Pegfilgrastim Group Research Articles

Differences in functional activity and antigen expression of granulocytes primed in vivo with filgrastim, lenograstim, or pegfilgrastim

Granulocyte-colony-stimulating factor (G-CSF) is known to affect functional activity and antigen expression of neutrophil granulocytes. Beside nonglycosylated filgrastim and glycosylated lenograstim, pegylated filgrastim (pegfilgrastim) has recently been introduced for single administration into clinical use. Here, granulocytes from 27 patients with nonmyeloid malignancies were compared functionally (migration, reactive oxygen species production, and G-CSF serum levels) and phenotypically (cell surface antigen expression) before and after G-CSF administration. After exposure to G-CSF, chemotaxis was reduced significantly in the filgrastim group. Immunophenotypically, in vivo G-CSF-primed granulocytes were more mature in the lenograstim than in the filgrastim and to lesser extent in the pegfilgrastim groups as shown by the expression profile for CD11b, CD14, and CD16. Of note, G-CSF serum levels were similar among the groups. Our data suggest that granulocytes exposed to glycosylated G-CSF in vivo seem to resemble more closely their steady-state phenotype than after treatment with nonglycosylated and to lesser extent pegylated G-CSF.

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

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

Sustained G-CSF plasma levels following administration of pegfilgrastim fasten neutrophil reconstitution after high-dose chemotherapy and autologous blood stem cell transplantation in patients with multiple myeloma

Pegfilgrastim has shown to decrease the duration of severe neutropenia after conventional chemotherapy, but its use after high-dose chemotherapy and autologous blood stem cell transplantation has not been established yet. Therefore we studied the efficacy and the pharmacokinetic profile of pegfilgrastim in patients with multiple myeloma undergoing high-dose chemotherapy. In total, 21 patients received a single subcutaneous injection of 6 mg pegfilgrastim on day +1 after transplantation and pegfilgrastim plasma levels were measured daily by enzyme-linked immunosorbent assay. Clinical outcome was compared with pegfilgrastim levels of 282 plasma samples and data of a historical control group of patients without granulocyte colony-stimulating factor (G-CSF) support. Pegfilgrastim levels showed an inverse correlation (r = -0.68, p < 0.01) with neutrophil counts. Peak levels were reached at day +4 (94 ng/mL; range: 37-205) and were maintained until day +7 (85 ng/mL; range: 35-186). Comparison with the control group without G-CSF support showed that time to neutrophil reconstitution was significantly shorter in the pegfilgrastim group with 10 vs 15 days, respectively (p < 0.001). There was no correlation of pegfilgrastim levels and the duration of neutropenia, although patients with a fivefold increase in neutrophil counts the day after pegfilgrastim administration had a significantly shorter median duration of neutropenia in comparison to patients who were less susceptible to G-CSF stimulation (5 vs 7 days, p < 0.01). Neutrophil reconstitution after high-dose chemotherapy could be accelerated by the use of pegfilgrastim in patients with myeloma. Responsiveness of neutrophils to pegfilgrastim before neutropenia was correlated with faster neutrophil reconstitution, whereas G-CSF levels had no impact on neutrophil recovery.

Pegfilgrastim compared with filgrastim after high‐dose melphalan and autologous hematopoietic peripheral blood stem cell transplantation in multiple myeloma patients

We undertook a comparative study of Pegfilgrastim vs. Filgrastim after high-dose melphalan and autologous peripheral blood stem cell transplantation (APBSCT) in multiple myeloma (MM) patients. Thirty-seven consecutive patients were randomly assigned to receive a single 6 mg dose of Pegfilgrastim on day 1 post-transplant (n = 18 patients) vs. daily subcutaneous injections of Filgrastim 5 microg/kg (n = 19 patients) starting on day 5 post-transplant. The median duration of grade 4 neutropenia in the Pegfilgrastim and Filgrastim groups was 5 and 6 d, respectively (P = ns). The results for the two groups were also not significantly different for time to neutrophil and platelet recovery, but incidence of febrile neutropenia (61.1% vs. 100%, P = 0.003) and duration of febrile neutropenia (1.5 d vs. 4 d, P = 0.005), were lower in the Pegfilgrastim arm. After initial haematopoietic reconstitution, we observed significantly higher value of leukocytes x 10(9) L on day 15 (6.0 vs. 2.7, P = 0.004), in the Pegfilgrastim group compared with the Filgrastim group. This study shows that a single injection Pegfilgrastim can be used with safety and efficacy similar to those provided by daily injections of Filgrastim and it is associated with a decrease incidence of infectious events after APBSCT in MM patients.

