Dose Of Pegfilgrastim Research Articles

Use of pegfilgrastim support on day 9 to maintain relative dose intensity of chemotherapy in breast cancer patients receiving a day 1 and 8 CMF regimen

In several commonly used regimens, chemotherapy doses are split across different days of the cycle. We aimed to determine the feasibility of growth factor support with once-per-cycle pegfilgrastim in this setting. This phase II study in breast cancer patients assessed the utility of a single 6 mg subcutaneous dose of pegfilgrastim administered on day 9 of an intravenous (IV) "split" CMF (cyclophosphamide 600 mg/m(2), methotrexate 40 mg/m(2) and 5-fluorouracil 600 mg/m(2)) chemotherapy regimen administered on days 1 and 8 and repeated every 28 days for 6 cycles. Fifty-eight patients were enrolled, with 49 completing the study. For the primary endpoint, 48 patients (83%) received >or=85% of the relative dose intensity (RDI) of chemotherapy over all 6 cycles (95% confidence interval [CI], 71-91%). Across all chemotherapy cycles, 41 patients (71%) received all scheduled cycles on time and most patients (n=49, 84%) received >or=85% of the planned dose of all chemotherapy agents in all cycles. In total, 295/319 cycles (92%) were delivered on schedule and >or=85% of the planned dose of all chemotherapy agents were administered in 309/319 cycles (97%). Febrile neutropenia was reported in only 2 patients (3%). There were no grade 4 adverse events related to pegfilgrastim. Day 9 pegfilgrastim administration was well tolerated and provided effective protection against neutropenia in patients receiving IV CMF on days 1 and 8, allowing chemotherapy to be delivered on time and at the scheduled dose in most patients.

Randomized Trial and Pharmacokinetic Study of Pegfilgrastim versus Filgrastim after Dose-Intensive Chemotherapy in Young Adults and Children with Sarcomas

To compare the effectiveness, tolerance, and pharmacokinetics of a single dose of pegfilgrastim to daily filgrastim in children and young adults with sarcomas treated with dose-intensive combination chemotherapy. Patients were randomized to receive a single dose of 100 mcg/kg of pegfilgrastim s.c. or 5 mcg/kg/day of filgrastim s.c., daily until neutrophil recovery after two treatment cycles with vincristine, doxorubicin, and cyclophosphamide (VDC) and two cycles of etoposide and ifosfamide (IE). The duration of severe neutropenia (absolute neutrophil count, < or =500/mcL) during cycles 1 to 4 and cycle duration for all cycles were compared. Pharmacokinetics of pegfilgrastim and filgrastim and CD34+ stem cell mobilization were studied on cycle 1. Growth factor-related toxicity, transfusions, and episodes of fever and neutropenia and infections were collected for cycles 1 to 4. Thirty-four patients (median age, 20 years; range 3.8-25.8) were enrolled, and 32 completed cycles 1 to 4. The median (range) duration of absolute neutrophil count of <500/mcL was 5.5 (3-8) days for pegfilgrastim and 6 (0-9) days for filgrastim (P = 0.76) after VDC, and 1.5 (0-4) days for pegfilgrastim and 3.75 (0-6.5) days for filgrastim (P = 0.11) after IE. More episodes of febrile neutropenia and documented infections occurred on the filgrastim arm. Serum pegfilgrastim concentrations were highly variable. Pegfilgrastim apparent clearance (11 mL/h/kg) was similar to that reported in adults. A single dose per cycle of pegfilgrastim was well tolerated and may be as effective as daily filgrastim based on the duration of severe neutropenia and number of episodes of febrile neutropenia and documented infections after dose-intensive treatment with VDC and IE.

Mobilization of Allogeneic Peripheral Blood Stem Cells in Family Donors with Single-Dose Pegfilgrastim.

Abstract 2148Poster Board II-125 Introduction:The standard procedure for obtaining peripheral blood stem cells (PBSC) is donor mobilization with G-CSF. Pegfilgrastim is a covalently bound conjugate of filgrastim and monomethoxypolyethylene glycol with longer half-life elimination due to decreased plasma clearance and could represent an alternative approach for PBSC mobilization in healthy donors. Design and Methods:From July 2006 till August 2009 28 related healthy donors (50% male, 50% female) were treated with single dose of 12 mg pegfilgrastim for mobilization of allogeneic PBSC. The harvests were performed as large-volume, continuous-flow collections using a Cobe Spectra blood cell separator on day 4 and if necessary on day 5 of the mobilization regimen. In case of inadequate CD34+ counts (less than 4×106/kg body weight of recipient on day 5), stimulation was continued with filgrastim. In addition, the serum level of filgrastim was determined twice daily. Results:We present the results of 27 donors (the results of the 28th donor are still pending). In all 27 cases the harvests were successful. In 22 out of 27 donors (82%) only a single apheresis was needed to reach the target. Two of the donors required additional treatment with non-pegylated filgrastim.The maximal concentration of circulating CD34+ cells was achieved on day 4 (median 74.3/μl; range 24.6-136.6). The median yield of CD34+ cells was 5.9×106/kg of the recipients body weight (range 3-14.5), and the median CD3+ count was 9.1×108/kg of the recipient body weight (range 1.4-6.2). Serum filgrastim level peak was on day 2 of the mobilization regimen with a median level of 226 ng/ml (range 35 to 1123 ng/ml), thus preceding the increase of CD34+ cells in blood. The main adverse events were WHO grade 1 and included headaches, bone pain and transient elevations of alkaline phosphatase and lactate dehydrogenase. Conclusion:PBSC mobilization with a single dose of pegfilgrastim is feasible for healthy donors. The graft composition was comparable to that obtained with the conventional regimen of short-term G-CSF. Long-term follow-up of healthy donors treated with pegfilgrastim should be further investigated. Disclosures:No relevant conflicts of interest to declare.

