to definitive treatment of hairy cell leukemia with interferon or pentostatin.
Recombinant human granulocyte-macrophage colony-stimulating factor in patients with advanced malignancy: a phase Ib trial.
Steis R G,VanderMolen L A,Longo D L,Clark J W,Smith J W,Kopp W C,Ruscetti F W,Creekmore S P,Elwood L J,Hursey J
Journal of the National Cancer Institute
We evaluated the toxic, hematopoietic, and immunomodulatory effects of recombinant human granulocyte-macrophage colony-stimulating factor (rHuGM-CSF). The rHuGM-CSF was administered at doses up to 50 micrograms/kg by daily 2-hour intravenous infusions to 11 patients with advanced malignancy. It induced dose-related increases in cells of the myeloid series, but it had no significant effect on reticulocyte or platelet counts. Bone marrow cellularity increased with higher doses of rHuGM-CSF, but there was a dose-related decrease in the number of colony-forming units--granulocyte-monocyte--and colony-forming units--granulocyte-erythrocyte-monocyte-megakaryocyte--per 10(5) bone marrow cells. The rHuGM-CSF caused transient increased expression of CD11b and CD16 on granulocytes but increased expression of HLA-DR and decreased expression of the high-affinity Fc receptor on monocytes and no change in monocyte production of H2O2. Thus, rHuGM-CSF has potent effects on granulocyte, eosinophil, and monocyte numbers in the peripheral blood and bone marrow. In addition, it enhances the expression of monocyte and granulocyte activation-associated surface markers.
Weekly CODE chemotherapy with recombinant human granulocyte colony-stimulating factor for relapsed or refractory small cell lung cancer.
Sato K,Tsuchiya S,Minato K,Sunaga N,Ishihara S I,Makimoto T,Naruse I,Hoshino H,Watanabe S,Saitoh R,Mori M
We used cisplatin, vincristine, doxorubicin, and etoposide (CODE) plus recombinant human granulocyte colony-stimulating factor (rhG-CSF) weekly for salvage chemotherapy in relapsed or refractory small cell lung cancer (SCLC). We reviewed the medical charts of patients between January 1993 and December 1996 at the National Nishi-Gunma Hospital. Twenty patients were treated with salvage chemotherapy. The overall response rate was 55.0%. The median survival time of extensive disease patients from the start of CODE therapy was 23 weeks and the 1-year survival rate was 21.0%. Toxicities were severe, especially in myelosuppression. CODE could be selected as a salvage therapy for chemotherapy- relapsed SCLC cases.
Biological Effects of Anti-Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) Antibody Formation in Patients Treated With GM-CSF (Sargramostim) as Adjuvant Therapy of Melanoma.
Spitler Lynn E,Cao Huynh,Piironen Timo,Whiteside Theresa L,Weber Robert W,Cruickshank Scott
American journal of clinical oncology
OBJECTIVES:We investigated the development of binding and neutralizing antibodies to granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients receiving prolonged therapy with GM-CSF as adjuvant therapy of melanoma and the impact of these antibodies on biological effects. METHODS:Fifty-three patients with high-risk melanoma that had been surgically excised were treated with GM-CSF, 125 μg/m daily for 14 days every 28 days for 1 year after surgical resection of disease. Serum samples for antibodies to GM-CSF were measured before treatment and on study days 155 and 351. Blood draws for testing biological effects were keyed to GM-CSF administration: days 0 (before), 15 (after 14 d on GM-CSF), 29 (after 14 d off GM-CSF), 155, and 351 (after 14 d on GM-CSF in the sixth and 13th cycle of treatment). RESULTS:Of 53 patients enrolled, 43 were evaluable for the development of anti-GM-CSF antibodies. Of these, 93% developed binding antibodies and 42% developed both binding and neutralizing antibodies. The increase in the white blood cell count, percent eosinophils, or neopterin levels engendered by GM-CSF administration was abrogated or markedly decreased in patients with neutralizing antibodies but not in patients who developed only binding antibodies. CONCLUSIONS:Ninety-three percent of patients with melanoma treated with GM-CSF as adjuvant therapy develop antibodies to GM-CSF. In those with neutralizing antibodies, a diminution of the biological effects of GM-CSF was observed. The development of neutralizing antibodies might also abrogate the potential clinical benefit of this treatment and should be considered in the design of future clinical trials.
Effects of recombinant human granulocyte colony-stimulating factor (filgrastim) on ECG parameters in neutropenic patients: a single-centre, prospective study.
Guneysel Ozlem,Onur Ozge Ecmel,Denizbasi Arzu
Clinical drug investigation
BACKGROUND AND OBJECTIVE:Human granulocyte colony-stimulating factor (G-CSF) is a haematopoietic hormone that promotes the growth, proliferation, differentiation and maturation of neutrophil precursors. Filgrastim is a recombinant human G-CSF. Myocardial infarction, atrial fibrillation and arrhythmia have been reported in several patients with malignancy receiving filgrastim, but a causal relationship with the drug has not been established. The purpose of this study was to investigate the changes in ECG parameters in neutropenic patients during treatment with filgrastim. METHODS:This was a single-centre, prospective study carried out in a hospital emergency room. Patients with neutropenia and malignancy who were required to receive filgrastim were eligible for the study. After a reference ECG had been obtained, filgrastim was administered to all patients at a dose of 5 microg/kg/day subcutaneously for 2 days. Follow-up ECGs were then obtained at 12-hourly intervals. Continuous telemetric monitoring was conducted throughout hospitalization. RESULTS:Serial ECG parameters were compared in 102 patients. There were no statistically significant differences between baseline and follow-up ECG measurements of rhythm, P-wave duration, PR interval, QRS-wave duration, corrected QT (QTc) interval, ECG axis, premature supraventricular events, ventricular arrhythmia, R-wave progression, right bundle branch block or left bundle branch block. There was a significant reduction in mean heart rate in subsequent ECGs compared with baseline (p < 0.05). CONCLUSION:This study did not demonstrate any ECG changes other than a significant reduction in mean heart rate in this selected population of neutropenic patients given 2 days' treatment with subcutaneous 5 microg/kg/day of filgrastim.
Reduction of Inappropriate Prophylactic Pegylated Granulocyte Colony-Stimulating Factor Use for Patients With Non-Small-Cell Lung Cancer Who Receive Chemotherapy: An ASCO Quality Training Program Project of the Cleveland Clinic Taussig Cancer Institute.
Goodman Lindsey Martin,Moeller Machelle B,Azzouqa Abdel-Ghani,Guthrie Amy E,Dalby Carole K,Earl Marc A,Cheng Connie,Pennell Nathan A,Shapiro Marc,Velcheti Vamsidhar,Stevenson James P
Journal of oncology practice
PURPOSE:Routine prophylactic pegylated granulocyte colony-stimulating factor (pGCSF) administration for patients receiving chemotherapy regimens associated with low risk (< 10%) for neutropenic fever (LRNF) is not recommended. Inappropriate use of pGCSF increases patient morbidity and health care costs. METHODS:A multidisciplinary team reviewed the charts of patients with non-small-cell lung cancer (NSCLC) at the Taussig Cancer Institute in whom a new chemotherapy regimen was initiated from April through November 2013. pGCSF use was identified and deemed appropriate if prescribed for chemotherapy associated with high risk of neutropenic fever (> 20%) or intermediate risk (10% to 20%) if other risk factors for neutropenic fever were present. Use with LRNF chemotherapy was recorded as inappropriate. RESULTS:One hundred eighty patients with NSCLC received a new chemotherapy regimen during the specified time period. Thirty-four of 119 patients (28%) treated with LRNF chemotherapy received pGCSF. Each patient received an average of 2.6 doses of pGCSF (total, 89 doses). We implemented three plan-do-study-act cycles: education of providers, development of Taussig Cancer Institute consensus guidelines for pGCSF in NSCLC, and removal of standing pGCSF orders from LRNF chemotherapy in the electronic medical record. Analysis during the change period revealed 4% of patients with NSCLC treated with LRNF chemotherapy received pGCSF. Cost analysis showed an 84% decrease in billed charges per month. No increase in neutropenic fever admissions was found. CONCLUSION:pGCSF was excessively prescribed for patients with NSCLC. Factors contributing to inappropriate use included provider lack of familiarity with guidelines and knowledge with regard to the risk of neutropenic fever for individual chemotherapy regimens, and electronic medical record chemotherapy templates that contain standing GCSF orders. Interventions to address these gaps quickly produced improved compliance with guidelines and led to significant cost savings.
