Mitoxantrone dose augmentation utilizing filgrastim support in combination with fixed-dose 5-fluorouracil and leucovorin in women with metastatic breast cancer

Based on reports of substantial antitumor efficacy of the combination of mitoxantrone (DHAD), 5-fluorouracil (FU) and leucovorin (LV), a clinical trial was performed to attempt augmentation of the dose of DHAD with filgrastim support. The doses and schedules, all intravenous, were DHAD (total dose divided over days 1 and 2), level I, 16 mg/m²; II, 20 mg/m²;III, 24 mg/m²; IV, 32 mg/m²;and LV, 300 mg, followed by FU, 350 mg/m²;,on days 1–3. Filgrastim was given at 5 g/kg/day subcutaneously on days 4–13. The planned cycle length was 21 days. Three or 4 patients were to be entered at each dose level and the maximum tolerated dose (MTD) was defined as thedose immediately below that which resulted in 2 patients with dose-limiting toxicity (DLT) in cycle 1. Once an apparent MTD was identified, an additional 6 patients were to be entered. Twenty patients (pts) were entered: level I: 3 pts; II: 3 pts; III: 10 pts; IV: 4 pts. The major toxicity was found to be cumulative thrombocytopenia with platelet counts 20,000/L occurring after cycle 1 at all levels beyond level I and five pts (25%) were removed from treatment solely because of platelet toxicity. Additional serious toxicities included grade 4 stomatitis in one patient (level IV) and cardiac toxicity in 2 patients with prior doxorubicin exposure. Ten pts had measurable and 8 had evaluable disease, and in 17 pts assessed, 5 (29%)achieved an objective response. The response rates in this study are lower than reported in the literature for the combination of DHAD, 5FU, LV and this may be related to the fact that only 40% of the patients were removed from protocol treatment because of disease progression. On the basis of limited DHAD-dose augmentation, toxicities observed, and modest response rate, the filgrastim-supported DHAD, 5FU, LV regimen as utilized in this study cannot be recommended for further development for treatment of women with metastatic breast cancer.     

Phase I and subsequent phase II study of filgrastim (r-met-HuG-CSF) and dose intensified cyclophosphamide plus epirubicin in patients with non-Hodgkin's lymphoma and advanced solid tumors

Background: To define a maximum tolerated dose (MTD) for the combination of epirubicin and cyclophosphamide with filgrastim (r-met-HuG-CSF) in patients with advanced solid tumors and non-Hodgkin's lymphoma (NHL).Patients and methods: Thirty-five patients with advanced solid tumors were enrolled in stages I and II. Twenty-one patients were treated in stage I in sequential cohorts of at least three patients at increasing dosage levels of cyclophosphamide and epirubicin, for up to six cycles every 21 days. At the completion of stage I, a MTD for epirubicin was established. Fourteen patients were treated in stage II, in cohorts of three or more. The epirubicin dose remained constant at the MTD dosage from stage I. Cyclophosphamide was further dose-escalated to establish its MTD. Twenty-one patients with previously untreated non-Hodgkin's lymphoma were treated in stage III with the MTD established in the prior stages.Results: The MTD in stage I was epirubicin 150 mg/m² and cyclophosphamide 1500 mg/m² with cumulative neutropenia as the dose-limiting toxicity (DLT). Cumulative thrombocytopenia prevented further dose-escalation of cyclophosphamide in stage II. The stage III regimen consisted of six, 21-day cycles of epirubicin 150 mg/m², cyclophosphamide 1500 mg/m², vincristine 2 mg, and prednisolone 100 mg for five days with filgrastim support. Nineteen of twenty-one patients (90%) completed six cycles of treatment, eight (38%) without dose reduction. Common toxicity criteria (CTC) grade 4 neutropenia (neutrophil nadir <0.5 × 10⁹/l) was documented in 85 of 118 cycles (72%). Neutropenic fever was documented in 17 of 21 patients (81%) on at least one occasion. Severe thrombocytopenia (<25 × 10⁹/l) was seen in fourteen of 118 cycles (12%) and increased with cycle number. There was no significant non-hematological toxicity.Conclusion: Significant dose-escalation of epirubicin and cyclophosphamide was possible with filgrastim support. The MTD achieved was approximately double that of standard-dose therapy. This study forms the basis of an ongoing randomized study evaluating dose-intensification in intermediate grade NHL.     