Is pegfilgrastim safe and effective in congenital neutropenia? An analysis of the French Severe Chronic Neutropenia registry

To examine the efficacy and safety of pegfilgrastim in patients with congenital neutropenia (CN). Seventeen patients enrolled in the French Severe CN Register received pegfilgrastim. Median age at pegfilgrastim introduction was 19.1 years (range 3.9-52.3 years). In 14 cases pegfilgrastim replaced GCSF (filgrastim or lenograstim), after a median of 6.9 years of GCSF therapy. The dose of pegfilgrastim was usually one full vial per injection (except in five children, who received 1/6 to 1/2 a vial), resulting in a dose of between 50 and 286 microg/kg. The pegfilgrastim schedule ranged from two injections every 7 days to one injection every 30 days, with treatment-free periods. The median interval between the first and last dose of pegfilgrastim was 0.8 years (0.01-4.1 years). The absolute neutrophil count tended to increase more strongly on pegfilgrastim than on GCSF, but the difference was not statistically significant. During pegfilgrastim therapy, a severe infection occurred in two patients and recurrent ENT infections in two other patients. Bone pain was reported by nine patients, anemia and thrombocytopenia occurred in one patient (WHO grade III), chronic urticaria occurred in one patient (WHO grade III), and a single pegfilgrastim injection was followed by respiratory distress and death 15 days later in a patient with GDSIb. At the last update, 10 patients had stopped receiving pegfilgrastim and seven patients were still receiving pegfilgrastim. Compared to conventional GCSF, pegfilgrastim is more difficult to use in congenital neutropenia, with more frequent adverse events and sometimes poor efficacy.

To analyze efficacy and safety of pegfilgrastim versus filgrastim in patients with breast cancer

e20587 Background: We evaluated the safety and efficacy of a single fixed 6 mg dose of pegfilgrastim (a pegylated version of filgrastim) per cycle of chemotherapy, compared with daily administration of filgrastim, in the provision of neutrophil support. Methods: Patients with carcinoma of breast, less than 65 yrs with ECOG performance status 0 or 1 treated at our institution were randomized to receive either a single 6 mg subcutaneous (s.c.) injection of pegfilgrastim or daily 5 mg/kg s.c. injections of filgrastim, after adjuvant or neoadjuvant chemotherapy with doxorubicin, cyclophosphamide and docetaxel (60 mg/m, 600 mg/m2 and 75 mg/m2, respectively)q3 wk. Duration of grade 4 neutropenia (DSN), incidence of febrile neutropenia (FN), grade 4 neutropenia (SN), IV anti-infective use (IV), hospitalization and adverse events like bony pain (BP), anemia &amp; thrombocytopenias were assessed as safety endpoints. Results: 71 patients were analyzed from Aug 2007 to Dec 2008. The median age in pegfilgrastim group is 58 years and filgrastim is 57 years respectively. Results are shown ( Table ). The mean duration of grade 4 neutropenia (DSN) in cycle 1 was 2.0 and 1.7 days for the pegfilgrastim and filgrastim groups, respectively. Results for all efficacy end points in cycles 2–6 were consistent with the results from cycle 1. A trend towards a lower incidence of febrile neutropenia was noted across all cycles with pegfilgrastim compared with filgrastim (10.7% versus 18.6%, respectively). Conclusions: A single fixed dose of pegfilgrastim administered once per cycle of chemotherapy was comparable to multiple daily injections of filgrastim. [Table: see text] No significant financial relationships to disclose.