Contribution of glycosylated recombinant human granulocyte colony-stimulating factor (lenograstim) use in current cancer treatment: review of clinical data.
Gunzer Katharina,Clarisse Bénédicte,Lheureux Stéphanie,Delcambre Corinne,Joly Florence
Expert opinion on biological therapy
IMPORTANCE OF THE FIELD:Granulocyte colony-stimulating factors (G-CSFs) such as lenograstim have improved the management of cancer patient treatments for 15 years. Their use in preventing chemotherapy-induced febrile neutropenia and for progenitor-cell transplantation has been evaluated. Although the main indications are nowadays defined in academic guidelines, some changes in traditional G-CSF use are being induced by the emergence of new chemotherapy schedules and new drugs. AREAS COVERED IN THIS REVIEW:Analyzing publications on G-CSFs and lenograstim identified in the PubMed database from 1985 to date, we summarise pharmacological data and clinical trials on lenograstim and discuss its effects and limits in current treatment regimens. WHAT THE READER WILL GAIN:Lenograstim is a glycosylated form of recombinant human G-CSF, more similar to the endogenous cytokine. Clinical trials have proven its efficacy for preventing chemotherapy-induced neutropenia and for progenitor-cell transplantation, almost similar to filgrastim. Its benefit is compelling in some well-defined settings (highly myelosuppressive chemotherapy, advanced cancer, high-risk patients). TAKE HOME MESSAGE:If usual indications are well defined nowadays, further investigations are still needed to better define optimal use (optimal time to start, treatment duration) and effects on quality of life. In addition, since new strategies for cancer management are emerging, such as oral chemotherapy or targeted therapies, there is a need for clinical data to define lenograstim use in these recent settings.
Characterization of granulocyte colony stimulating factor for in vitro induction of regulatory T cells for cellular immune intervention in transplant medicine.
Lammers Stefanie Schulze,Ukena Sya N,Velaga Sarvari,Franzke Anke
Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation
OBJECTIVES:The application of regulatory T cells in the field of solid-organ and hematopoietic stem cell transplantation is under investigation to develop novel cellular strategies for tolerance induction. Establishing in vitro procedures to induce and expand regulatory T cells seeks to overcome the limiting small number of this rare T cell population. The present study is based on growing evidence that granulocyte colony stimulating factor exerts immune regulatory function in the adaptive immune system and may induce regulatory T cells in vivo. MATERIALS AND METHODS:We analyzed the effect of recombinant granulocyte colony stimulating factor to directly convert CD4+CD25- T cells into regulatory T cells in vitro. Marker molecules were analyzed by quantitative reverse transcriptase-polymerase chain reaction and fluorescent-activated cell sorter analyses. Functional assays were performed to investigate the suppressive capacity of granulocyte colony stimulating factor stimulated T cells. RESULTS:Kinetic analyses of Foxp3 gene expression uncovered increased levels early after in vitro stimulation with granulocyte colony stimulating factor. However, protein analyses for the master transcription factor Foxp3 and other regulatory T cells revealed that granulocyte colony stimulating factor did not directly induce a regulatory T cell phenotype. Moreover, functional analyses demonstrated that granulocyte colony stimulating factor stimulation in vitro does not result in a suppressive, immune regulatory T cell population. CONCLUSIONS:Granulocyte colony stimulating factor does not induce regulatory T cells with a specific phenotype and suppressive potency in vitro. Therefore, granulocyte colony stimulating factor does not qualify for developing protocols aimed at higher regulatory T cell numbers for adoptive transfer strategies in solid organ and hematopoietic stem cell transplantation.
A phase I study of different doses and frequencies of pegylated recombinant human granulocyte-colony stimulating factor (PEG rhG-CSF) in patients with standard-dose chemotherapy-induced neutropenia.
Qin Yan,Han Xiaohong,Wang Lin,Du Ping,Yao Jiarui,Wu Di,Song Yuanyuan,Zhang Shuxiang,Tang Le,Shi Yuankai
Chinese journal of cancer research = Chung-kuo yen cheng yen chiu
OBJECTIVE:The recommended dose of prophylactic pegylated recombinant human granulocyte-colony stimulating factor (PEG rhG-CSF) is 100 μg/kg once per cycle for patients receiving intense-dose chemotherapy. However, few data are available on the proper dose for patients receiving less-intense chemotherapy. The aim of this phase I study is to explore the proper dose and administration schedule of PEG rhG-CSF for patients receiving standard-dose chemotherapy. METHODS:Eligible patients received 3-cycle chemotherapy every 3 weeks. No PEG rhG-CSF was given in the first cycle. Patients experienced grade 3 or 4 neutropenia would then enter the cycle 2 and 3. In cycle 2, patients received a single subcutaneous injection of prophylactic PEG rhG-CSF on d 3, and received half-dose subcutaneous injection in cycle 3 on d 3 and d 5, respectively. Escalating doses (30, 60, 100 and 200 μg/kg) of PEG rhG-CSF were investigated. RESULTS:A total of 26 patients were enrolled and received chemotherapy, in which 24 and 18 patients entered cycle 2 and cycle 3 treatment, respectively. In cycle 2, the incidence of grade 3 or 4 neutropenia for patients receiving single-dose PEG rhG-CSF of 30, 60, 100 and 200 μg/kg was 66.67%, 33.33%, 22.22% and 0, respectively, with a median duration less than 1 (0-2) d. No grade 3 or higher neutropenia was noted in cycle 3 in all dose cohorts. CONCLUSIONS:The pharmacokinetic and pharmacodynamic profiles of PEG rhG-CSF used in cancer patients were similar to those reported, as well as the safety. Double half dose administration model showed better efficacy result than a single dose model in terms of grade 3 neutropenia and above. The single dose of 60 μg/kg, 100 μg/kg and double half dose of 30 μg/kg were recommended to the phase II study, hoping to find a preferable method for neutropenia treatment.
Recombinant granulocyte colony-stimulating factor (rG-CSF) in the management of neutropenia induced by anthracyclines and ifosfamide in patients with soft tissue sarcomas (NEUSAR).
Bongiovanni Alberto,Monti Manuela,Foca Flavia,Recine Federica,Riva Nada,Di Iorio Valentina,Liverani Chiara,De Vita Alessandro,Miserocchi Giacomo,Mercatali Laura,Amadori Dino,Ibrahim Toni
Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer
PURPOSE:Anthracycline and ifosfamide-based chemotherapy represents a widely used regimen both in early and advanced settings in soft tissue sarcoma (STS). Prophylaxis with granulocyte colony-stimulating factor (G-CSF) reduces the severity of chemotherapy-induced neutropenia. The aim of this study was to assess the efficacy and safety of biosimilar G-CSF in these patients. METHODS:Between 2003 and 2013, 67 patients with soft tissue tumors under epirubicin and ifosfamide (EI) treatment receiving biosimilar filgrastim (Zarzio®), originator filgrastim (Granulokine®, Neupogen®), and lenograstim (only originator Myelostim®) as primary prophylaxis for a total of 260 cycles of therapy were retrospectively analyzed. Baseline patient characteristics were summarized in a propensity score (PS). RESULTS:The incidence of febrile neutropenia (FN) was 44.0 % in biosimilar filgrastim, 40.0 % in originator filgrastim, and 45.5 % in the lenograstim groups (p = 0.935). All grade and G4 neutropenia were similar in the three groups with the same safety profile. The use of biosimilar filgrastim achieved cost savings of €225.25 over originator filgrastim and €262.00 over lenograstim. CONCLUSION:Biosimilar G-CSF was effective in preventing FN and in reducing the need for hospitalization in STS patients undergoing EI treatment. It also proved comparable to its reference products from both a clinical and cost-effective standpoint.