Fixed-dose single administration of pegfilgrastim vs daily filgrastim in patients with breast cancer and lymphoma undergoing autologous peripheral blood stem cell transplantation

16534 Background: Pegylated filgrastim is a new formulation of a granulocyte colony-stimulating factor that has a long circulating half-life, permitting a single dose of filgrastim per cycle of chemotherapy. Methods: To evaluate whether a single subcutaneous injection of pegfilgrastim (6 mg) is as safe and effective as daily filgrastim (5 mcg/kg/day), 40 consecutive autologous stem cell transplantations performed for breast cancer and lymphomas have been analysed. Median age was 47 yrs (20–61) and 48 yrs (30–63) in pegfilgrastim and filgrastim group, respectively. All patients had normal bone marrow biopsy. The first cohort of patients received 5 mcg/kg/day of filgrastim starting from day 5 post transplantation and the second cohort of patients received a single subcutaneous injection of 6 mg pegfilgrastim on day 5 after transplantation. Results: Median duration of grade 4 neutropenia in the pegfilgrastim and filgrastim groups was 7 (4–9) and 6 (5–9) days, respectively (P 0.29). Neutropenic fever incidence was significantly higher in filgrastim group, 9/20 vs 16/20 (P 0.048), the median duration was not significantly different, 1 (1–6) vs 3 (1–7) days. The grade 3–4 mucositis was higher in filgrastim patient group, 4/20 vs 13/20 in pegfilgrastim and filgrastim, respectively (P 0.009). The adverse events observed during post-transplant aplasia were attributable to complications arising from myelo-suppressive chemotherapy or the primary disease. The only occurring adverse event considered to be cytokine related was mild to moderate bone pain. The overall incidence of bone pain requiring non-narcotic analgesia was not statistically different, 20% (4/20) in pegfilgrastim patients and 40% (8/20) in filgrastim patients. The patients in filgrastim group received a mean of 9.8 daily injections. Conclusions: A single injection of pegfilgrastim administered at day 5 post transplant shows comparable safety and efficacy profiles to daily injections of filgrastim and may be cost-effective. No significant financial relationships to disclose.

Pegfilgrastim compared with Filgrastim after autologous hematopoietic peripheral blood stem cell transplantation

In order to assess the effect of Pegfilgrastim on the duration of neutropenia and clinical outcome of patients after autologous peripheral blood stem cell (PBSC) transplantation, we compared 20 consecutive patients with lymphoma or multiple myeloma receiving a single 6-mg dose of Pegfilgrastim on day 1 posttransplant to an historical control group of 60 patients receiving daily Filgrastim 5 microg/kg starting on day 1 posttransplant. The duration of neutropenia was similar in the Pegfilgrastim group compared with the control group. There were no differences in time to neutrophil, erythroid, or platelet engraftment nor in the incidence of fever and infections. The duration of antibiotic therapy, transfusion support, and time to hospital discharge were similar in the two groups. However, after initial hematopoietic reconstitution, we observed significantly higher values of lymphocytes (e.g., 1,660+/-1,000 versus 970+/-460 on day 80, p=0.0002), neutrophils (e.g., 3,880+/-2,030 versus 2,420+/-1,500 on day 25, p=0.0004), reticulocytes (e.g., 148,160+/-90,590 versus 87,140+/-65,920 on day 25, p<0.0001), and platelets (e.g., 210,700+/-116,090 versus 150,240+/-58,230 on day 55, p=0.0052) up to day 100 in the Pegfilgrastim group compared with the Filgrastim group. These observations had no impact on clinical outcome of the patients after day 30 due to the low incidence of infectious events after engraftment in autologous PBSC transplantation. We conclude that the effect of Pegfilgrastim administrated on day 1 posttransplant is comparable to that of daily Filgrastim on initial hematopoietic reconstitution. The possibly superior effect of Pegfilgrastim on cell counts we observed after initial engraftment should be further tested in a prospective randomized trial.

Use of Filgrastim among Febrile Inpatients who Received Outpatient Filgrastim or Pegfilgrastim

Purpose To characterize the inpatient use of filgrastim in cancer patients hospitalized for management of post-chemotherapy fever after receiving either outpatient filgrastim or pegfilgrastim. Method Retrospective review of chart records in a single-center, tertiary-care, teaching hospital and outpatient oncology center of cancer patients hospitalized for fever after outpatient chemotherapy and proactive administration of filgrastim or pegfilgrastim. Patients with the following tumor types were included: breast cancer, cervical cancer, colon cancer, Hodgkin disease, intermediate- or high-grade non-Hodgkin lymphoma, small cell or non-small cell lung cancer, and ovarian cancer. Result Billing data identified 1,438 outpatient chemotherapy patients treated with filgrastim or pegfilgrastim; 261 (18.2%) of whom were hospitalized for fever. All patients in the filgrastim groups, and 78% of those in the pegfilgrastim group, were given inpatient filgrastim. Duration of filgrastim administration in the inpatient setting was significantly shorter ( P &lt; 0.001) for the pegfilgrastim group. Conclusions Filgrastim was frequently administered to cancer patients hospitalized for fever, even after outpatient pegfilgrastim was administered as an adjunct to chemotherapy. Patients treated with once-per-cycle pegfilgrastim in an outpatient setting do not require filgrastim if they are hospitalized for fever before neutrophil recovery. Thus, hospitals could realize immediate cost savings by not treating those patients with filgrastim. This study illustrates the need to develop operational procedures in institutions to rapidly identify prior outpatient pegfilgrastim administration as a patient is admitted for post-chemotherapy fever.