Pegfilgrastim in pediatric sarcoma patients undergoing dose-intensive chemotherapy: Phase II study results

10024 Background: Children with cancer undergoing dose-intensive chemotherapy often require G-CSF support. Patients (pts) &lt; 2 yrs have the highest risk of prolonged neutropenia due to imprecise dosing and immature drug clearance. Once-per-cycle pegfilgrastim may be beneficial due to neutrophil-mediated clearance that allows adequate serum levels throughout the neutropenic period. Young pts, who receive relatively more myeloablative chemotherapy, should have the highest pegfilgrastim exposure. Methods: Pts ≤21 yrs (age groups 0–5, 6–11, and ≥12 yrs) with sarcoma and scheduled to receive VAdriaC (cycles 1 &amp; 3) and IE (cycles 2 &amp; 4) were randomized 6:1 to receive pegfilgrastim 100 μg/kg or filgrastim (5 μg/kg/d until ANC ≥ 10×109/L) 24 hrs after chemotherapy administration. Post-nadir ANC recovery, incidence of ANC recovery by day 21 of cycles 1 &amp; 3, pharmacokinetics (PK), and safety by age group were evaluated. Results: 43 pts (63% male) received pegfilgrastim (n=37) or filgrastim (n=6). Maximum pegfilgrastim concentration was achieved ∼24-hrs postdose and sustained until ANC nadir. Pegfilgrastim levels fell rapidly as ANC recovered. One child did not achieve ANC recovery by day 21 in cycle 1: an 8-mo-old 7.9-kg boy with non-metastatic undifferentiated sarcoma had 24 days of severe neutropenia in cycle 1. The youngest age group (including this child) had longer duration of severe neutropenia and, consequently, higher pegfilgrastim exposure ( Table ). Treatment-related adverse events were generally mild to moderate (pegfilgrastim 22%, filgrastim 33%); the only treatment-related event reported by &gt;1 pt was bone pain (pegfilgrastim=11%, filgrastim=17%). Conclusions: ANC, PK, and safety profiles in pediatric patients were comparable with those in adults and support pegfilgrastim dosing across pediatric age groups. Consistent with neutrophil-mediated clearance, adequate exposure to pegfilgrastim was maintained in the youngest pts who received the most myelosuppressive chemotherapy. [Table: see text] [Table: see text]

Pegfilgrastim in colorectal cancer (CRC) patients (pts) receiving every-two-week (Q2W) chemotherapy (CT): Long-term results from a phase II, randomized, controlled study

4072 Background: Survival in advanced CRC is prolonged by adding oxaliplatin (Ox) and/or irinotecan (Iri) to Q2W 5-fluorouracil/leucovorin (5FU/LV). Combination therapy, however, has a higher incidence of febrile neutropenia (FN) and related toxicities. This study evaluated pegfilgrastim dosing on day 4 of Q2W regimens in CRC. Here we present long-term follow-up of these pts. Methods: Advanced CRC pts were randomized (1:1) to pegfilgrastim 6mg or placebo, which was stratified by CT regimen received: FOIL, FOLFOX, or FOLFIRI. We previously reported grade 3/4 neutropenia (primary endpoint) in 43% placebo and 13% pegfilgrastim pts in the 4-cycle treatment phase (odds ratio = 0.19, 95% CI: 0.10–0.37; p &lt; 0.0001). After end of treatment, pts were followed long term for ≤ 2 years (inclusive of ≤ 8 additional cycles) for serious adverse events (SAEs), overall survival (OS), and progression-free survival (PFS). Median follow-up time was 519 days. Kaplan-Meier methods estimated OS and PFS from study day 1. The study was not powered to detect PFS or OS differences between treatment groups. Results: Of 241 pts analyzed (123 pegfilgrastim, 118 placebo), 49% received FOLFOX, 26% FOLFIRI, and 25% FOIL. In the treatment period, 8% placebo and 2% pegfilgrastim pts had grade 3/4 FN ( Table ). Pegfilgrastim was well tolerated with no dose delays attributed to leukocytosis. Pegfilgrastim and placebo had similar PFS and OS ( Table ). No SAEs related to study drug were reported in the follow-up period. Conclusions: In this randomized, placebo-controlled study, pegfilgrastim significantly lowered neutropenic risk. Bone pain incidence in this CRC population was lower than in breast cancer pts treated with a taxane (Vogel J Clin Oncol 2005); the incidence in pegfilgrastim pts was modestly increased over placebo. Leukocytosis was not a concern despite the 11-day dosing interval. Long-term results suggest similar PFS and OS in the pegfilgrastim and placebo pts in this CRC study. [Table: see text] [Table: see text]

A Pharmacokinetic and Dose Escalation Study of Pegfilgrastim (KRN125) in Lung Cancer Patients with Chemotherapy-induced Neutropenia

The aim of this study was to investigate the safety, pharmacokinetic and pharmacodynamic profiles of pegfilgrastim (KRN125), a long-acting granulocyte colony-stimulating factor, in lung cancer patients with chemotherapy-induced neutropenia. Eighteen Japanese lung cancer patients who had experienced severe neutropenia (absolute neutrophil counts <0.5 x 10(9) cells/l) were enrolled. Six patients were sequentially enrolled in each pegfilgrastim dose cohort (dose levels of 30, 60 or 100 microg/kg). Patients received the same chemotherapy regimen as in their previous cycle and pegfilgrastim was injected subcutaneously the day after chemotherapy ended in each treatment cycle. Pharmacokinetic, pharmacodynamic and safety analyses were performed. Dose-limiting toxicity and serious adverse events related to pegfilgrastim were not observed in any patients. Pegfilgrastim antibodies were not detected. Maximum serum concentrations and area under the serum concentration-time curves of pegfilgrastim were dependent on the pegfilgrastim dose in a non-linear manner. Of the 18 patients, severe neutropenia occurred in 4 (22.2%), and, of these, 1 patient (5.5%) required rescue treatment by filgrastim. A single dose of pegfilgrastim increases the serum concentration of pegfilgrastim for several days in a dose-dependent manner and is not associated with significant toxicity. Good efficacy of pegfilgrastim for the prevention of severe neutropenia was observed at all dose levels. Based on these data, further studies are warranted to determine the recommended dose of pegfilgrastim for Japanese patients with chemotherapy-induced neutropenia.