Clinical safety of tbo-filgrastim, a short-acting human granulocyte colony-stimulating factor.
Pettengell Ruth,Bias Peter,Mueller Udo,Lang Nicole
Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer
The recombinant human granulocyte colony-stimulating factor (G-CSF) known as filgrastim (Tevagrastim(®), Ratiograstim(®), Biograstim(®)) in Europe (approved in 2008) and tbo-filgrastim (Granix(®)) in the USA (approved in 2012; Teva Pharmaceutical Industries Ltd., Petach Tikva, Israel) is indicated to reduce the duration of severe neutropenia in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia. This article presents pooled clinical data for tbo-filgrastim compared with Neupogen(®) (Amgen, Thousand Oaks, CA, USA) as well as tbo-filgrastim post-marketing safety data. The safety and efficacy of tbo-filgrastim were evaluated in three phase III studies in 677 patients receiving myelosuppressive chemotherapy and study drug (348 patients with breast cancer, 237 with lung cancer, 92 with non-Hodgkin lymphoma). In each study, the efficacy of tbo-filgrastim was similar to that of Neupogen. Overall, 633 (93.5 %) patients receiving the study drug experienced 6093 treatment-emergent adverse events (AEs), most of which were related to chemotherapy. Adverse events related to the study drug (tbo-filgrastim or Neupogen) were experienced by 185 (27.3 %) patients; 19 (2.8 %) had severe drug-related AEs, 5 (0.7 %) had drug-related serious AEs, and 6 (0.9 %) discontinued the study due to drug-related AEs. Overall, the most common drug-related AEs were bone pain (7.1 %), myalgia (4.0 %), and asthenia (4.4 %). The post-marketing safety profile of tbo-filgrastim was consistent with that observed during the clinical studies. The availability of tbo-filgrastim, a G-CSF with safety and efficacy comparable to those of Neupogen, provides physicians with an alternative treatment option for supportive care of patients with non-myeloid malignancies receiving myelosuppressive chemotherapy.
Severe Drug-Induced Agranulocytosis Successfully Treated with Recombinant Human Granulocyte Colony-Stimulating Factor.
Kubota Yohei,Toh Yoon Ezekiel Wong
Case reports in medicine
When elderly patients are prescribed many different medications, the risk for developing serious adverse events should be kept in mind. One of these adverse events is agranulocytosis, which, although rare, can be life-threatening if left untreated. The majority of agranulocytosis cases are caused by drugs, including antibiotics. Here, we report a case of severe agranulocytosis in a 96-year-old woman following antibiotic therapy which was successfully managed using recombinant human granulocyte colony-stimulating factor (rhG-CSF) and the appropriate choice of antibiotics to treat her concomitant infection.
Clinical significance of primary prophylactic pegylated-granulocyte-colony stimulating factor after the administration of ramucirumab plus docetaxel in patients with previously treated non-small cell lung cancer.
Mouri Atsuto,Kaira Kyoichi,Shiono Ayako,Yamaguchi Ou,Murayama Yoshitake,Kobayashi Kunihiko,Kagamu Hiroshi
Whether primary prophylactic pegylated-granulocyte-colony stimulating factor (PEG-G-CSF) should be administered immediately after the initiation of ramucirumab plus docetaxel (DR) to prevent the occurrence of febrile neutropenia (FN) is unclear. Our retrospective study aimed to elucidate whether PEG-G-CSF could control the occurrence of FN as a result of DR in patients with previously treated non-small-cell lung cancer. Thirty-three patients with previously treated non-small-cell lung cancer who had received DR were eligible for our analysis. Of the 33 patients, 29 received prophylactic PEG-G-CSF immediately after DR, but none developed FN. However, FN was observed in 2 (50%) of the 4 patients that were not administered PEG-CSF. The overall response and disease control rates in the 29 patients with prophylactic PEG-GSF were 31% and 62%, respectively. The median progression-free and overall survival rates of the patients with and without prophylactic PEG-GSF were 177 and 163 days (P = 0.20), and 628 and 274 days (P = 0.13), respectively. Primary prophylactic PEG-G-CSF suppressed the occurrence of FN secondary to the administration of DR.
Clinical observation of the therapeutic effects of pegylated recombinant human granulocyte colony-stimulating factor in patients with concurrent chemoradiotherapy-induced grade IV neutropenia.
Wu Feng-Peng,Wang Jun,Wang Hui,Li Na,Guo Yin,Cheng Yun-Jie,Liu Qing,Yang Xiang-Ran
Experimental and therapeutic medicine
The aim of the present study was to investigate the efficacy and side-effects of preventive treatment with pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) on concurrent chemoradiotherapy-induced grade IV neutropenia and to provide a rational basis for its clinical application. A total of 114 patients with concurrent chemoradiotherapy-induced grade IV neutropenia were enrolled. A randomized approach was used to divide the patients into an experimental group and a control group. The experimental group included three subgroups, namely a P-50 group, P-100 group and P + R group. The P-50 group had 42 cases, which were given a single 50-μg/kg subcutaneous injection of PEG-rhG-CSF. The P-100 group had 30 cases, which received a single 100-μg/kg subcutaneous injection of PEG-rhG-CSF. The P + R group comprised 22 cases, which were given a single 50-μg/kg subcutaneous injection of PEG-rhG-CSF and rhG-CSF 5 μg/kg/day; when the absolute neutrophil count (ANC) was ≥2.0×10/l, the administration of rhG-CSF was stopped. The control group (RC group) comprised 20 patients, who received rhG-CSF 5 μg/kg/day by subcutaneous injection until the ANC was ≥2.0×10/l. Changes in the neutrophil proliferation rate and ANC values over time, the neutropenic symptom remission time and incidence of adverse drug reactions were analyzed statistically in each group of patients. In the experimental group, the neutrophil proliferation rate and ANC values were significantly higher than those in the control group; the clinical effects began 12-24 h after treatment in the experimental group, and indicated that the treatment improved neutropenia in ~48 h after treatment. There was no significant difference in the neutrophil proliferation rate and ANC values between the P-50 and P+R groups. In the experimental group, the remission time of neutropenia-induced fever and muscle pain after administration was significantly shorter than that in the control group, with a statistically significant difference (P<0.05). The adverse drug reaction rates showed no significant difference between the experimental group and the control group. PEG-rhG-CSF had good efficacy and safety in the treatment of concurrent chemotherapy-induced grade IV neutropenia. For the treatment of concurrent chemotherapy-induced grade IV neutropenia, a single subcutaneous injection of 50 μg/kg PEG-rhG-CSF is the recommended dose. The effects begin at 12-24 h; if the ANC values are not significantly improved during this time, no supplementary administration of rhG-CSF is necessary.
An assessment of the pharmacokinetics, pharmacodynamics, and tolerability of GCPGC, a novel pegylated granulocyte colony-stimulating factor (G-CSF), in healthy subjects.