Use of PEG-filgrastim or filgrastim after high dose conditioning with BEAC chemotherapy in patients with lymphoma

Colony stimulating factors are routinely used after high dose chemotherapy and autologous transplant. Few data are available addressing the efficacy of PEG-filgrastim. Thirty-one consecutive patients who underwent BEAC conditioning and autologous transplant for lymphoma at a single institution were analyzed. One patient died prior to neutrophil recovery and is not included in this analysis. Nineteen patients received filgrastim either 480 mcg if they weighed >60 kg or 300 mcg for a weight <60 kg subcutaneously daily starting day +5 and continuing until ANC > 500. Eleven patients received 6 mg PEG-filgrastim on day +1. The median number of CD34+ cells/kg was 3.9 (1.7–8.2) in the filgrastim group and 2.9 (1.7–9.1) in the PEG-filgrastim group. The median number of prior cytotoxic chemotherapeutic regimens was 1 (1–3) in the filgrastim group and 1 (1–2) in the PEG-filgrastim group. Diagnoses in the filgrastim group: diffuse large B-cell lymphoma (6), follicular lymphoma (7), or mantle cell lymphoma (6). Diagnoses in the PEG-filgrastim group: diffuse large B-cell lymphoma (2), follicular lymphoma (3), mantle cell lymphoma (3), anaplastic T cell lymphoma (1), or cutaneous T cell lymphoma (2). For the filgrastim group, the median time to neutrophil engraftment was 10 days (9–13); the median time to platelet engraftment was 10 days (8–15). For the PEG-filgrastim group the median time to neutrophil engraftment in was 11 days (8–16); the median time to platelet engraftment was 14 days (10–16). The median number of injections in the filgrastim group was 5 (4–7). Conclusions: Both filgrastim and PEG-filgrastim allow for prompt neutrophil recovery in patients undergoing BEAC conditioning and autologous transplant. Factors other than efficacy such as convenience, patient comfort and cost should be considered when choosing a post transplant colony stimulating factor. Colony stimulating factors are routinely used after high dose chemotherapy and autologous transplant. Few data are available addressing the efficacy of PEG-filgrastim. Thirty-one consecutive patients who underwent BEAC conditioning and autologous transplant for lymphoma at a single institution were analyzed. One patient died prior to neutrophil recovery and is not included in this analysis. Nineteen patients received filgrastim either 480 mcg if they weighed >60 kg or 300 mcg for a weight <60 kg subcutaneously daily starting day +5 and continuing until ANC > 500. Eleven patients received 6 mg PEG-filgrastim on day +1. The median number of CD34+ cells/kg was 3.9 (1.7–8.2) in the filgrastim group and 2.9 (1.7–9.1) in the PEG-filgrastim group. The median number of prior cytotoxic chemotherapeutic regimens was 1 (1–3) in the filgrastim group and 1 (1–2) in the PEG-filgrastim group. Diagnoses in the filgrastim group: diffuse large B-cell lymphoma (6), follicular lymphoma (7), or mantle cell lymphoma (6). Diagnoses in the PEG-filgrastim group: diffuse large B-cell lymphoma (2), follicular lymphoma (3), mantle cell lymphoma (3), anaplastic T cell lymphoma (1), or cutaneous T cell lymphoma (2). For the filgrastim group, the median time to neutrophil engraftment was 10 days (9–13); the median time to platelet engraftment was 10 days (8–15). For the PEG-filgrastim group the median time to neutrophil engraftment in was 11 days (8–16); the median time to platelet engraftment was 14 days (10–16). The median number of injections in the filgrastim group was 5 (4–7). Conclusions: Both filgrastim and PEG-filgrastim allow for prompt neutrophil recovery in patients undergoing BEAC conditioning and autologous transplant. Factors other than efficacy such as convenience, patient comfort and cost should be considered when choosing a post transplant colony stimulating factor.

Safety and efficacy of pegfilgrastim compared to granulocyte colony stimulating factor (G-CSF) supporting a dose-intensive, rapidly cycling anti-metabolite containing chemotherapy regimen (Hyper-CVAD) for lymphoid malignancy

Pegfilgrastim (Neulasta®) has proven efficacy as supportive therapy in a variety of 21-day chemotherapy regimens, but has not been studied in dose intensive, rapidly cycling regimens utilising cell-cycle active drugs (e.g. anti-metabolites) such as hyper-CVAD. This study examined whether pegfilgrastim was safe and lead to similar kinetics of neutrophil recovery as daily granulocyte colony stimulating factor (G-CSF). Using retrospective analysis, patients receiving pegfilgrastim (6 mg) were matched with controls (G-CSF 5 μg kg−1 per day) for a cycle of chemotherapy, prior chemotherapy, dose of cytarabine received, age (<60 or >60 years), diagnosis and bone marrow involvement. The primary endpoint was duration of grade IV neutropenia (absolute neutrophil count, ANC < 500 μl−1). Secondary endpoints included time to neutrophil recovery, incidence of febrile neutropenia, positive blood cultures and delay in subsequent chemotherapy. This study identified 124 pegfilgrastim supported cycles in 43 patients and successfully matched them to 124 G-CSF supported cycles from 38 patients treated between January 1999 and July 2005. There were no significant differences between pegfilgrastim and G-CSF groups in baseline or treatment-related variables. The median duration of grade IV neutropenia was 4 days in both groups (P = 0.55). Time to neutrophil recovery, incidence of febrile neutropenia, positive blood cultures and delay in subsequent chemotherapy were similar in both groups. Once per cycle dosing of pegfilgrastim appears safe and as effective as daily G-CSF for supporting the hyper-CVAD chemotherapy regimen.

Pegfilgrastrim Compared with Filgrastim after Autologous Hematopoietic Peripheral Blood Stem Cell Transplantation.

