Physiological neutrophilia of pregnancy is not associated with a rise in plasma granulocyte colony-stimulating factor (G-CSF)

A patient with neutropenia and life-threatening infections secondary to T-γ lymphoproliferative disease, who did not respond to treatment with recombinant human G-CSF (filgrastim), was treated with filgrastim plus cyclosporine A (CyA). The patient achieved a good response in the absolute neutrophil count and subsequently required a dose reduction in the filgrastim. The patient was eventually discontinued from the CyA but continues on filgrastim alone. While on therapy, the large granular lymphocytes disappeared from the circulation and the beta-TCR rearrangement, which was present prior to beginning therapy, became undetectable. The patient had no significant toxicity to the CyA or the filgrastim and he has not experienced any serious infections or required hospitalization. Filgrastim has proven to be relatively nontoxic and of some benefit to patients with this disease and should probably be utilized first when treatment is necessary. However, if improvement is not observed, these findings suggest that a trial of the combination of CyA plus filgrastim may be beneficial.     

Chemotherapy dose intensity in non-Hodgkin's lymphoma: is dose intensity an emerging paradigm for better outcomes?

BACKGROUND: Higher chemotherapy dose intensity has been studied as a way of improving the clinical outcomes in various malignancies, including non-Hodgkin's lymphoma (NHL). METHODS: We reviewed clinical trials that have studied the relation between dose and response in cancer chemotherapy, the theory behind dose-intense chemotherapy, and the clinical results with dose-escalated and dose-dense therapy in aggressive NHL. RESULTS: Myeloablative high-dose chemotherapy with stem cell transplantation produces higher 5-year survival rates than standard salvage chemotherapy in relapsed aggressive lymphoma, but its role as initial therapy is not yet clear. Nonmyeloablative dose-escalated chemotherapy is feasible with granulocyte colony-stimulating factor (G-CSF) support, but this approach does not improve outcomes. Dose-dense (14-day) CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) with G-CSF support produces better results than 21-day CHOP in patients with previously untreated aggressive lymphoma, without additional toxicity. The addition of etoposide to dose-dense CHOP may provide further benefits in younger patients. The addition of rituximab to G-CSF-supported dose-dense CHOP is feasible. Preliminary data suggest the feasibility of dose-dense chemotherapy for NHL with the once-per-cycle G-CSF, pegfilgrastim. CONCLUSION: Dose-dense chemotherapy with G-CSF support produced better clinical outcomes in both younger and older patients. Phase 3 trials of dose-dense CHOP plus rituximab with CSF support are warranted.     

Discrete Choice Experiment to Estimate Breast Cancer Patients’ Preferences and Willingness to Pay for Prophylactic Granulocyte Colony-Stimulating Factors

ObjectivesRising out-of-pocket costs for cancer patients have increased shared decision making. Clinical guidelines recommend prophylactic granulocyte colony-stimulating factor (G-CSF) for patients receiving chemotherapy with a 20% or greater risk of febrile neutropenia. A discrete choice experiment was conducted to explore breast cancer patients’ preferences and willingness to pay (WTP) for prophylactic G-CSF to decrease the risk of chemotherapy-induced febrile neutropenia.MethodsAn online discrete choice experiment questionnaire survey of a national US convenience sample of self-reported breast cancer patients with prior chemotherapy treatment was conducted. Sixteen paired G-CSF treatment scenarios, each with four attributes (risk of disruption to chemotherapy schedule due to low white blood cell counts, risk of developing an infection requiring hospitalization, frequency of administration, and total out-of-pocket cost) were presented with a follow-up “no treatment” option. Participant preferences and WTP out of pocket were estimated by logistic regression.ResultsParticipants (n = 296) preferred G-CSF regimens with lower out-of-pocket costs, lower risk of chemotherapy disruption, lower risk of infection, and greater convenience (one G-CSF injection per chemotherapy cycle). Participants’ WTP was $1076 out of pocket per cycle to reduce the risk (high to low) of disrupting their chemotherapy schedule, $884 per cycle to reduce the risk (24% [high] to 7% [low]) of infection, and $851 per cycle to decrease the number of G-CSF injections (11 to 1) per cycle.ConclusionsParticipants highly valued specific features of prophylactic G-CSF treatment including maintaining their chemotherapy schedule, lowering their risk of infection, and reducing the number of injections. Physicians should consider patient preferences to inform the best treatment choices for individual patients.     