Shin Kwang-Hee,Lim Kyoung Soo,Lee Howard,Jang In-Jin,Yu Kyung-Sang
Investigational new drugs
INTRODUCTION:A pegylated recombinant human granulocyte colony-stimulating factor (G-CSF) is effective in reducing the severity and duration of neutropenia. This study was performed to investigate the pharmacokinetics (PK), pharmacodynamics (PD), and tolerability of GCPGC, a new formulation of pegylated G-CSF, in healthy volunteers and to compare them with those of pegfilgrastim (Neulasta®). METHODS:Twenty-five healthy Korean male volunteers randomly received a single subcutaneous (SC) GCPGC injection at a dose of 30 (n = 10), 100 (n = 10), or 300 (n = 5) μg/kg or placebo in a 4:1 ratio in a double-blind manner. Additionally, 8 subjects received a SC dose of pegfilgrastim at 100 μg/kg. Blood samples were collected up to 14 days after both therapies. The absolute neutrophil count (ANC) and CD34(+) cell counts were the PD markers. RESULTS:After GCPGC administration, 4 different pharmacokinetic phases were identified, indicating target-mediated drug disposition (TMDD) for the elimination of GCPGC, which was slowed down as the dose was increased, resulting in a higher than proportional dose-normalized exposure to GCPGC. Although GCPGC was cleared faster than pegfilgrastim, leading to a 19 % lower systemic exposure to pegylated G-CSF, the increase in ANC and CD34(+) were ~20 % greater by GCPGC at 100 μg/kg than pegfilgrastim. Thrombocytopenia, splenomegaly, and hemoperitoneum occurred in one subject in the 300 μg/kg GCPGC group, which resolved completely with appropriate care. CONCLUSIONS:GCPGC showed a non-linear TMDD. The PK-PD characteristics of GCPGC at 30-100 μg/kg were comparable to those of pegfilgrastim at 100 μg/kg. GCPGC at 30-100 μg/kg was well tolerated in healthy Korean males.
Use of recombinant human granulocyte colony-stimulating factor prior to autologous bone marrow transplantation in dogs with lymphoma.
Lane Amy E,Chan Marisa J Y,Wyatt Kenneth M
American journal of veterinary research
OBJECTIVE:To retrospectively assess the safety and efficacy of recombinant human granulocyte colony-stimulating factor (G-CSF) used as part of autologous bone marrow transplantation in dogs with lymphoma. ANIMALS:21 dogs with lymphoma at any disease stage. PROCEDURES:Medical records of dogs with lymphoma that underwent intensified chemotherapy and received an autologous bone marrow transplant following owner administration of recombinant human G-CSF (5 μg/kg, SC, q 12 h) for 7 days between January 2007 and July 2009 were reviewed. Results of physical examinations and CBCs performed before and at intervals during a 24-month period after G-CSF treatment were assessed. The safety of recombinant human G-CSF administration was determined via assessment of both short-term (ie, during the 7-day G-CSF treatment period) and long-term adverse effects. RESULTS:None of the dogs developed any adverse effect attributable to the administration of recombinant human G-CSF during G-CSF administration or during follow-up periods of 1 month to 2 years (median follow-up period, 4 months). Among the 18 dogs for which CBC results were available for analysis, mean circulating neutrophil count significantly increased after administration of recombinant human G-CSF, compared with value before treatment. CONCLUSIONS AND CLINICAL RELEVANCE- Results indicated that recombinant human G-CSF administered SC at a dosage of 5 μg/kg every 12 hours for 7 days appeared to be safe and effective when used in dogs with lymphoma that were undergoing autologous bone marrow transplant.
Safety of polyethylene glycol recombinant human granulocyte colony-stimulating factor in treating non-small cell lung cancer patients at I b stage.
Yan Bo,Zhang Wei,Lu Fang,Chen Zhong-Lin,Han Bao-Hui,Jiang Li-Yan
Asian Pacific journal of tropical medicine
OBJECTIVE:To investigate resistance and safety of HHPG-19K in treating non-small cell lung cancer patients. METHODS:A total of 30 cases were selected and randomly divided into 5 groups: three HHPG-19K groups of different dosage (60 μg/kg/day, 100 μg/kg/day, 200 μg/kg/day), positive control group (Filgrastim, namely G-CSF5 μg/kg/day) and negative control group. Safety indexes of 5 groups were observed and compared. RESULTS:All patients had adverse event (100%) in three HHPG-19K groups, and increased ALP, ALT and AST were main events. The degree was mild to moderate. There was no significant difference in the incidence of adverse event between dosage groups and positive control group no difference. But the incidence of negative control group was 13%, which was significantly lower than dosage groups and positive control group. CONCLUSIONS:non-small cell lung cancer patients have satisfactory tolerance to HHPG-19K, and have no resistance. Besides, dosage at 100 μ g/kg is the most safe.
Myeloid-derived suppressor cells (MDSCs) in patients with solid tumors: considerations for granulocyte colony-stimulating factor treatment.
Pilatova Katerina,Bencsikova Beatrix,Demlova Regina,Valik Dalibor,Zdrazilova-Dubska Lenka
Cancer immunology, immunotherapy : CII
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.
Clinical study on safety and efficacy of JiSaiXin (recombinant human granulocyte colony stimulating factor injection manufactured in China) for Chinese undergoing chemotherapy.
Wang Lin,Huang Xin-En
Asian Pacific journal of cancer prevention : APJCP
OBJECTIVES:To assess safety and efficacy of JiSaiXin (Recombinant Human Granulocyte Colony Stimulating Factor Injection manufactured in China, G-CSF) 150ug per day for three days and whether this regimen could reduce the incidence of febrile neutropenia caused by chemotherapy. METHOD:From July 2014 to December 2014 patients treated by chemotherapy in our hospital were randomly divided into two groups: Group A with prophylactic use of G-CSF (JiSaiXin) 24 hours after chemotherapy for consecutive 3 days; and Group B with G-CSF (JiSaiXin) after neutropenia. Routine blood tests were performed 7 days and 14 days after chemotherapy. RESULTS:A total of 100 patients fulfilled study criteria, and the incidence of severe neutropenia (grade III/IV) and the incidence of febrile neutropenia in Group A were lower than those in Group B. Nine patients were found severe neutropenia (grade III/IV) in Group B, but one in Group A, three febrile neutropenia in Group B, but 0 in Group A. CONCLUSIONS:This study suggested that prophylactic use of G-CSF (JiSaiXin) 150ug per day 24 hours after chemotherapy for consecutive 3 days is safe and could be effective for preventing febrile neutropenia in patients with chemotherapy.
A Phase I study to determine safety, pharmacokinetics, and pharmacodynamics of ANF-RHO™, a novel PEGylated granulocyte colony-stimulating factor, in healthy volunteers.
Misra Hemant,Berryman John,Jubin Ronald,Abuchowski Abraham
Investigational new drugs
Patients receiving pegfilgrastim (Neulasta®) for the treatment of neutropenia can experience bone pain following the injections required to achieve effective neutrophil levels. The safety, pharmacokinetic (PK), and pharmacodynamic (PD) profiles of ANF-RHO™, a novel pegylated granulocyte colony stimulating factor, were assessed in a randomized, controlled, double-blind Phase 1 clinical study in healthy volunteers. Subjects received a single subcutaneous dose of ANF-RHO over a range of 6 doses (5-50 μg/kg), placebo (saline), or the recommended clinical dose of pegfilgrastim administered at the labeled fixed 6 mg dosage (equivalent to 80-100 μg/kg). The primary outcome measure was safety and tolerability. Secondary outcomes included PK and PD effects on absolute neutrophil count (ANC) and number of CD34+ progenitor cells. Severity of bone pain was also assessed. In healthy volunteers, ANF-RHO was administered at ascending doses up to 50 μg/kg without significant adverse effects; appeared to be better (5 to 30 μg/kg) or equally well (50 μg/kg) tolerated, and had lower mean bone pain scores as compared to pegfilgrastim. ANF-RHO achieved CD34+ and ANC numbers at significantly lower doses, and had a significantly longer circulating half-life than pegfilgrastim. These results suggest that ANF-RHO can be provided less frequently, at a lower dose, and with fewer side effects. ANF-RHO had unique, prolonged PK/PD attributes as compared to marketed pegfilgrastim, suggesting that it may provide an improved clinical benefit in further clinical studies in patients with chemotherapy-induced or chronic idiopathic neutropenia.
A clinical study of polyethylene glycol recombinant human granulocyte colony-stimulating factor prevention neutropenia syndrome in patients with esophageal carcinoma and lung cancer after concurrent chemoradiotherapy.