In order to assess the effect of Pegfilgrastim on the duration of neutropenia and clinical outcome of patients after autologous peripheral blood stem cell transplantation (PBSCT), we compared 20 consecutive patients with lymphoma or multiple myeloma receiving a single 6 mg dose of Pegfilgrastim on day 1 posttransplant to a historical control group of 60 patients receiving daily Filgrastim 5 μg/kg starting on day 1 posttransplant. There were 54 M and 26 F, 30 patients with lymphoma and 50 with myeloma, 26 in CR and 54 not in CR. Mean age was 55±10 yrs and 25 had already received a previous autologous transplant. The two groups were matched for disease and disease status, transplant number, age and sex. Cell dose infused tended to be higher in the Pegfilgrastim group (7.16±3.82 vs 10.03±6.25 x106 CD34+ cells/kg, p=0.0575). There were no differences (p>0.05) in time to 0.5 (8 vs 9 days) or 1 (9 vs 9 days) x109/L neutrophils; to 1 % reticulocytes (13 vs 15 days) or 9 (12 vs 14 days) or 10 (30 vs 25 days) g/dL Hb; to 20 (9 vs 9 days) or 100 (20 vs 31 days) x 109/L platelets. The number of days with fever (2.7±2.3 vs 2.3±2.4 days), incidence of infections (all infections; bacteremia; bacterial, fungal or viral infections; FUO), duration of antibiotic therapy (8.7±5.9 vs 8.4±5.9 days), RBC (1.1±1.6 vs 0.9±1.6) and platelet (1.0±1.7 vs 1.2±1.8) transfusions, and time to hospital discharge (14.5±5.3 vs 15.4±5.8 days) were similar in the Pegfilgrastim compared to the Filgrastim group. However, after initial hematopoietic recovery, several differences between the groups became apparent, with the group always showing higher counts compared to the Filgrastim group (p values <0.05 to <0.001). Neutrophils remained significantly higher in the Pegfilgrastim group between days 14–30, lymphocytes between days 56–90, monocytes between days 21–24, reticulocytes between days 17–42 and platelets between days 35–90, respectively. These differences had no impact on clinical outcome after day 30 due to the low incidence of infectious events after engraftment. We conclude that Pegfilgrastim administrated on day 1 posttransplant facilitates early hematopoietic reconstitution comparable to daily Filgrastim. However, despite a trend towards fewer CD34+ cells transplanted, the Pegfilgrastim group enjoyed higher trilineage cell counts for some time after initial engraftment. This should be further tested in prospective randomized trials.

Successful Engraftment of Autologous CD34+ Stem Cells after High-Dose Therapy and Fixed Dose (6 mg) Pegfilgrastim.

High-dose (HD) therapy plus Autologous Stem Cell Transplantation (ASCT) is a milestone treatment program for most hematologic malignancies. Daily subcutaneous injections of G-CSF (filgrastim/lenograstim) until ANC > 500/μl are routinely administered following ASCT, in order to accelerate hematopoietic recovery and reduce neutropenic complications. Pegfilgrastim has been shown to have similar efficacy when compared to G-CSF for chemotherapy-induced neutropenia, but little is known about its use in the ASCT setting. We used a 6 mg fixed dose of Pegfilgrastim on day +4 following ASCT in 46 patients (22 M/24 F; median age 56 yrs; r 22-70 yrs) with multiple myeloma (25 pts) and relapsed or refractory Hodgkin's and non-Hodgkin's lymphoma (21 pts). Patients received peripheral CD34+ stem cells (median number 4.4 x 106/Kg; r 1.8 – 11.8) harvested after mobilizing chemotherapy (cytoxan, vinorelbine/cytoxan, R-IEV, IGEV, R-ICE) and G-CSF. Standard conditioning regimens (HD-Melphalan or BEAM) were used. Engraftment results were compared to those from a historical control group of 182 patients (median age 56 yrs; r 16-74 yrs) who had received HD-Melphalan or BEAM and ASCT (median CD34+ cells 7.6 x 106/Kg, r 1.8–4.6) supported by G-CSF (5 μg/kg/day from day +5 until ANC>500/μl). Median number of days to ANC>500/μl were comparable between the Pegfilgrastim (10, r 8-15) and G-CSF (11, r 7–22) groups, as well as the median number of days to PLT>20,000/μl (Pegfilgrastim = 12, r 9–20 vs G-CSF= 12, r 7–29). Overall infectious rates, including FUO and documented infections, were of 48% and 39% for Pegfilgrastim and G-CSF groups, respectively (p=NS). Median number of days on i.v. antibiotics were 0 (r 0–18) and 6 (r 0–13) for the Pegfilgrastim and G-CSF groups, respectively. No significant differences in the incidence of bone pain, intensity of transfusion support and length of hospital stay were documented between the two groups. These data indicate that a fixed (6 mg) single-dose of Pegfilgrastim is safe and effective to accelerate engraftment after ASCT. No significant differences with G-CSF were apparent as to engraftment times and overall infectious complications. Growth factor costs were however in favor of Pegfilgrastim (Euro 690 vs 892 for a median of 10.5 G-CSF doses).

Pegfilgrastim and Daily Granulocyte Colony-Stimulating Factor (G-CSF) Patterns of Use and Neutropenia-Related Outcomes in Cancer Patients in Spain: Results of the Learn Study.