Pegfilgrastim for peripheral CD34+ mobilization in patients with solid tumours

The efficacy of pegfilgrastim+/-chemotherapy for mobilizing stem cells in patients with solid tumours was assessed. In cycle 0, a 14-day prechemotherapy cycle, patients (N=61) were randomized open-label to single doses of pegfilgrastim (6, 12 or 18 mg) on day 1, or daily filgrastim (10 microg/kg) for < or =7 days. Mean peak peripheral CD34+ cell counts increased with pegfilgrastim dose, but were significantly higher than filgrastim only at the 18 mg dose (10.17 vs 4.96 x 10(4)/ml; P=0.014). In the clinically relevant period of days 3-7, both 12 and 18 mg pegfilgrastim doses produced significantly higher peak CD34+ counts (8.18 and 9.96 vs 4.51 x 10(4)/ml for filgrastim; P=0.034 and 0.006). In cycle 1, patients received carboplatin/paclitaxel on day 1, followed from day 2 by pegfilgrastim 6-18 mg or daily filgrastim (5 microg/kg/day for < or =14 days) as per randomization in cycle 0. There were no significant differences in mean peak CD34+ count between pegfilgrastim and filgrastim, but there was an advantage for pegfilgrastim 18 mg in the relevant period of days 7-12 (3.14 vs 1.19 x 10(4)/ml; P=0.043). A single pegfilgrastim dose (> or =6 mg) could be substituted for daily filgrastim in cytokine-only peripheral CD34+ cell mobilization.

Matrix Metalloproteinase 9 Levels Are Increased in Pegfilgrastim and Filgrastim Induced Mobilisation but Do Not Predict Efficiency of Mobilisation

Release of matrix metalloproteinase 9 (MMP-9), neutrophil elastase and cathespin-G from bone marrow stromal cells and granulocytic precursors in response to cytokines and chemotherapy results in degradation of important retention signals such as SDF-1 and V-CAM and promotes egress of progenitor cells from the bone marrow into the peripheral blood. In this study we investigated whether plasma MMP-9 levels could predict efficiency of haemopoietic progenitor cell mobilizationMethods: Plasma MMP-9 levels were assessed at 0, 24 and 48 hours in chemotherapy naïve patients with solid tumours. Patients were randomised to receive a single administration of 6, 12 or 18mg of pegfilgrastim on day 1 or daily administration of filgrastim 10 μg/kg/day from day 1 until day 7. Eight subjects were studied in each group. Each group was balanced in terms of baseline characteristics. Blood samples for peripheral CD34+ cell count and colony assays were collected on the first 7 days and day 9 and 12 post therapy.Results: The most common tumour types were non-small cell lung cancer (n = 15; 47%) and ovarian cancer (n = 9; 28%). In the filgrastim and pegfilgrastim 6mg, 12mg and 18mg groups a significant rise in MMP-9 levels were seen between 0 and 24 hours (380 vs. 2020 ng/ml, p=0.002; 220 vs 1920 ng/ml, p=0.015; 610 vs. 2510 ng/ml, p=0.0002 and 250 vs. 2050 ng/ml, p=0.003, respectively). In all groups, there was no significant increase in plasma MMP-9 levels between 24 and 48 hours. No significant differences in MMP-9 levels were observed between the 4 cytokine groups over 0 to 48 hours. Across all the groups no significant correlation was seen between plasma MMP-9 levels and peak colony forming units (CFU) per millilitre of blood and peak CD34 positive cells per millilitre of blood (r2=0.103, p=0.08; r2=0.09, p=0.1, respectively).Conclusion: In all cytokine groups, a significant increase in plasma MMP-9 levels occurred between day 1 and 2. No association between MMP-9, levels numbers of peripheral blood CD34 positive cells and CFU levels could be established. Plasma MMP-9 levels were not affected by pegfilgrastim dose. MMP-9 does not appear to be a predictor of mobilization efficiency for filgrastim or pegfilgrastim at doses up to 18mg.