Liu Fang,Du Yu,Cai Boning,Yan Maohui,Yang Wei,Wang Qianqian
Journal of cancer research and therapeutics
OBJECTIVE:To compare the efficacy and safety of PEG-rhG-CSF and recombinant human G-CSF (rhG-CSF) for the prevention and delayed application in febrile neutropenia, hospitalization rate in concurrent chemoradiotherapy of tumors. METHODS:A total of 163 patients, who received concurrent chemoradiotherapy for solid tumors. There were 75 patients in the PEG-rhG-CSF group (PEG group), who received 146 cycles of concurrent chemoradiotherapy, of which 132 cycles (90.42%) were prophylactic therapy, while 9 cycles (6.16%) were delayed therapy. There were 88 patients in the rhG-CSF group (rhG group), who received 164 cycles of concurrent chemoradiotherapy, of which 48 cycles (29.3%) were prophylactic, while 116 cycles (70.7%) were delayed therapy. G-CSF was used for prophylaxis in 180 cycles of chemotherapy, with delayed use in 130 cycles. RESULTS:Comparison between the prevention group and the delayed group showed that the incidence of neutropenia-related hospitalization was 4.44% and 14.62%, respectively (OR = 0.272, 95% CI, 0.115-0.642) (P = 0.002). Intravenous antibiotics usage was 2.78% vs. 11.54%, (OR = 0.004, 95% CI, 0.077-0.619) (P = 0.004). Dose reduction of chemotherapy or delay was 5% vs. 17.69% (OR = 0.245, 95% CI, 0.109-0.549) (P = 0.001). The prevention group had protective effects from all factors as compared to the delayed group (all P < 0.05, and all OR < 1). Moreover, the protective role of intravenous antibiotics was the strongest in the prevention group. CONCLUSION:Prophylactic use of GSF reduced hospitalization rate and the rate of intravenous application of antibiotics.
In vivo pharmacokinetics and pharmacodynamics of positional isomers of mono-PEGylated recombinant human granulocyte colony stimulating factor in rats.
Kang Jung Seok,Lee Kang Choon
Biological & pharmaceutical bulletin
In this study, the pharmacokinetic and pharmacodynamic properties of Lys(35), Met(N-terminal), and Lys(17)-mono-PEGylated recombinant human granulocyte colony stimulating factor (rhG-CSF) positional isomers were evaluated in rats. The in vitro biological activities of Lys(35), Met(N-terminal), and Lys(17)-mono-PEGylated rhG-CSF were determined by examining NFS-60 cell proliferation. Plasma concentrations of rhG-CSF and white blood cell (WBC) counts and absolute neutrophil conunt (ANC) were measured and pharmacokinetic and pharmacodynamic properties were determined after a single subcutaneous administration of the Lys(35), Met(N-terminal), or Lys(17) isomers at 0.1 mg/kg in rats. The in vitro biological activities of Lys(35), Met(N-terminal), and Lys(17)-mono-PEGylated rhG-CSF individual positional isomers were 20.1%, 37.4%, and 15.3%, respectively, that of rhG-CSF. However, all three mono-PEGylated rhG-CSF isomers had a greater blood half-life (T1/2) and in vivo efficacy as determined by WBC counts and ANC than rhG-CSF, but no significant difference was observed between the three isomers. In conclusion, Lys(35), Met(N-terminal), and Lys(17)-mono-PEGylated rhG-CSF individual positional isomers exhibit an enhanced the in vivo pharmacokinetics and pharmacodynamics. Furthermore, three isomers have comparable in vivo pharmacokinetic and pharmacodynamic properties, but their in vitro biological activities are PEGylation site dependent.
[Clinical observation of the salvage therapy using pegylated recombinant human granulocyte colony stimulating factor for grade IV neutropenia induced by concurrent chemoradiotherapy].
Wu Fengpeng,Wang Hui,Li Na,Guo Yin,Cheng Yunjie,Liu Qing,Yang Xiangran,Wan Xin,Wang Jun
Zhonghua zhong liu za zhi [Chinese journal of oncology]
OBJECTIVE:To investigate the efficacy and safety of pegylated recombinant human granulocyte colony stimulating factor (PEG-rhG-CSF) in the salvage therapy for the grade IV neutropenia induced by concurrent chemoradiotherapy, and to provide evidence for its clinical rational application. METHODS:114 malignant tumor patients suffered with grade IV neutropenia induced by concurrent chemoradiotherapy were treated in the following groups. In the P-50 group, 42 patients received a single subcutaneous injection of 50 µg/kg PEG-rhG-CSF. In the P-100 group, 30 patients received a single subcutaneous injection of 100 µg/kg PEG-rhG-CSF. In the P+R group, 22 patients received a single subcutaneous injection of 50 µg/kg PEG-rhG-CSF and multiple subcutaneous injections of 5 µg×kg(-1)×d(-1) rhG-CSF, until the absolute neutrophil count (ANC) ≥ 2.0×10(9)/L. In the R group, 20 patients received multiple subcutaneous injections of 5 µg×kg(-1)×d(-1) rhG-CSF, until ANC ≥ 2.0×10(9)/L. The P-50, P-100 and P+R groups were experimental groups, and the R group was defined as control group. In each group, the neutrophil proliferation rate and the neutrophil counts at different time points, the period of neutropenia symptom relief, and the rate of adverse reactions induced by above drugs were analyzed. RESULTS:Both neutrophil proliferation rates and neutrophil counts in the patients of experimental groups at different time points were significantly higher than those in the control group. In the experimental groups the period of the clinical effect began in 12-24 hours, and the conditions of neutropenia were improved in 36 hours. In the experimental groups, the period of the symptom relief such as fever and skeletal muscle pain was (30.00 ± 7.48) hours and (30.00 ± 5.10) hours, respectively, significantly shorter than (72.00 ± 17.89) hours and (59.00 ± 11.46) hours in the control group (P < 0.05). The adverse drug reaction rate was 26.1% in the experimental groups and 25.0% in the control group (P > 0.05). CONCLUSIONS:For the treatment of grade IV neutropenia induced by concurrent chemoradiotherapy, PEG-rhG-CSF is effective and safe. The recommend dose of this drug for the salvage therapy for those patients is a single hypodermal injection of 50 µg/kg. Usually it becomes effective in 12-24 hours.
[A Case of Aortitis Caused by a Granulocyte-Colony-Stimulating Factor during Chemotherapy for Pancreatic Cancer].
Miyazaki Kento,Takadate Tatsuyuki,Motoi Fuyuhiko,Kamei Takashi,Naitoh Takeshi,Unno Michiaki
Gan to kagaku ryoho. Cancer & chemotherapy
BACKGROUND:Pegfilgrastim, a long-acting granulocyte-colony-stimulating factor(G-CSF), has been used as prophylaxis for severe hematotoxicity induced by chemotherapy. We report a case of aortitis induced by pegfilgrastim administration during modified FOLFIRINOX(mFOLFIRINOX)chemotherapy for metastatic pancreatic cancer. CASE REPORT:A 65-year-old woman underwent a distal pancreatectomy for pancreatic tail cancer. Liver metastases appeared 2 years after the surgery. mFOLFIRINOX chemotherapy was started with prophylactic administration of pegfilgrastim. Eight days after the first administration and 6 days after administration of the 8th course, the patient developed a fever. The blood test results indicated severe inflammation. Computed tomography revealed a thickened aorta indicating aortitis. The symptoms rapidly improved with antibiotic therapy. We diagnosed aortitis induced by pegfilgrastim administration. CONCLUSION:Aortitis should be considered when a patient has unidentified inflammatory findings after receiving pegfilgrastim.
Real-world safety experience of tevagrastim/ratiograstim/biograstim and tbo-filgrastim, short-acting recombinant human granulocyte colony-stimulating factors.