Background: Daily G-CSFs(Filgrastim, lenograstim) are widely used to reduce duration of chemotherapy-induced neutropenia(CIN) and incidence of febrile neutropenia(FN) in cancer patients(pts). Data on their patterns of use and effectiveness in routine clinical practice are however limited. The introduction of the once-per-cycle G-CSF pegfilgrastim(Neulasta®) in Spain in 2003 may have changed patterns of use of daily G-CSFs and CIN-related outcomes.Methods: Multicentre, retrospective, observational study of daily G-CSF and pegfilgrastim patterns of use and outcomes in adult subjects with non-myeloid malignancies receiving myelosuppressive chemotherapy(CT). Consecutive patient medical records with documented use of daily G-CSF or pegfilgrastim were abstracted from 10 Spanish centers during 2003.Endpoints: percentage of proactive(primary prophylaxis) vs reactive(secondary prophylaxis/treatment) use of G-CSFs, duration of treatment with G-CSF, and CIN-related outcomes(dose delay, dose reduction, incidence of FN, hospitalization and antibiotic consumption).Results: 248 charts documented pegfilgrastim or daily G-CSF use; 75 pts received pegfilgrastim only; 111 pts received daily G-CSF only(99 Filgrastim, 12 lenograstim); 62 pts received both daily G-CSF and pegfilgrastim during their CT(data not shown). Most common tumor types were lung(25%), breast(20%), malignant lymphomas(20%). Pattern of use (% pts on primary or secondary prophylaxis, or treatment at any time during CT) was:pegfilgrastim(39%,48%,17%, respectively) vs daily G-CSF(40%,48%,30%, respectively). Median number of injections/cycle in the daily G-CSF group was 6 (range 1–13) in primary prophylaxis, and 5 (range 1–11) in secondary prophylaxis and treatment. CIN-related outcomes are shown in the table below.Conclusions: Patterns of use of daily G-CSFs and pegfilgrastim were similar for primary and secondary prophylaxis, but a potential trend to less frequent treatment use in the pegfilgrastim group was observed. CIN-related complications, including incidence of FN, were observed to be lower in pts receiving pegfilgrastim.CT-related complications% pts (95% CI)Pegfilgrastim(n=75)Daily G-CSF(n=111)Dose Delay44% (33; 55)46% (36; 55)Dose Reduction14.7% (8.2; 24.6)20.7% (14.2; 29.2)Dose Reduction due to Neutropenia6.7% (2.5; 15.0)20.7% (14.1; 29.2)Febrile Neutropenia (FN)10.7% (5.3; 19.9)24.3% (17.2; 33.1)Hospitalization due to FN9.3% (4.3; 18.3)19.8% (13.4; 28.3)Antibiotic Consumption due to FN8.0% (3.4; 16.7)17.1% (11.2; 25.3)

Functional Activity of Granulocytes Primed In Vivo with Glycosylated Granulocyte Colony-Stimulating Factor (G-CSF) Is Superior To Priming with Non-Glycosylated G-CSF.

Recombinant granulocyte colony-stimulating factor (G-CSF) is widely used in the treatment of chemotherapy-induced neutropenia as well as in mobilization of peripheral blood stem cells in context with autologous bone marrow transplantation. Beside recombinant non-glycosylated G-CSF expressed in E.coli (Filgrastim) and glycosylated G-CSF expressed in CHO-cells (Lenograstim), pegylated filgrastim (Pegfilgrastim) has been introduced for single-administration into clinical use. Previous studies suggest a different functional activity of glycosylated vs. non-glycosylated G-CSF. Here we study the effects of these different G-CSF on chemotaxis, oxidative burst and antigen expression of granulocytes including and correlated the results with G-CSF serum levels.Granulocytes were obtained from 27 patients with hematological malignancies before and after the administration of one of the three G-CSFs (10 Lenograstim, 9 Filgrastim, 8 Pegfilgrastim) and isolated using a polymorphprep density gradient. Chemotactic properties were assessed using a Boyden chamber assay in combination with an under agarose assay, both using fMLP as chemotactic stimulus. Release of superoxide anions served as measure of the oxidative burst after stimulation with PMA using a chemiluminescence assay. The viability and surface antigen expression were assessed by FACS. In addition G-CSF serum levels were determined by ELISA.Patients receiving Filgrastim showed a significantly impaired chemotaxis contrary to patients receiving Lenograstim (p<0.05), in the Pegfilgrastim group patients showed a strong, yet not significant reduction when compared to Lenograstim. No significant effects could be shown in production of superoxide anions in a chemiluminescence assay.In all three groups, FACS analysis showed a decrease in expression of CD10, CD11b, CD18 and CD62L and a significant increase of the LPS-receptor CD14 as well as an increased expression of the IgG receptor FcγRI (CD64) following G-CSF treatment. The increase of CD64 in the Pegfilgrastim group was significantly stronger compared to the other groups. Moreover, we observed a significantly stronger increase of CD14 in patients receiving Lenograstim when compared to the Filgrastim group. We did not observe significant differences in G-CSF serum levels between the three groups, the highest mean serum concentrations were found in the Pegfilgrastim group.Our data argue for an improved functionality of granulocytes primed with glycosylated G-CSF.