Mobilization of peripheral blood stem cells in myeloma with either pegfilgrastim or filgrastim following chemotherapy

Quality and quantity of mobilized peripheral blood stem cells determine the safety of tandem autologous transplants in myeloma. Using the same mobilization chemotherapy with DT-PACE in two consecutive protocols, robustness of stem cell collection and rapidity of engraftment after transplantation were assessed. We employed either twice a day filgrastim versus two doses of pegfilgrastim. Advantages of pegfilgrastim were: (i) a higher percentage of patients collected 15x10(6)/kg in the first three days (p<0.001); (ii) the median number of CD34 cells/kg collected on day 1 was higher (p=0.004); (iii) the median number of growth factor injections was 2 versus 26 (p<0.0001); (iv) post-transplantation neutrophil recovery was faster after first and second transplant (p<0.001) and (v) platelet recovery was faster after first transplant (when less stem cells were infused) (p=0.01). Pegfilgrastim may be considered the standard of care for stem cell mobilization.

A single dose of pegfilgrastim compared with daily filgrastim for supporting neutrophil recovery in patients treated for low-to-intermediate risk acute myeloid leukemia: results from a randomized, double-blind, phase 2 trial

BackgroundPatients with acute myeloid leukemia (AML) are often neutropenic as a result of their disease. Furthermore, these patients typically experience profound neutropenia following induction and/or consolidation chemotherapy and this may result in serious, potentially life-threatening, infection. This randomized, double-blind, phase 2 clinical trial compared the efficacy and tolerability of pegfilgrastim with filgrastim for assisting neutrophil recovery following induction and consolidation chemotherapy for de novo AML in patients with low-to-intermediate risk cytogenetics.MethodsPatients (n = 84) received one or two courses of standard induction chemotherapy (idarubicin + cytarabine), followed by one course of consolidation therapy (high-dose cytarabine) if complete remission was achieved. They were randomized to receive either single-dose pegfilgrastim 6 mg or daily filgrastim 5 μg/kg, beginning 24 hours after induction and consolidation chemotherapy.ResultsThe median time to recovery from severe neutropenia was 22.0 days for both pegfilgrastim (n = 42) and filgrastim (n = 41) groups during Induction 1 (difference 0.0 days; 95% CI: -1.9 to 1.9). During Consolidation, recovery occurred after a median of 17.0 days for pegfilgrastim versus 16.5 days for filgrastim (difference 0.5 days; 95% CI: -1.1 to 2.1). Therapeutic pegfilgrastim serum concentrations were maintained throughout neutropenia. Pegfilgrastim was well tolerated, with an adverse event profile similar to that of filgrastim.ConclusionThese data suggest no clinically meaningful difference between a single dose of pegfilgrastim and multiple daily doses of filgrastim for shortening the duration of severe neutropenia following chemotherapy in de novo AML patients with low-to-intermediate risk cytogenetics.Trial registrationClinicaltrials.gov NCT00114764

Empiric dose reduction of pegfilgrastim in breast cancer patients receiving cytotoxic chemotherapy

20636 Background: Pegfilgrastim greatly reduces the incidence of febrile neutropenia in patients receiving myelosuppressive chemotherapy, but is associated with side effects such as bone pain often requiring analgesics. Empiric dose reduction from 6mg to 4mg administered on the day after chemotherapy was used to ameliorate pain while maintaining count recovery in these patients. Methods: We retrospectively reviewed 25 female breast cancer patients who were undergoing adjuvant or neoadjuvant chemotherapy with pegfilgrastim support who had empiric dose reductions because of bone pain with concomitant normal or high leukocyte counts during recovery. Data of blood counts, complaints of bone pain and analgesic use were collected. Weekly complete blood counts (CBC’s) were analyzed. White cell counts and ANC before and after pegfilgrastim dose reduction and treatment delays post dose reduction were recorded. Results: Median age was 52 yrs (5 < 40, 6 < 50, 6 < 60, 4 < 70 while 2 were more than 70); 18 were African Americans, 7 Caucasians; 4 stage I, 13 were stage II and 8 were stage III. Seven patients received neoadjuvant chemotherapy and 18 received it in the adjuvant setting. Thirteen patients (52%) were estrogen receptor positive; 56% patients received Doxorubicin and cyclophosphamide (60/600 mg/m2) followed by docetaxel (100 mg/m2). Median number of cycles given was 7 (range 4–10) and total number of CBC’s recorded were 397. After dose reduction, the highest white cell count noted on day 8 of the cycle was 48,600 and 41,300 on day 15; 8 patients had WBC >20,000. The lowest nadir WBC count after dose reduction was 800 with an ANC of 200 on day 8. Seven patients required narcotics for pain control at standard dose of pegfilgrastim. None of the 25 patients experienced bone pain after dose reduction. We were able to give 100% of the planned doses without dose delays in all cases after a dose reduction to 4 mg per cycle. Conclusions: From this small experience, it appears that dose reduction may be a viable and safe option to avoid the undesirable side effects of pegfilgrastim especially bone pain in patients receiving cytotoxic chemotherapy. A prospective well designed study in appropriately selected patients is warranted to investigate the optimal dose in these patients. No significant financial relationships to disclose.