基于FAERS数据库的非格司亭不良事件信号挖掘与分析

目的 挖掘并分析非格司亭相关不良事件的信号,为该药的临床安全使用提供参考依据。方法 收集FAERS中的2013年1月1日—2023年12月31日关于非格司亭的不良事件数据,采用比例失衡法中的ROR、PRR和BCPNN法进行信号挖掘,对报告频数和信号强度排名前20位以及各系统器官分类的不良事件进行统计分析。结果 共收集非格司亭相关的不良事件报告数4 434份,挖掘到相关信号328个,以发热、骨痛、白细胞计数降低等较为常见;共涉及22个系统器官,主要集中在血液及淋巴系统疾病、感染及侵染类疾病、各类检查等。挖掘到78个说明书未记录的新发现可疑不良反应,以脓毒症、恶性肿瘤、骨整合不充分为主。结论 非格司亭在真实世界中发生的常见不良反应与说明书有一致性,但存在部分新发现可疑的不良反应,临床用药宜密切关注,做好患者用药前风险评估,用药后及时监测,以保证患者用药安全。     

Pegfilgrastim in children with severe congenital neutropenia

Two pediatric patients affected by severe congenital neutropenia (SCN) were treated with 100 mcg/L/dose every 9–12 days within a pilot study (Observatory of the Italian Ministry of Health, Eudract Code 2005‐003096‐20) on the use of pegfilgrastim in patients with chronic neutropenia. Both children increased their absolute neutrophil count, reduced their infectious load, and improved their quality of life. Serum concentrations of G‐CSF observed in pegfilgrastim mirrored those seen in filgrastim. These data suggest that pegfilgrastim may be beneficial in SCN patients with an exposure of hematopoietic cells to G‐CSF similar to that on filgrastim. Pediatr Blood Cancer 2010;54:465–467. © 2009 Wiley‐Liss, Inc.     

Duration of filgrastim mobilization and apheresis yield of CD34+ progenitor cells and lymphoid subsets in normal donors for allogeneic transplantation

Seventy-seven normal donors underwent leukapheresis for peripheral blood progenitor cell collection beginning on day 4 ( n  = 45) or day 5 ( n  = 32) of filgrastim mobilization (12 μg/kg/d). The two groups were comparable for age, weight, blood volumes processed during leukapheresis and target CD34⁺ cell dose to be collected. The day 5 schedule allowed a more consistent achievement of the target cell dose with one apheresis ( P  = 0.005) and resulted in the initial collection of a significantly larger number of CD34⁺ cells ( P  = 0.009). There was no statistically significant difference in the leukapheresis yield of lymphoid subsets and natural killer cells.     

A phase II dose finding study of darbepoetin alpha and filgrastim for the management of anaemia and neutropenia in chronic hepatitis C treatment

Summary. Dose reductions of pegylated interferon alpha and ribavirin may be avoided by using growth factors. This phase II clinical trial assesses the dose, efficacy and safety of darbepoetin alpha and filgrastim for treatment of anaemia and neutropenia associated with combination therapy for hepatitis C virus (HCV). Chronic hepatitis C patients (n = 101) received pegylated interferon alpha‐2b (1.5 μg/kg once weekly) and ribavirin (800–1400 mg once daily). Patients with anaemia [haemoglobin (Hb) ≤ 10.5 g/dL] received darbepoetin alpha (3 μg/kg once every 2 weeks); the dose was titrated to achieve a Hb level of 12.0 g/dL. Patients with neutropenia [absolute neutrophil count (ANC) ≤ 0.75 × 10⁹/L] received filgrastim with the dose titrated from 150 μg QW to 300 μg thrice weekly to maintain ANC ≥ 0.75 × 10⁹/L and <10 × 10⁹/L. During antiviral therapy, 52% of patients required darbepoetin alpha, filgrastim or both. Hb at the time of darbepoetin alpha initiation was 10.2 ± 0.4 g/dL. After 81 days of darbepoetin alpha, Hb increased by 1.9 ± 1.0 g/dL to 12.1 ± 1.1 g/dL (P < 0.0001). Filgrastim resulted in a significant increase in ANC [0.75 ± 0.16 × 109/L to 8.28 ± 5.67 × 10⁹/L (P < 0.0001)]. In treatment‐naïve patients, 48% achieved sustained virological response (SVR), whereas 27% of patients previously treated with a course of pegylated interferon alpha achieved SVR. Low viral load, nongenotype 1 and treatment with growth factors were independently associated with SVR. Mild and severe anaemia were associated with quality of life impairments. Darbepoetin alpha resulted in an improvement in the Vitality domain of Short Form‐36. No significant adverse events were related to growth factors. During anti‐HCV therapy, filgrastim improved neutropenia and darbepoetin alpha improved both anaemia and quality of life. Future randomized clinical trials are needed to establish the impact of growth factors in improving sustained virological response.     