A Combined Analysis of Average Relative Dose Intensity in the Chemotherapy of Solid Tumors with Pegfilgrastim or Filgrastim Support

A metaanalysis of 4 clinical studies that treated adult solid tumors with standard combination chemotherapy and growth factor support was conducted to study average relative dose intensity. All studies compared pegfilgrastim with filgrastim in a randomized, doubleblinded design. A total of 564 patients were included in the analyses: 291 who received pegfilgrastim and 273 who received filgrastim. For all cycles of treatment, the mean duration of filgrastim dosing was between 10 and 11 days, compared with 1 dose per cycle of pegfilgrastim. Median average dose intensities were between 99% and 100% of planned intensity in the pegfilgrastim and filgrastim groups. Across all studies, 96% of patients receiving pegfilgrastim and 95% of patients receiving filgrastim received an average relative dose intensity of ≥ 85%. Less than 10% of patients in the pegfilgrastim and filgrastim groups experienced a dose delay, and < 5% of patients received a chemotherapy reduction. We conclude that the use of prophylactic growth factor support was associated with a high proportion of chemotherapy cycles that were delivered on schedule and at full dose.

Fixed-dose single administration of Pegfilgrastim vs daily Filgrastim in patients with haematological malignancies undergoing autologous peripheral blood stem cell transplantation

Infectious complications are frequent events in patients undergoing high-dose cytotoxic chemotherapy with subsequent autologous peripheral blood stem cell transplantation (PBSCT). To evaluate whether a single subcutaneous injection of pegfilgrastim (6 mg) is as safe and effective as daily filgrastim (5 mug/kg/day), 60 consecutive autologous stem cell transplantations performed for various haematological malignancies have been analysed. In total, 24 patients undergoing 30 consecutive PBSCT received a single subcutaneous injection of 6 mg pegfilgrastim on day 5 after transplantation and were compared retrospectively with 30 patients receiving 5 mug/kg/day of filgrastim starting from day 7 post transplantation. The mean duration of grade 4 neutropenia in the pegfilgrastim and filgrastim groups was 8.3 and 9.5 days, respectively (P=0.047). The results of the two groups were not significantly different for incidence of febrile neutropenia and toxicity profile. However, duration of febrile neutropenia (1.6 vs 3.0 days) and total days of fever (1.73 vs 4.1) were different (P=0.017 and 0.003, respectively), favouring the pegfilgrastim arm. Consequently, a higher incidence of transplants with documented infectious complications associated with the filgrastim group could be observed (56 vs 26%) (P=0.02). A single injection of pegfilgrastim administered at day 5 post transplant shows comparable safety and efficacy profiles to daily injections of filgrastim.

Pegfilgrastim Shows Safety and Efficacy Similar to Filgrastim in Patients Undergoing Autologous Stem Cell Transplantation for Hematological Malignancies.

Infectious complications are frequent events in patients undergoing high dose cytotoxic chemotherapy with subsequent autologous hematopoietic stem cell transplantation. In order to determine whether a single subcutaneous injection of pegfilgrastim (6mg) is as safe and effective as daily filgrastim (5mcg/kg/d) for reducing duration of grade 4 neutropenia and infectious complications, 60 consecutive autologous stem cell transplantations (ASCT) performed for various hematological malignancies have been analyzed retrospectively at our institution. 24 patients undergoing 30 consecutive ASCT received a single subcutaneous injection of 6 mg pegfilgrastim on day 5 after transplantation and were compared retrospectively to 30 patients receiving 5mcg/kg/d of filgrastim starting from day 7 post-transplantation. Both patient cohorts were comparable with respect to baseline patient and transplant characteristics. Duration of grade 4 neutropenia, infectious complications including incidence of febrile neutropenia, microbiological surveillance data and safety parameters were assessed. The mean duration of grade 4 neutropenia in the pegfilgrastim and filgrastim groups was 8.3 and 9.5 days, respectively (p=0,058). The results of the two groups were also not significantly different for febrile neutropenia, time to neutrophil recovery and toxicity profile, including bone pain episodes. However, a higher incidence of infectious complications associated with the filgrastim vs the pegfilgrastim group could be observed (50% vs 20%) (p=0,011). Pegfilgrastim was safe and well tolerated in this patient population. A single injection of pegfilgrastim administered at day 5 post-transplant shows comparable safety and efficacy profiles to that provided by daily injections of filgrastim. A fixed-dose pegfilgrastim facilitates the management of aplasia following autologous stem cell transplantation and may offer significant benefits for patients and health care providers. Consequently, it may serve as an attractive alternative to a repetitive single G-CSF administration modus. However, prospective randomized studies are warranted to corroborate the results obtained by this retrospective analysis.

Transplantation of Peripheral Blood Stem Cells Mobilized by Chemotherapy and Single Dose Pegylated G-CSF in Patients with Multiple Myeloma: Equivalence of 6 mg and 12 mg Pegfilgrastim.