A phase 2 pilot study of pegfilgrastim and filgrastim for mobilizing peripheral blood progenitor cells in patients with non-Hodgkin's lymphoma receiving chemotherapy

Growth factors are frequently used to aid peripheral blood progenitor cell mobilization from bone marrow. This phase 2 study examined the efficacy and safety of pegfilgrastim for mobilizing peripheral blood progenitors cells for autologous transplantation. Patients with non-Hodgkin's lymphoma received one cycle of mobilizing chemotherapy (ifosfamide, carboplatin and etoposide, ICE). Twenty-four hours later they were randomized, double-blind, to receive a single dose of pegfilgrastim 6 mg or 12 mg, or filgrastim 5 mug/kg/day (until the end of leukapheresis). Following leukapheresis (collection phase), patients rested or received one or two 'salvage' cycles of ICE. High-dose BEAM chemotherapy was then given before peripheral blood progenitor cell transplantation. The primary end-point was the patients' mean yield of CD34(+) cells/kg during the collection phase. Ninety patients were randomized and received a study drug; 63% completed the collection phase. The patients' mean (95% CI) CD34(+) cell harvest per leukapheresis was 0.8 (0.5-1.4), 0.8 (0.5-1.6) and 1.2 (0.7-2.0)x10(6) cells/kg for the pegfilgrastim 6 mg, pegfilgrastim 12 mg and filgrastim groups, respectively. Twenty (69%), 17 (59%) and 23 (72%) patients in these three groups achieved the targeted minimum harvest (>/=2 x 10(6) cells/kg). The mean total harvests were 1.7, 1.4 and 2.2 x 10(6) cells/kg, respectively. Post-transplantation, the median days to absolute neutrophil count recovery (>/=0.5 x 10(9)/L) were 12, 11, and 11, respectively. Pegfilgrastim and filgrastim were generally well tolerated. Pegfilgrastim (6 or 12 mg) was effective for mobilizing peripheral blood progenitors cells in patients with non-Hodgkin's lymphoma. These data may aid the design of studies to clarify optimal dosing and leukapheresis with pegfilgrastim.

GlycoPEGylated Filgrastim XM22 Demonstrates Dose-Dependent Activity in Comparison to Pegfilgrastim in a Dose-Escalating Study in Healthy Volunteers after Body-Weight Dependent Single Dose.

XM22 is a glycoPEGylated recombinant human G-CSF that interacts with the G-CSF receptor by binding and activation. In pilot studies in non-neutropenic animals, XM22 demonstrated a similar PK/PD profile compared to pegfilgrastim. Because of its longer duration of action compared to filgrastim, XM22 is intended to be dosed once per cycle for the reduction of duration of severe neutropenia and incidence of febrile neutropenia in cancer patients undergoing chemotherapy.METHODS: A single center, randomized, single-blind study of XM22, administered as single escalating body-weight (bw) dependent doses given by the s.c. route was conducted to assess safety, pharmacokinetic profile and pharmacodynamic properties based on absolute neutrophil count (ANC) and CD34+ cell count. Male or female healthy volunteers were assigned to one of 3 XM22 dose groups, at 25 μg/kg bw dose (n=8), at 50 μg/kg bw (n=15), and 100 μg/kg bw (n=15) compared to 100 μg/kg bw pegfilgrastim (n=15).RESULTS: 53 healthy volunteers were enrolled in the three dose groups and completed 21 day follow-up. Injections were generally well-tolerated with no discontinuations due to adverse events or serious adverse events. XM22 at a dose of 100 μg/kg bw exhibited a PK profile with increased bioavailability and extended half life compared to the same dose of pegfilgrastim. ANC area over baseline effect curve (AOBEC) and CD34+ AOBEC were higher after treatment with XM22 100 μg/kg bw (6818.55 hr*neut./nl and 7340.16 hr*cell count/μl geometric mean respectively) compared to the same dose of pegfilgrastim. Antibody data will be presented.CONCLUSIONS: Single body-weight dependent doses up to 100 mg/kg of XM22 administered to healthy volunteers were generally well-tolerated with regard to the expected side effect profile and demonstrated dose-dependent increases in absolute neutrophil count and CD34+ cell count. These data supplement results from another study in healthy volunteers in which XM22 was administered as a fixed dose.

Pegfilgrastim in Congenital Neutropenia: An Observational Survey from the French SCN Registry.