非格司亭防治卵巢癌化疗后骨髓抑制继发感染的临床分析

目的研究不同方法应用非格司亭(格拉诺赛特)对卵巢癌化疗后白细胞和中性粒细胞减少的防治作用. 方法将96例的卵巢上皮性癌术后需化疗的患者随机分为A、B、C、D组,A组(共111个化疗周期)和B组(共61个周期)为治疗性应用,分别为白细胞计数＜2.0×109/L和1.0×109/L时给予非格司亭,50 μg/d和150 μg/d,C组(共126个疗程)自化疗结束后48 h起给予非格司亭50 μg/d,均皮下注射;D组(共89疗程)不用非格司亭. 结果 C组白细胞最低值的持续时间明显短于A、B和D组(P＜0.01),平均最低值分别为3.01×109/L和0.97×109/L,A、B组较D组短,但差异无显著性. 结论非格司亭可维持白细胞和中性粒细胞的水平,减低感染的发生,预防性用药优于治疗性用药.     

Pegfilgrastim: a recent advance in the prophylaxis of chemotherapy-induced neutropenia

Chemotherapy-induced neutropenia is a frequent complication in cancer patients receiving myelosuppressive chemotherapy. Chemotherapy-induced neutropenia can result in febrile neutropenia and potentially life-threatening infections requiring hospitalization and intravenous anti-infectives. Chemotherapy dose may be reduced or delayed as a result of chemotherapy-induced neutropenia, which can negatively impact treatment outcomes. Granulocyte colony-stimulating factors, such as filgrastim, stimulate neutrophil production and can therefore reduce the incidence and severity of chemotherapy-induced neutropenia. Filgrastim undergoes rapid renal clearance and needs to be administered daily. The development of pegfilgrastim represents a significant advance in the management of chemotherapy-induced neutropenia as the longer serum half-life allows once-per-chemotherapy administration, and evidence supports increased prophylactic effectiveness in reducing the incidence of febrile neutropenia. This paper reviews the development of pegfilgrastim and summarizes recent clinical data on the use of this simple, effective and well-tolerated option for the management of chemotherapy-induced neutropenia in patients with cancer.     

Characterization of peripheral blood progenitor cells (PBPC) mobilized by filgrastim (rHuG-CSF) in normal volunteers: dose–effect relationship for filgrastim with the character of mobilized PBPC

Filgrastim (rHuG-CSF)-mobilized peripheral blood progenitor cells (PBPC) in healthy Japanese volunteers were characterized in detail using two clonal cell culture systems and double-colour flow cytometry to detect multilineage colony-forming cells and subsets of CD34⁺ cells. The kinetics of PBPC during the administration of filgrastim was studied, and possible differences in the character of progenitor cells relative to given doses of filgrastim were investigated. Filgrastim was administered subcutaneously to normal volunteers for 7 d at doses of 100, 200 or 400 μg/m² (10 per cohort). Treatment with 100 or 200 μg/m² filgrastim was well tolerated; however, the 400 μg/m² dose level was not completed because of bone pain and myalgia. The treatment strikingly mobilized various types of progenitor cells, including highly proliferative megakaryocytic colony-forming cells. The number of progenitor cells peaked on days 5 and 6. The fold increase of circulating progenitor cells from the baseline value in the volunteers treated with 200 μg/m² filgrastim was more pronounced than in those treated with 100 μg/m². Treatment with 200 μg/m² also released the less mature progenitor cells (i.e. mixed colony-forming cells, CD34⁺/33⁻ cells, and CD34⁺/HLA-DR⁻ cells) into circulation better than the 100 μg/m² dose. These results suggest that daily subcutaneous injection with 200 μg/m² filgrastim for 5 d will effectively mobilize, both qualitatively and quantitatively, PBPC in healthy donors.     