To date the most effective treatment for patients (pts) with multiple myeloma consists of conventional induction chemotherapy followed by either single or tandem high-dose chemotherapy and autologous blood stem cell transplantation. Collection of sufficient numbers of hematopoietic stem cells is essential for high-dose chemotherapy. Current regimens for stem cell mobilization are based on daily subcutaneous injections of human recombinant G-CSF starting shortly after cytotoxic therapy. Here we examined the use of polyethyenglycole (PEG)-conjugated G-CSF (pegfilgrastim) at two different doses in patients with stage II or III multiple myeloma. Patients received induction therapy with 2–4 cycles ID or VAD. Following cytotoxic therapy with cyclophosphamide (4g/m2) we administered either a single dose of 6 mg pegfilgrastim (n=10 pts; median age: 55 years), 12 mg pegfilgrastim (n=12 pts; median age: 51 years) or daily doses of 8,5 μg/kg unconjugated G-CSF (filgrastim) (n=12 pts; median age: 51 years). The growth factor was given on day 4 (range 2–5 days) in the “6 mg pegfilgrastim group”, on day 5 (range 2–7 days) in the “12 mg pegfilgrastim group” and on day 4 (range 3–6 days) in the “filgrastim group” after cyclophosphamide. Numbers of CD34+ cells were determined during leukocyte recovery and harvested by large volume apheresis using a cobe spectra blood cell separator.Pegfilgratim was associated with an earlier leukocyte recovery both at the 6mg dose (median 12 days, range 8–16 days) and the 12mg dose (median 12 days, range 7–16 days) as compared to filgrastim (median 14 days, range 11–15 days, p=0.04). Similarily, the peripheral blood CD34+ cell peak occurred earlier in patients who received pegfilgrastim (median 12 days, range 11–18 days versus median 15 days, range 12–18). On the other hand the peripheral blood CD 34+ peak did not differ significantly between the three groups (median 129/μl with 6 mg pegfilgrastim, range 30–433, median 78/μl with 12 mg pegfilgrastim, range 20– 1055 and median 111/μl with filgrastim, range 28–760, p=0.95). With a median of 1.0x10E7 CD34+ cells per kg (range 5.8x10E6-1.9x10E7) in the “6 mg pegfilgrastim group”, 7.4x10E6 CD34+ cells per kg (median, range 4.9x10E6- 3.8x10E7) in the “12 mg pegfilgrastim group” and 10.8x10E6 CD34+ cells per kg (median, range 5.0x10E6-8.7x10E7) in the “filgrastim group” there were no significant differences in the total number of harvested CD34+ cells. Following high-dose therapy with melphalan (200 mg/m2) and autografting leukocyte and platelet reconstitution was similar within all groups. In summary, a single dose of pegfilgrastim after high dose cyclophosphamide is capable of mobilizing a sufficient number of CD 34+ cells for succesful autografting and sustained hematological reconstitution in patients with multiple myeloma. No difference could be observed between 6 mg and 12 mg of pegfilgrastim. Our data provide the basis for randomized studies evaluating the optimal dose and timing of pegfilgrastim as well as long-term outcome in larger cohorts of patients.

Pegfilgrastim Versus Filgrastim To Accelerate Hematopoietic Recovery after High Dose Melphalan and Autologous Hematopoietic Stem Cell Transplant (ASCT) for Multiple Myeloma.

High-dose melphalan followed by ASCT is a common component of the early treatment for patients with multiple myeloma. Daily subcutaneous injections of filgrastim (Neupogen) at 5 ug/kg/day until ANC > 500/ul are routinely administered at our center from day +4 following ASCT, in order to accelerate hematopoietic recovery and lessen neutropenic complications. Pegfilgrastim (Neulasta) as a single 6 mg fixed dose subcutaneous injection has been shown to have similar efficacy and ease of use when compared to filgrastim in the non-transplant setting, but little data is available in the transplant setting. We began using pegfilgrastim day +1 following ASCT for patients with multiple myeloma and performed a retrospective cohort study comparing those who received filgrastim (n=6) with those who received pegfilgrastim (n=11). Transplants occurred between July 2002 and January 2004 and included all patients transplanted for myeloma in that time period for whom sufficient data was available. All patients had at least 2 x 106 CD34+ cells/kg peripheral stem cells harvested after cytoxan and filgrastim mobilization. Main outcome measures were: days from stem cell infusion to WBC nadir, days to ANC>500/ul, and days to ANC>1000/ul. Subjects were excluded if CBCs were drawn less frequently than every four days. There were no significant differences between the filgrastim and pegfilgrastim groups with respect to the following demographic variables: age, gender, hemoglobin, creatinine, calcium, albumin and beta-2 microglobulin at diagnosis. The groups were also balanced with respect to SPEP, UPEP, presence of lytic lesions and number of prior lines of therapy. The median number of CD34+ cells infused was similar: 5.7 x 106 in the filgrastim group vs 4.8 x 106 in the pegfilgrastim group (p=0.28). After transplant, median number of days to WBC nadir in the filgrastim group (FG) was 7 (range 5–9) vs 6 (range 5–8) in the pegfilgrastim group (PG) (p=0.31). However, median number of days to ANC>500/ul in the FG was 11.5 (range 11–17) vs 10 (range 9–12) for PG (p=0.02). Similarly, median number of days to ANC>1000/ul was 12 (range 11–17) for FG vs 11 (range 10–13) for PG (p=0.03). Five of six patients in the FG had neutropenic fever after transplant, compared to five of eleven patients in the PG (p=0.30). Currently, no significant differences in infection or relapse rates between groups have been noted and there were no deaths in either group. In this retrospective cohort study, pegfilgrastim was safe and at least equivalent to filgrastim for accelerating hematopoiesis after ASCT for multiple myeloma. Furthermore, there was no significant difference in the incidence of neutropenic fever, infection and survival, suggesting a similar clinical utility.

Pegfilgrastim Supports Delivery of CHOP-R Chemotherapy Administered Every 14 Days: A Randomised Phase II Study.