G-CSF: filgrastim,lenograstim and biosimilars

Introduction: The identification, purification and molecular cloning of granulocyte colony-stimulating factor G-CSF in the 1980s; the nonclinical studies in the mid-1980s; and the subsequent development of G-CSF as a therapeutic agent in the late 1980s and 1990s have had a major influence on the treatment of many diseases. In the clinical setting, filgrastim and lenograstim are of benefit to patients receiving chemotherapy or myeloablative treatment. They have been shown to reduce morbidity and mortality in many patient populations. Stem cell transplantation using G-CSF-mobilised peripheral-blood stem cells revolutionised stem cell transplantation, making it simpler, more efficient and more widely applicable in the clinic.

Areas covered: This review discusses the development and clinical uses of filgrastim, lenograstim and other biosimilar G-CSFs.

Expert opinion: In the next few years, the economics of G-CSF may even change with the introduction of biosimilars. Initial concerns about the use of biosimilar G-CSFs, appear to be unfounded. Adoption of cost-effective biosimilars should help reduce healthcare costs and improve patient access to biological treatments.     

Granulocyte colony-stimulating factor given in addition to interferon-α to mobilize peripheral blood stem cells for autologous transplantation in chronic myeloid leukaemia

In order to potentially mobilize and harvest the Ph^? cells observed in most patients with chronic myeloid leukaemia (CML) during interferon-α (IF-α) therapy, G-CSF (filgrastim), 5 μg/kg/d, was administered subcutaneously together with IF-α to 30 CML patients in haematological remission but with various degrees of cytogenetic remission, after IF-α therapy. Peripheral blood stem cells (PBSC ) were harvested using standard aphereses from day 5 of G-CSF. Patients underwent one to four (median three) aphereses. Median total yields/kg were 7.6 (range 3.8–25) × 10⁸ MNC, 3.4 (0–140) × 10⁶ CD34⁺ cells, and 17 (1.1–107) × 10⁴ CFU-GM. No patient had a significant increase in the percentage of Ph⁺ cells in the bone marrow under G-CSF therapy. The percentage of Ph⁺ cells in apheresis products tended to decrease between the first and the last apheresis (P = 0.05). 14 patients who were not responsive to IF-α were transplanted after conditioning with busulphan 16 mg/kg and melphalan 140 mg/m². Median time to neutrophils > 0.5 × 10⁹/l was 20 d (16–114 d) and to platelets > 50 × 10⁹/l 18 d (12–149 d). Nine patients had a major cytogenetic response post graft, which correlated with the amount of Ph⁺ cells reinfused with the graft (P = 0.02). We conclude that this procedure is feasible, allowing the harvest of enough PBSC, some of them Ph^? in patients who responded to IF-α, to allow autologous transplantation.     

Comparable efficacy and safety profiles of once-per-cycle pegfilgrastim and daily injection filgrastim in chemotherapy-induced neutropenia: a multicenter dose-finding study in women with breast cancer.

BACKGROUND: Neutropenia is common in patients receiving myelotoxic chemotherapy. Pegfilgrastim, a sustained-duration filgrastim is a once-per-cycle therapy for prophylactic neutrophil support. PATIENTS AND METHODS: Women, treated with four cycles of doxorubicin/docetaxel chemotherapy every 21 days, received pegfilgrastim or filgrastim 24 h after chemotherapy as a single subcutaneous injection per chemotherapy cycle (pegfilgrastim 30, 60 or 100 microg/kg) or daily subcutaneous injections (filgrastim 5 microg/kg/day). Safety, efficacy and pharmacokinetics were analyzed. RESULTS: The incidence of grade 4 neutropenia in cycle 1 was 95, 90 and 74%, in patients who received pegfilgrastim 30, 60 and 100 microg/kg, respectively, and 76% in patients who received filgrastim. Mean duration of grade 4 neutropenia in cycle 1 was 2.7,2 and 1.3 days for doses of pegfilgrastim, and 1.6 days for filgrastim. The pharmacokinetics of pegfilgrastim were non-linear and dependent on both dose and neutrophil count. Pegfilgrastim serum concentration was sustained until the neutrophil nadir occurred then declined rapidly as neutrophils started to recover, consistent with a self-regulating neutrophil-mediated clearance mechanism. The safety profiles of pegfilgrastim and filgrastim were similar. CONCLUSIONS: A single subcutaneous injection of pegfilgrastim 100 microg/kg provided neutrophil support and a safety profile comparable to daily subcutaneous injections of filgrastim during multiple chemotherapy cycles.