PegFilgrastim is registered in France since 2002. Its pharmacokinetic characteristic allows the possibility to limit the number of injections in patients with congenital neutropenia receiving long term G-CSF therapy. To date, no report has been issued about the outcome of patients with congenital neutropenia receiving this drug. At the cut-off date of July 31th, 2007, 339 patients with congenital neutropenia had been included in the French Severe chronic neutropenia (Severe congenital neutropenia n=142, WHIM n=16, Cyclic n=75; GSDIb n=16 SDS n=90). Eight patients (SCN n=4, Cyclic n=3 and GSDIb n=1) had been identified to receive PegFilgrastim. Median age at PegFilgrastim onset was 18.2 years (min 6.1-max 37.6). In 7 cases, PegFilgrastim was given in the continuation of Filgrastim (n=3) or Lenograstim(4), with a median delay of 13 years after G-CSF onset and in one case, PegFilgrastim was the initial prescription of cytokine. Dose of PegFilgrastim was usually a vial per injection, except in one child (1/2vials) resulting in a dose per injection between 90 and 286 μg/kg per injection. The rhythm of PegFilgrastim injection varied from 1 injection every 7 days until 1 injection every 14 days, with discontinuation period. The median duration (between onset of PegFilgrastim and the last dose) was 0.7 year (min 0.3–2.7). The efficiency measured by ANC criteria appears to better than G-CSF (fig 1: baseline Median ANC 156/mm3, Under G-CSF 501/mm3, Under PegFilgrastim 1901/mm3/ Kruskall Wallis test p=0.02). Severe infection was never reported under PegFilgrastim, but neither in the previous G-CSF therapeutic periods for the 7 patients. More frequent ENT infection was observed in one patient who consider the PegFilgrastim as less efficient than G-CSF. The side effects appeared to be more frequent compare to the G-CSF therapy. Bone pains were reported in 7 patients, anemia and thrombocytopenia (WHO gr II) in one, urticarian chronic skin rash in 3. Finally, at the last update, 7 patients had withdrawn PegFilgrastim, and had resumed G-CSF therapy. Only one patient is still receiving PegFilgrastim. In conclusion, PegFilgrastim appeared efficient in Congenital neutropenia, but more frequent short term side effects were observed compare to standard G-CSF therapy, resulting in a limited quality of life improvement, leading to drug withdrawn in most of the patients. [Display omitted]

Rituximab Combined to ACVBP (R-ACVBP) Supported by Pegfilgrastim as a New Inductive Treatment Followed by High-Dose Consolidative Autotransplantation (HDC) for Poor Risk Diffuse Large B-Cell Lymphoma (DLBCL) in First-Line. Results of LNH 03–39B. A GELA Study.

ACVBP dose-intense induction regimen followed by HDC provides a better event-free survival and overall survival (OS) as compared to a conventional consolidative treatment in responding patients (pts) with aggressive lymphoma presenting with 2 or 3 factors of the age-adjusted International Prognostic Index (aa-IPI). However, complete response rate (CRR = CR+CRu) after ACVBP is not superior to 65%. Besides, it is established that Rituximab (R) combined with CHOP improves CRR and OS. Several controlled studies have demonstrated that a single dose of pegfilgrastim provides similar neutrophil recovery than filgrastim after chemotherapy in cancer patients. The main objective of this study was to evaluate the efficacy of a single dose of pegfilgrastim (6 mg) at d3 of the 4 cycles of R-ACVBP inductive regimen (rituximab 375 mg/m2 d1,doxorubicin 75 mg/m2 d1, cyclophosphamide 1,200 mg/m2 d1, vindesine 2 mg/m2, bleomycin 10 mg d1 and d5 and prednisone 60 mg/m2 d1-d5) delivered every 15 days in order to maintain an optimal combined dose intensity (CDI). CDI was defined as the minimum received dose intensities of doxorubicin and cyclophosphamide by each patient. Secondary objectives were to investigate if R combined to ACVBP translates into an improvement of CRR and progression free survival (PFS). The number of leukaphereses and CD34+ cells collected in responding pts were also analyzed. Responding pts received HDC with BEAM followed by stem cell rescue. From 01/2004 to 12/2005, 60 pts were enrolled: median age was 50 y (range: 21–60), 80% with aaIPI 2 and 20% with aa-IPI 3. The mean CDI was 89 (95% CI: 86–93), greater than theoretical cut-off of 85% (p=0.0017). After induction, 63% of pts achieved CR/CRu, 25% were in PR; 2 pts died during the induction phase. At least one episode of grade 3–4 neutropenia was observed in 98% of pts, 67% experienced grade 3–4 anemia, 38% thrombocytopenia and 73% febrile neutropenia. More than 2.106 CD34+ cells/kg were collected in 80% of the pts after the 3rd and/or 4th R-ACVBP while a collection failure was observed in 11 pts (20%), 7 of them being further collected with filgrastim. The median number of leukaphereses was 2. Among the 56 responding pts, 48 received HDC. With a median follow-up of 2 years, 2-year PFS was 71% (95% CI:61–84), and OS was 91% (95% CI:74–97). We conclude that CDI is satisfactory with pegfilgrastim support. R-ACVBP dose-intense induction regimen is feasible and safe on such high-risk pts but does not increase the complete response rate. However, PFS and OS seem encouraging; a longer follow-up is needed to see whether the addition of rituximab definitely contributes to decrease the relapse rate.