Mobilization and harvesting of peripheral blood stem cells: randomized evaluations of different doses of filgrastim

The effects of different doses of filgrastim on yields of CD34⁺ peripheral blood stem cells were evaluated in patients with breast cancer. 55 were randomized to receive filgrastim 10, 20, 30 or 40 μg/kg/d with more CD34⁺ cells/kg/apheresis harvested after the three highest dose levels. 35 additional patients were randomized to receive 10 or 30 μg/kg. The median number of CD34⁺ cells collected after 10 μg/kg (n= 31) was 0.7 × 10⁶/kg/apheresis (range 0.1–4.4) as compared to 1.2 (range 0.1–6.8) after 30 μg/kg (n= 32) (P= 0.04). Among patients randomized to 10 v 30 μg/kg, more (50%) achieved 5.0 × 10⁶ CD34⁺ cells/kg and less aphereses were required to achieve 2.5 × 10⁶ CD34⁺ cells/kg after the higher dose (P= 0.04). In multivariate analyses, patients receiving 10 μg/kg (n= 31) had lower yields of CD34⁺ cells (P= 0.026) and had a 3.3-fold increase in the probability of not achieving 5.0 × 10⁶ CD34⁺ cells/kg as compared to patients receiving 20–40 μg/kg (n= 59). Patients who had received radiation had a 2.9-fold probability of not achieving 2.5 × 10⁶ CD34⁺ cells/kg. These data suggest that, in patients with good marrow reserves, doses of filgrastim > 10 μg/kg/d mobilized more CD34⁺ cells and may be useful when high numbers of CD34⁺ cells are desired.     

Pegfilgrastim vs. filgrastim for supportive care after autologous stem cell transplantation: can we decide?

Granulocyte-colony-stimulating factors are helpful for the support of patients receiving autologous hematopoietic stem cell transplantation, resulting in faster neutrophil recovery and lower incidence of febrile neutropenia (FN). Our aim was to evaluate the use of pegfilgrastim vs. filgrastim with regard to absolute neutrophil count (ANC) recovery, risk, and duration of FN and length of hospital stay. Mean difference was the summary effect for continuous data, and odds ratio for binary data, using random-effects modeling. MEDLINE, EMBASE, and the Cochrane Registry of Randomized Controlled Trials were included in the search. Randomized controlled trials (RCTs), case-control studies, and studies with historical control group for filgrastim were eligible. Of the initial 114 studies screened, 12 studies were analyzed (four were RCTs, including one phase III trial). The use of pegfilgrastim resulted in a one d gain in ANC recovery (mean difference -0.82, 95% CI -1.07 to -0.57, p < 0.001) and duration of FN (-0.67, 95% CI -1.28 to -0.06, p < 0.001) but had no effect on the risk of FN or length of stay. Pegfilgrastim was more expensive (baseline marginal cost €116.97, p < 0.001), which was largely determined by the treatment duration and pegfilgrastim cost. Non-randomized setting attenuated the effect on duration of FN whereas delayed onset of filgrastim injections (to pegfilgrastim) overestimated the protective effect on the risk of FN. Both drugs are at least equally effective, though methodology and disease stratification in published trials warrant further improvement.     

Pegfilgrastim; a neutrophil mediated granulocyte colony stimulating factor–expanding uses in cancer chemotherapy

Background: Currently G-CSFs such as filgrastim (Neupogen^®, Amgen, Inc.) and pegfilgrastim (Neulasta^®, Amgen, Inc.) are widely used to reduce chemotherapy-induced neutropenia. Pegfilgrastim is a novel recombinant human G-CSF and its unique neutrophil-mediated clearance allows it to be administered once per chemotherapy cycle. Objective: To address the pharmacology of pegfilgrastim and provide an overview of its current clinical use in cancer chemotherapy. Methods: Review and summary of publications on pegfilgrastim indexed in the PubMed electronic database. Results/conclusion: The efficacy of pegfilgrastim is similar to or greater than that of filgrastim and an important advantage of pegfilgrastim is its schedule of administration that may be associated with greater treatment compliance and improved patient quality of life. Ongoing clinical trials continue to explore further potential uses for pegfilgrastim.