Abboud Camille N,Lang Nicole,Fung Henry,Lammerich Andreas,Buchner Anton,Liu Patrick,Mueller Udo,Pettengell Ruth,Diel Ingo J,Link Hartmut,Pathak Ashutosh
Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer
PURPOSE:Recombinant granulocyte colony-stimulating factors (rG-CSFs), such as filgrastim, are administered to prevent complications in patients receiving chemotherapy. In Europe, a biosimilar to filgrastim, tevagrastim/ratiograstim/biograstim, was approved in 2008. In the USA, the same product was approved as tbo-filgrastim under a 351(a) biologic license application in 2012 with the brand name Granix®. Postmarket surveillance remains a priority for monitoring the safety of biologics and biosimilars to identify rare and immunogenicity-related events. We report the global and US pharmacovigilance data for tevagrastim/ratiograstim/biograstim and tbo-filgrastim, respectively. METHODS:Cumulative exposure and adverse event data from initial approval in Europe to December 31, 2016, were collected globally from spontaneous reports submitted by healthcare professionals and consumers, scientific literature, competent authorities, and solicited case reports from non-interventional studies. A separate search was conducted on the global data set to identify reports originating from the USA and Puerto Rico to describe the US experience. RESULTS:Overall, the global safety profile of tevagrastim/ratiograstim/biograstim in the postmarket, real-world setting was comparable to clinical trial experience. Postmarket safety experience of tbo-filgrastim in the USA was consistent with global data. The most common SAEs were febrile neutropenia and decreased white blood cell count. The most common non-serious event was bone pain. There was no evidence of immunogenicity. CONCLUSIONS:This pharmacovigilance analysis indicates that postmarket experience of tevagrastim/ratiograstim/biograstim and tbo-filgrastim is consistent with clinical trials. Adverse reactions associated with the originator rG-CSF (capillary leak syndrome and glomerulonephritis) have not been observed with tevagrastim/ratiograstim/biograstim or tbo-filgrastim during the postmarket period.
Pegylated recombinant human granulocyte colony-stimulating factor regulates the immune status of patients with small cell lung cancer.
Sun Jing,Bai Hua,Wang Zhijie,Duan Jianchun,Li Jin,Guo Ruimin,Wang Jie
BACKGROUND:Small cell lung cancer (SCLC) is an aggressive disease involving immunodeficiency for which chemotherapy is the standard treatment. Pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) is widely used for primary or secondary prophylaxis of febrile neutropenia (FN) in chemotherapy. However, whether PEG-rhG-CSF influences immune cells, such as lymphocytes, remains unclear. METHODS:A total of 17 treatment-naïve SCLC patients were prospectively enrolled and divided into the PEG-rhG-CSF and control groups according to their FN risk. Longitudinal sampling of peripheral blood was performed before, after and 4-6 days after the first cycle of chemotherapy. Flow cytometry was used to assess lymphocyte subsets, including CD3 T, CD4 T, CD8 T, NK, and B cells. The diversity and clonality of the T-cell receptor (TCR) repertoire was analyzed by next-generation sequencing. RESULTS:In the PEG-rhG-CSF group, the proportions of CD3 T and CD4 T cells had increased significantly (P = 0.002, P = 0.020, respectively), whereas there was no increase in CD8 T cells. Further, TCR diversity increased (P = 0.009) and clonality decreased (P = 0.004) significantly after PEG-rhG-CSF treatment. However, these factors showed opposite trends before and after chemotherapy. Vβ and Jβ gene fragment types, which determine TCR diversity, were significantly amplified in the PEG-rhG-CSF group. The change in TCR diversity was significantly correlated with changes in the CD3 T or CD4 T cell proportions, but not the CD8 T cell proportion. CONCLUSIONS:PEG-rhG-CSF regulates the immune status of SCLC patients; CD4 T cells may be the main effector cells involved in this process. These findings may optimize the treatment of SCLC. KEY POINTS:PEG-rhG-CSF regulates SCLC immunity. PEG-rhG-CSF increased CD3 T and CD4 T cell proportions. PEG-rhG-CSF increased TCR diversity and decreased clonality in peripheral blood. Change in TCR diversity were correlated with CD3 T or CD4 T changes.
The safety and clinical efficacy of recombinant human granulocyte colony stimulating factor injection for colon cancer patients undergoing chemotherapy.
Chen Jie,Pan Yin
Revista da Associacao Medica Brasileira (1992)
OBJECTIVE:The present study was designed to evaluate safety and efficacy of recombinant human granulocyte colony stimulating factor (G-CSF) injection and whether this regimen could reduce the incidence of adverse events caused by chemotherapy. METHOD:A total of 100 patients with colon cancer who were treated with chemotherapy in our hospital from January 2011 to December 2014 were randomly divided into two groups, with 50 patients in each group. The patients in the treatment group received G-CSF 24 hours after chemotherapy for consecutive three days; the patients in the control group received the same dose of normal saline. Routine blood tests were performed 7 days and 14 days after chemotherapy. RESULTS:Compared with the control group, the incidences of febrile neutropenia and leukocytopenia in the treatment group were significantly lower (p<0.05). In addition, the incidence of liver dysfunction in the treatment group was lower than that of the control group, without statistical significance. The incidence of myalgia in the treatment was higher than that of the control group without statistical significance. CONCLUSION:The present study indicated that G-CSF injection after chemotherapy is safe and effective for preventing adverse events in colon cancer patients with chemotherapy.
[Application of pegylated recombinant human granulocyte colony-stimulating factor to prevent chemotherapy-induced neutropenia in patients with lymphoma: a prospective, multicenter, open-label clinical trial].
Huang H Q,Bai B,Gao Y H,Zou D H,Zou S H,Tan H,Song Y P,Li Z Y,Jin J,Li W,Su H,Gong Y P,Zhong M Z,Shuang Y R,Zhu J,Zhang J Q,Cai Z,Teng Q L,Sun W J,Yang Y,Xia Z J,Chen H L,Hua L M,Bao Y Y,Wu N
Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi
To evaluate the efficacy and safety of pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) in prophylaxis neutropenia after chemotherapy in patients with lymphoma. This was a multicenter, single arm, open, phase Ⅳ clinical trial. Included 410 patients with lymphoma received multiple cycles of chemotherapy and PEG-rhG-CSF was administrated as prophylactic. The primary endpoint was the incidence of Ⅲ/Ⅳ grade neutropenia and febrile neutropenia (FN) after each chemotherapy cycle. Meanwhile the rate of antibiotics application during the whole period of chemotherapy was observed. ①Among the 410 patients, 8 cases (1.95%) were contrary to the selected criteria, 35 cases (8.54%) lost, 19 cases (4.63%) experienced adverse events, 12 cases (2.93%) were eligible for the termination criteria, 15 cases (3.66%) develpoed disease progression or recurrence, thus the rest 321 cases (78.29%) were into the Per Protocol Set. ②During the first to fourth treatment cycles, the incidences of grade Ⅳ neutropenia after prophylactic use of PEG-rhG-CSF were 19.14% (49/256) , 12.5% (32/256) , 12.18% (24/197) , 13.61% (20/147) , respectively. The incidences of FN were 3.52% (9/256) , 0.39% (1/256) , 2.54% (5/197) , 2.04% (3/147) , respectively. After secondary prophylactic use of PEG-rhG-CSF, the incidences of Ⅳ grade neutropenia decreased from 61.54% (40/65) in the screening cycle to 16.92% (11/65) , 18.46% (12/65) and 20.75% (11/53) in 1-3 cycles, respectively. The incidences of FN decreased from 16.92% (11/65) in the screening cycle to 1.54% (1/65) , 4.62% (3/65) , 3.77% (2/53) in 1-3 cycles, respectively. ③The proportion of patients who received antibiotic therapy during the whole period of chemotherapy was 34.39% (141/410) . ④The incidence of adverse events associated with PEG-rhG-CSF was 4.63% (19/410) . The most common adverse events were bone pain[3.90% (16/410) ], fatigue (0.49%) and fever (0.24%) . During the chemotherapy in patients with lymphoma, the prophylactic use of PEG-rhG-CSF could effectively reduce the incidences of grade Ⅲ/Ⅳ neutropenia and FN, which ensures that patients with lymphoma receive standard-dose chemotherapy to improve its cure rate.
The effects of recombinant human granulocyte colony-stimulating factor mouthwash on radiotherapy-induced oral mucositis in locally advanced nasopharyngeal carcinoma patients.