Pegfilgrastim-Induced Hyperleukocytosis

To report a pediatric case of pegfilgrastim-induced hyperleukocytosis. A 3-year-old boy with medulloblastoma therapy presented with white blood cell (WBC) count 0.1 x 10(3)/microL and absolute neutrophil count (ANC) 0.014 x 10(3)/microL on day 27 following a course of induction chemotherapy. The patient received pegfilgrastim 200 microg/kg the following day. On his return 6 days later for the next planned course of chemotherapy, hyperleukocytosis was determined, with WBC 149 x 10(3)/microL and ANC 110 x 10(3)/microL ("neutrophil overshoot"). No sources of the elevated WBC count other than administration of pegfilgrastim (eg, steroids, antiepileptics, infection) were present. Chemotherapy was delayed until the WBC count had fallen to 35.2 x 10(3)/microL (ANC 28.9 x 10(3)/microL). No sequelae from this adverse effect occurred. Pegfilgrastim has unique saturable neutrophil receptor-mediated clearance, the ability for self-regulation. Due to this clearance mechanism, hyperleukocytosis associated with pegfilgrastim use is uncommon in adults and has not been previously reported in pediatrics. The pegfilgrastim dose in children is under investigation; however, 100-110 microg/kg has been effective and safe in this population. Use of the Naranjo probability scale suggested that pegfilgrastim was the probable cause of hyperleukocytosis in our patient. Pegfilgrastim 200 microg/kg, in excess of the 100 microg/kg dose used in limited pediatric clinical trials, appeared to exceed saturable neutrophil receptor-mediated clearance. The inability of this mechanism to self-regulate neutrophil counts in the normal range led to neutrophil overshoot. Routine pediatric use of the pegylated dosage form of G-CSF should await further published clinical trials to validate a safe and effective dose.

Pegfilgrastim compared with filgrastim after autologous peripheral blood stem cell transplantation in patients with solid tumours and lymphomas

To evaluate the safety and efficacy of pegfilgrastim administered as haematological support after autologous peripheral blood stem cell transplantation, we compared 44 patients with solid tumours and lymphomas receiving a 6-mg single dose of pegfilgrastim on day +5 after transplantation to a historical control group of 25 patients receiving filgrastim 5 microg kg(-1) day(-1) starting on day +5. There were no significant differences in haematological recovery nor in the incidence and duration of neutropenic fever. Median duration of grade 4 neutropenia in the pegfilgrastim and filgrastim group was similar. The incidence of grade III-IV mucositis was lower in pegfilgrastim than in filgrastim group due to the significant difference observed among the patients with solid tumours (p = 0.00). The only adverse event considered to be cytokine related was mild to moderate bone pain occurring during haematological recovery. According to the present study design and taking into account the current prices in our institution, the cost of the two drugs was similar in both treatment groups. In conclusion, a single injection of pegfilgrastim administered at day +5 post-transplantation shows comparable safety and efficacy profiles to daily injections of filgrastim and may be cost effective.

Comparison of pegfilgrastim with filgrastim on febrile neutropenia, grade IV neutropenia and bone pain: a meta-analysis of randomized controlled trials

ABSTRACTBackground and objective: While head-to-head clinical trials demonstrate pegfilgrastim to be as efficacious as filgrastim in reducing chemotherapy-induced neutropenia, these studies lacked the statistical power to demonstrate better outcomes with one therapy compared to the other. Our objective was to obtain a pooled estimate of the effect of pegfilgrastim compared with filgrastim on incidence of febrile neutropenia (FN), and related outcomes among patients with solid tumors and malignant lymphomas receiving myelosuppressive chemotherapy.Research design and methods: We searched PubMed and EMBASE for articles published from January 1, 1990 to August 31, 2006 reporting on randomized controlled trials (RCTs) that compared the efficacy and safety of pegfilgrastim versus filgrastim. We only accepted studies in which filgrastim (5 µg/kg/day) and pegfilgrastim (100 µg/kg or a fixed dose of 6 mg) were administered at approved doses indicated on the package insert. Pooled relative risk (RR) was estimated using the conservative random effects, empirical Bayesian method of Hedges and Olkin.Main outcome measures: Rates of grade IV neutropenia and of FN, time to absolute neutrophil count (ANC) recovery, and bone pain.Results: We identified five RCTs, with a total of 617 patients, evaluating the efficacy of a single dose of pegfilgrastim per cycle versus daily filgrastim injections. Although only one study had a statistically significant difference in FN reductions favoring pegfilgrastim over filgrastim (relative risk reduction of 50%; p = 0.027), the pooled RR showed a statistically significant favorable result for pegfilgrastim (RR = 0.64; 95% CI, 0.43–0.97). Grade IV neutropenia rates (for cycle 1: RR = 0.99; 95% CI, 0.91–1.08; cycle 2: RR = 0.88; 95% CI, 0.70–1.11; cycle 3: RR = 0.80; 95% CI, 0.47–1.36; cycle 4: RR = 0.90; 95% CI, 0.71–1.13), time to ANC (SMD = 0.11, 95% CI, –0.34–0.56), and incidence of bone pain (RR = 0.95; 95% CI, 0.76–1.19) were similar between the two G‑CSFs. The included trials varied in the type of cancer, chemotherapy regimen and type of trial.Conclusion: A single dose of pegfilgrastim performed better than a median of 10–14 days of filgrastim in reducing FN rates for patients undergoing myelosuppressive chemotherapy.