CHOP chemotherapy administered every 21 days has been the standard regimen for treatment of aggressive NHL for many years. Recent studies have shown improvements in both complete remission and survival following addition of Rituximab to CHOP 21 (Coffier et al, NEJM 2002) and following reduction of the cycle length of standard 21 day CHOP to 14 days (Pfreundschuh et al, Blood 2004). Previous studies with CHOP 14 have demonstrated the need for filgrastim to allow for administration of chemotherapy at planned dose and on time in this setting. The primary aim of this study was to explore the feasibility of 14 day CHOP chemotherapy plus Rituximab (CHOP-R 14) with pegfilgrastim and filgrastim. This was an open-label, randomised study of a single administration pegfilgrastim (6mg, day 2) or daily administration filgrastim (5 μg/kg; day 2 until ANC>10x109/L) in subjects with aggressive B-cell NHL being treated with CHOP-R 14 for up to 6 cycles. The endpoints of the study were proportion of cycles given at planned dose on time, proportion of subjects receiving planned dose of chemotherapy on time, and clinical response. A cycle was considered “on time” if it started <17 days after the start of the previous cycle, and at “planned dose” if a dose of >75% was administered for each agent (excluding prednisone and vincristine). This was an exploratory study using descriptive statistics to summarise endpoints therefore no formal comparisons were made between the groups. Twenty-seven subjects were randomised to filgrastim and 33 to pegfilgrastim. Twenty-six (96%) filgrastim and 32 (97%) pegfilgrastim subjects received study drug; 22 (81%) filgrastim and 30 (91%) pegfilgrastim subjects received all 6 cycles of chemotherapy. The treatment groups were generally well balanced at baseline but in the pegfilgrastim group there were more subjects randomised and more subjects completed all 6 cycles. Of the cycles planned, 93% (145/156) in the filgrastim group and 98% (188/192) in the pegfilgrastim group were administered. Of the cycles administered, 94% (137/145) and 93% (175/188) respectively were at planned dose and on time. Across the whole study, the proportion of subjects receiving chemotherapy at planned dose and on time was 81% (21/26) filgrastim and 69% (22/32) pegfilgrastim; with the proportion of subjects decreasing from cycle 2–6 (92% filgrastim and 100% pegfilgrastim in cycle 2 vs. 91% and 83% in cycle 6). The proportion of subjects reporting severe or life threatening adverse events were comparable (9 subjects, 35% filgrastim, 13 subjects, 41% pegfilgrastim). The only events reported by more than 2 subjects in either treatment group were anaemia (4, 15% vs. 4, 13%), febrile neutropenia (1, 4% vs. 3, 9%), and pyrexia (0% vs. 3, 9%). By the end of treatment, the overall response rate was 96% (25/26) for filgrastim and 94% (30/32) for pegfilgrastim subjects. This exploratory study suggests that it is feasible to deliver CHOP-R chemotherapy at planned dose and on time every 14 days, with once per cycle administration of pegfilgrastim or daily administration of filgrastim. Pegfilgrastim is safe and well tolerated with a safety profile similar to daily filgrastim in this subject population.

Peg-Filgrastim after Autologous Peripheral Blood Stem Cell Transplantation in Hematological Malignancies.

ASCO guidelines recommend the use of granulocyte-colony stimulating factors (G-CSF) as adjuvant agents after autologous peripheral blood stem cell transplantation (PBSCT), for shortening the period of severe neutropenia and reducing the related risk of life-threatening infections. The recently available pegylated formulation of G-CSF (peg-filgrastim) could have some potential advantages in phase of recovery after PBSCT, such as self-regulation mechanisms, particularly useful when neutropenia duration is unforeseeable, possible reduction/standardization of growth factor costs and possibility of more manageable outpatient treatments. We investigated the effects of a single s.c. injection of peg-filgrastim (6 mg) on day 3 in 11 patients (8 with multiple myeloma, MM; 2 with non-Hodgkin's lymphomas, NHL; 1 with acute myeloid leukemia, AML) planned to receive autologous PBSCT. Mean age was 55 years (range 24–65). In 7 patients PBSCT was performed as consolidation in first complete or partial remission, while 4 patients received the procedure as salvage treatment for chemo-sensitive disease. Conditioning regimens were intermediate/high dose melphalan in MM, BEAM protocol in NHL and TBI plus cyclophosphamide in AML. For comparison, we selected a group of 11 historical controls matched for age, type and status of disease, conditioning regimen, and number of CD34+ stem cells infused, who had received standard daily s.c. administration of G-CSF (300 mcg/d) from day 5 to neutrophil recovery after autologous PBSCT. No adverse events occurred in patients treated with peg-filgrastim. Bone pain was the only side effect referred by one patient. There was no difference between the two groups in terms of median time to hemoglobin recovery, days of febrile neutropenia and number of red cell or platelet transfusions received. However, the median times to neutrophil > 0.5 x 109/L (10 days, range 9–13 vs 12 days , range 11–14, p < 0.000) and platelet > 20 x 109/L (10 days, range 8–15 vs 13 days, range 12–20, p < 0.003) were significantly shorter in peg-filgrastim group. The median number of G-CSF injections in controls was 12 (range 9–20), so that the mean cost of this drug for single patient was 1,764 euros, as compared to 910 euros for patients receiving peg-filgrastim. We conclude that peg-filgrastim and G-CSF have comparable safety and efficacy profiles in patients affected by hematological malignancies who undergo autologous PBSCT. In this specific setting of patients, peg-filgrastim could be cost-effective. Whether peg-filgrastim may be also superior in reducing the periods of neutropenia and thrombocytopenia, requires to be confirmed and further investigated in larger studies.