Liang Gai,Du Wei,Ke Qinghua,Huang Bing,Yang Jiyuan
Advances in clinical and experimental medicine : official organ Wroclaw Medical University
BACKGROUND:Acute oral mucositis is a common complication of radiotherapy for nasopharyngeal carcinoma (NPC) patients. OBJECTIVES:The aim of the study was to observe the effects of recombinant human granulocyte colony-stimulating factor (rhG-CSF) on radiotherapy-induced oral mucositis in locally advanced NPC patients. MATERIAL AND METHODS:The study involved 64 locally advanced NPC patients that were randomly allocated to receive either rhG-CSF mouthwash (2 μg/mL rhG-CSF; group A, n = 34) or a compounded mouth rinse (10 μg/mL vitamin B12, 0.48 mg/mL gentamicin and 0.04 mg/mL dexamethasone in saline; group B, n = 30) during radiotherapy. Both mouthwashes were used 6 times daily at the onset of oral mucositis, and the treatments continued until the end of all intensity-modulated radiotherapy sessions. Oral mucositis was graded according to the Radiation Therapy Oncology Group acute radiation morbidity scoring criteria. A visual analog scale was used to assess peak mouth pain once a week, and the duration of oral mucositis was recorded. RESULTS:In comparison with group B, the patients in group A had a significantly lower incidence of oral mucositis of grade 3 or above (38.2% vs 66.7%, p < 0.05) and less peak mucosal pain in the 5th, 6th and 7th weeks of radiotherapy (p < 0.05). group A patients also had shorter durations of oral mucositis (35.1 days vs 39.4 days, p < 0.05) and lower peak swallowing function scores (p < 0.05). CONCLUSIONS:The rhG-CSF mouthwash may be more effective than the compounded mouth rinse in preventing and treating radiotherapy-induced mucositis and mucositis-related pain, and thus improving the quality of life for locally advanced NPC patients. These effects should be further investigated in a prospective controlled study.
[Comparative study on the efficacy and safety between pegfilgrastim (PEG-rhG-CSF) and recombinant human granulocyte colony-stimulating factor in promoting hematopoietic recovery after allogeneic hematopoietic stem cell transplantation after hematological malignancy].
Yang F,Sun X D,Yuan L,Zhang J C,Hu J W,Liu N,Lou X,Su Y F,Yu Z Y,Chen J L,Li Y H,Hu L D,Chen H,Jiang M
Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi
To observe the efficacy and safety between Pegfilgrastim (PEG-rhG-CSF) and Recombinant human granulocyte colony stimulating factor (rhG-CSF) in hematological malignancy after allogeneic hematopoietic stem cell transplantation (allo-HSCT) . 157 patients after allo-HSCT were enrolled in this study from June 2015 to November 2016. Two agents of G-CSF were used to stimulate hematopoietic recovery after transplantation. There were 65 cases in PEG-rhG-CSF and 92 cases in rhG-CSF groups. Patients in PEG-rhG-CSF group were given a single subcutaneous dose of 6 mg on the first day and +8 d, while cases in rhG-CSF group were given in dose of 5 μg·kg(-1)·d(-1) by subcutaneous injection from +1 d continuing to neutrophils more than 1.5×10(9)/L, and then the indicators and survival rates in two groups after transplantation were compared. ①There were no significant differences of the neutrophil implantation time[13.5 (8-12) d 13 (9-24) d, =0.393] and platelet implantation time [14 (9-160) d 14 (9-92) d, =0.094] between PEG-rhG-CSF and rhG-CSF groups respectively. There were no significant differences in terms of neutropenia period (=0.435) , number of cases who got fever during neutropenia (=0.622) , and the median time of fever in neutropenia period (=0.460) , respectively between the two groups. There were no significant differences of erythrocyte and platelet transfusions (=0.074, =0.059) within 1 month after transplantation. ②There were no significant differences with regard to the incidences of acute GVHD[23.1% (15/65) 34.8% (32/92) , =0.115], chronic GVHD[20.0% (13/65) 32.6% (32/92) , =0.081], Ⅱ-Ⅳdegree of acute GVHD[30.0% (13/65) 30.4% (30/92) , =0.287] and extensive chronic GVHD[9.2% (6/65) 20.7% (19/92) , =0.135] between PEG-rhG-CSF and rhG-CSF groups. ③There were no significant differences in terms of disease free survival (DFS) (62.5% 61.4%, =0.478) and overall survival (OS) (67.4% 67.3%, =0.718) between PEG-rhG-CSF and rhG-CSF groups. ④There was no significant difference of the non-relapse mortality (NRM) between PEG-rhG-CSF and rhG-CSF groups[20.5% (95% 11.4%-37.0%) 32.6% (95% 22.2%-47.9%) , =0.141]. The relapse rate was not statistically significant[14.9% (95% 7.4%-29.8%) 10.0% (95% 5.0%-20.0%) , =0.299]. Compared with rhG-CSF, PEG-rhG-CSF could reduce the times of injection. There were no differences in terms of hematopoietic recovery, the incidence of GVHD, relapse rate, DFS and OS rates after allo-HSCT between two groups.
Pharmacokinetics and Pharmacodynamics of Two Formulations of Pegylated Recombinant Human Granulocyte Colony-Stimulating Factor in Healthy Chinese Subjects: An Open-Label, Randomized, Parallel-Design Bioavailability Study.
Hu Chaoying,Ji Bingxin,Hu Xiao,Yang Cuicui,Sun Wanling,Zhao Xiaowei,Li Lin,Li Xiaoying,Zhang Lan
Clinical pharmacology in drug development
Pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF, pegfilgrastim) is a long-acting derivative of recombinant human granulocyte colony-stimulating factor with limited renal clearance and a longer half-life. It is used for the prevention of febrile neutropenia, owing to its capacity to promote neutrophil recovery. In this study, the pharmacokinetics, pharmacodynamics, safety, and immunogenicity of 2 formulations of PEG-rhG-CSF were evaluated in healthy Chinese subjects. Twenty-four male subjects who received a single dose of subcutaneous PEG-rhG-CSF 100 µg/kg were randomized to either treatment A (3 mg/mL) or treatment B (1 mg/mL). Noncompartmental pharmacokinetic parameters of PEG-rhG-CSF were derived from serum concentration-time data. In addition, absolute neutrophil count (ANC) as a pharmacodynamic maker, immunogenicity through antidrug antibody testing, and safety were evaluated. The mean area under the concentration-time curve from time zero to the last quantifiable concentration (AUC ) and the mean maximum concentration (C ) of PEG-rhG-CSF after treatment A were 5070 ng·h/mL and 125 ng/mL, respectively; these values were comparable to those measured after treatment B (5340 ng·h/mL and 123 ng/mL, respectively). The mean value of area under the △ANC (baseline-adjusted ANC)-time curve and the maximum △ANC values were 4380 × 10 h/L and 33.1 × 10 /L, respectively, in the treatment A group, and 5170 × 10 h/L and 38.6 × 10 /L, respectively, in the treatment B group. The pharmacokinetic and pharmacodynamic profiles were similar for the 2 PEG-rhG-CSF formulations following a single dose of 100 µg/kg. The safety and immunogenicity profiles were also similar, with no significant differences. The dose adjustment of PEG-rhG-CSF was not considered necessary for formulation transformation.
[The role of prophylactic use of pegylated recombinant human granulocyte colony-stimulating factor(PEG-rhG-CSF) in breast cancer receiving adjuvant chemotherapy].
Zhang J Y,Liu Y X,Wang H,Mi L,Song G H,Jiang H F,Yan Y,Shao B,Kong W Y,Zhang R Y,Ran R,Liu X R,Wang J,Lin Y T,Li H P
Zhonghua yi xue za zhi
To investigate the efficacy and safety of prophylactic use of pegylated recombinant human granulocyte colony-stimulating factor(PEG-rhG-CSF) in breast cancer receiving docetaxel as adjuvant chemotherapy. A total of 58 patients with breast cancer receiving adjuvant chemotherapy with docetaxel were included between January 2014 to October 2017. Prophylactic use of PEG-rhG-CSF was administered.Patients were further divided into two groups according to the frequency of PEG-rhG-CSF use: frequent use group (≥3 cycles) and non-frequent use group (<3 cycles). There were significant differences in the incidence rates of grade 3/4 neutropenia between the prophylactic group and non-prophylactic group in cycle 1-3(<0.05). Less febrile neutropenia (FN) was also noted in the prophylactic group compared with the non-prophylactic group in cycle 1 and cycle 3 (<0.05). Grade 3/4 neutropenia and FN were less in the frequent use of group compared with the non-frequent use group(<0.001). The most common side effects of PEG-rhG-CSF included fatigue (10.2%), bone joint pain(50.8%), and 2 patients (3.4%) refused further treatment because of bone joint pain. PEG-rhG-CSF should be prophylactically used for preventing neutropenia and febrile neutropenia in breast cancer patients receiving adjuvant chemotherapy with docetaxel regimen.
Recombinant human granulocyte macrophage colony stimulating factor (hGM-CSF): Possibility of nanoparticle-mediated delivery in cancer immunotherapy.
Vanitha Selvarajan,Chaubey Nidhi,Ghosh Siddhartha S,Sanpui Pallab
Most of the cancer treatment strategies from chemotherapy to radiotherapy render cancer cells apoptotic and these apoptotic cancer cells accumulate at the tumor sites. The accumulation of apoptotic cancer cells often result in inflammation and autoimmune responses causing serious health implications. Macrophages, which are effective immune combatants, can help in the clearance of these deleterious occupants. Granulocyte macrophage colony stimulating factor (GM-CSF) is a key cytokine, modulator of immune system and responsible for growth and differentiation of granulocytes and macrophages. In this regard, supply of recombinant GM-CSF can enhance the capability of macrophages for clearance of apoptotic cancer cells. However, delivery of the cytokine in vivo can suffer from certain disadvantages like faster depletion, less stability and low targeting efficiency. We believe that the stability and sustained release of GM-CSF can be improved through its encapsulation inside appropriately designed nanoparticles.
Randomized controlled clinical trial of polyethylene glycol recombinant human granulocyte colony-stimulating factor in the treatment of neutropenia after chemotherapy for breast cancer.
Huang Weiwei,Liu Jian,Zeng Yi,Wu Fan,Li Nani,Chen Kan,Hong Yi,Wang LiLi,Zhen Hongyu,Lin Lin
Cancer chemotherapy and pharmacology
PURPOSE:To explore the efficacy and safety of daily administration of recombinant human granulocyte colony-stimulating factor (rhG-CSF), and a single subcutaneous injection of polyethylene glycol recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF, a sustained-duration rhG-CSF) in neutropenia induced after chemotherapy. METHODS:Each patient received two cycles of chemotherapy. In the trial cycle, the patients received a single subcutaneous injection of PEG-rhG-CSF 100 µg/kg 72 h after completion of chemotherapy; and in the control cycle, rhG-CSF 5 µg/kg/day was subcutaneous injected once a day which began 72 h after completion of chemotherapy for continued 14 days or until the absolute neutrophil count (ANC) was ≥ 10.0 × 10/l twice. Therapeutic effect on primary endpoint was the incidence and duration of grade IV ANC neutropenia: comparing the incidence and the mean time of duration of PEG-rhG-CSF with those of rhG-CSF under the circumstance of ANC < 0.5 × 109/l. The immune populations evaluated included, CD3+ T cells, CD4+ T cells, CD8+ T cells, and NK cells. RESULTS:After chemotherapy, comparing to PEG-rhG-CSF, the CD4/CD8 ratio (0.84 ± 0.19 vs.1.06 ± 0.25) and the number of NK cells of rhG-CSF group (12.18 ± 2.13 vs. 15.78 ± 2.57) decreased significantly. The number of NK cells (12.18 ± 2.13 vs. 13.78 ± 2.57) of rhG-CSF group after chemotherapy is significantly less than that before chemotherapy, and the number of CD3+ (54.31 ± 7.51 vs. 57.96 ± 5.55), CD4+ (26.28 ± 6.25 vs. 29.48 ± 6.44), CD8+ (29.97 ± 6.47 vs. 31.68 ± 5.96) is lower than that before chemotherapy in rhG-CSF group, but the difference is not significant. CONCLUSION:The efficacy and side effects of a single subcutaneous injection of PEG-rhG-CSF were similar to that of rhG-CSF multiple administrations. PEG-rhG-CSF may have the effect of promoting immune function repairing.
Randomized phase III intergroup trial of etoposide and cisplatin with or without paclitaxel and granulocyte colony-stimulating factor in patients with extensive-stage small-cell lung cancer: Cancer and Leukemia Group B Trial 9732.
Niell Harvey B,Herndon James E,Miller Antonius A,Watson Dorothy M,Sandler Alan B,Kelly Karen,Marks Randolph S,Perry Micheal C,Ansari Rafat H,Otterson Grefory,Ellerton John,Vokes Everett E,Green Mark R,
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
PURPOSE:To determine, in a randomized comparison, whether the addition of paclitaxel to etoposide and cisplatin improves the time to progression and overall survival in patients with extensive small-cell lung cancer (SCLC) compared with standard etoposide and cisplatin and to compare the regimens' toxicity. PATIENTS AND METHODS:Eligible patients (N=587) with untreated extensive SCLC were randomly assigned to receive either cisplatin 80 mg/m2 on day 1 and etoposide 80 mg/m2 on days 1 through 3 administered every 3 weeks for six cycles (EP) or cisplatin 80 mg/m2 on day 1, paclitaxel 175 mg/m2 over 4 hours on day 1, and etoposide 80 mg/m2 on days 1 to 3 followed by recombinant human granulocyte colony-stimulating factor on days 4 to 18 administered every 3 weeks for six cycles (PET). RESULTS:Reporting of demographics, response, and survival included 565 patients, of whom 282 were randomly assigned to receive EP and 283 were assigned to receive PET. Overall response rates were 68% for the EP arm and 75% for the PET arm. Median failure-free survival time was 5.9 months for the EP arm and 6 months for the PET arm (P = .179). Median overall survival time was 9.9 months for patients on EP and 10.6 months for patients on PET (P = .169). Toxic deaths occurred in 2.4% of the patients on EP and 6.5% of patients on PET. CONCLUSION:PET did not improve the time to progression or survival in patients with extensive SCLC compared with EP alone and was associated with unacceptable toxicity.
Fully Synthetic Granulocyte Colony-Stimulating Factor Enabled by Isonitrile-Mediated Coupling of Large, Side-Chain-Unprotected Peptides.
Roberts Andrew G,Johnston Eric V,Shieh Jae-Hung,Sondey Joseph P,Hendrickson Ronald C,Moore Malcolm A S,Danishefsky Samuel J
Journal of the American Chemical Society
Human granulocyte colony-stimulating factor (G-CSF) is an endogenous glycoprotein involved in hematopoiesis. Natively glycosylated and nonglycosylated recombinant forms, lenograstim and filgrastim, respectively, are used clinically to manage neutropenia in patients undergoing chemotherapeutic treatment. Despite their comparable therapeutic potential, the purpose of O-linked glycosylation at Thr133 remains a subject of controversy. In light of this, we have developed a synthetic platform to prepare G-CSF aglycone with the goal of enabling access to native and designed glycoforms with site-selectivity and glycan homogeneity. To address the synthesis of a relatively large, aggregation-prone sequence, we advanced an isonitrile-mediated ligation method. The chemoselective activation and coupling of C-terminal peptidyl Gly thioacids with the N-terminus of an unprotected peptide provide ligated peptides directly in a manner complementary to that with conventional native chemical ligation-desulfurization strategies. Herein, we describe the details and application of this method as it enabled the convergent total synthesis of G-CSF aglycone.