Single Dose Of Pegfilgrastim Research Articles

Plerixafor Plus Single-Dose Pegfilgrastim for Hematopoietic Stem and Progenitor Cell Mobilization: An Efficient and Safe Regimen In Good and Poor Mobilizer Patients

AbstractAbstract 2256Plerixafor (Mozobil®) is indicated in combination with daily filgrastim for hematopoietic stem and progenitor cell (HSPC) mobilization and subsequent autologous transplantation in patients with non-Hodgkin Lymphoma and multiple myeloma. In off-label use, pegfilgrastim (Neulasta®) is known to mobilize HSPC with a single injection. We hypothesise that pegfilgrastim is an attractive adjunct to plerixafor as a combination mobilizing regimen in both good- and poor-HSPC mobilizer patients, much like filgrastim but with the advantage to the patient of fewer injections. To-date there have been no published trials examining this combination. Aim:To investigate the tolerability, kinetics and efficacy of plerixafor plus pegfilgrastim for HSPC mobilization in patients with lymphoma or myeloma. Method:Twelve patients with lymphoma (n=10) and myeloma (n=2) underwent HSPC mobilization using single-dose pegfilgrastim (6mg SC mane D1) and nightly plerixafor (0.24 mg/kg SC nightly commencing 2200–2300hrs D3). Peripheral blood (PB) CD34+ monitoring commenced D3 and continued until the completion of apheresis. Apheresis commenced in all patients on D4. Nightly plerixafor/daily apheresis continued for up four doses/procedures, or until the target CD34+ yield (5×106/kg) was reached. CD34+ yields and kinetics were compared with historical controls mobilized with pegfilgrastim alone. Historical controls were mobilized with a single pegfilgrastim injection (6mg or 12mg SC mane D1), and PB CD34+ monitoring commenced on D4. Patients:Six ‘predicted poor-mobilizers’ (5 prior failed, 1 fludarabine-exposed) and 6 ‘predicted adequate-mobilizers’ were mobilized with pegfilgrastim plus plerixafor. Historical controls (n=22; 4 poor mobilizers) were mobilized with pegfilgrastim alone. Results:Four of 12(33%) study patients had a PB CD34+ count ≥5×106/L (our institutional threshold for collection) on D3 post-pegfilgrastim, however apheresis was commenced on D4 in all patients; all study patients surpassed this threshold by D4 (i.e. post-D3 evening dose of plerixafor). PB CD34+ counts peaked on D4 in 6/12 study patients and were sustained ≥5×106/L for 4 and 5 days in 8/12(67%) and 4/12(33%), respectively. Compared to historical controls, study patients were more heavily pre-treated (median prior regimens 2(1-4) vs. 1(0-2); P=0.002), and contained a higher proportion of poor mobilizers (50% vs. 18%; P=0.06). All study patients and 20/22 controls collected ≥2×106/kg CD34+ cells within 4 aphereses (P=0.53). Eleven of 12(92%) study patients vs. 16/22(76%) controls achieved this target after 2 apheresis procedures (P=0.37). After a maximum of 4 aphereses, there was a trend to higher median total CD34+ yields in the plerixafor plus pegfilgrastim patients compared to pegfilgrastim-alone patients; 8.0 ×106/kg (2.4-12.9 ×106/kg) vs. 4.8 (0.4-14.0 ×106/kg) (P=0.07), within a median of 1(1-4) vs. 2(1-4) collections (P=0.57). Study patients were assessed for the presence of tumor cells in the PB or apheresis product. One study patient with minimal BM involvement by lymphoplasmacytic lymphoma at baseline developed minimal detectable plasma cells in the PB and the apheresis product on D4 (post-plerixafor). One historical control patient with POEMS syndrome developed hyperleukocytosis after 12mg pegfilgrastim, which resolved without incident. The plerixafor plus pegfilgrastim combination was well tolerated: bone pain (worst grade=3, n=2), gastrointestinal symptoms (diarrhoea: worst grade=2, n=2) and facial paraesthesiae (n=3) were the most frequent adverse events. Engraftment data is currently being collected. Conclusion:Plerixafor plus pegfilgrastim is a simple, safe and effective HSPC mobilization regimen in myeloma and lymphoma, in both poor and good mobilizers. Comparison with historical controls suggests that the addition of plerixafor to pegfilgrastim may overcome risk factors for failed mobilization such as prior mobilization failure and heavy prior chemotherapy exposure, enabling even predicted poor mobilizer patients to achieve target CD34+ yields, often within just two apheresis procedures. Disclosures:Herbert: Genzyme: Research Funding, Speakers Bureau; Amgen: Speakers Bureau. Off Label Use: Pegfilgrastim was used for hematopoietic stem and progenitor cell mobilization, which is an off-label indication. The use of pegfilgrastim for this purpose is widely published. Prince: Amgen: Consultancy, Honoraria, Research Funding.

Equivalence of Pegfilgrastim and Filgrastim in Lymphoma Patients Treated with BEAM Followed by Autologous Stem Cell Transplantation

Objective: To evaluate the impact of pegfilgrastim on engraftment, hospital stay and resources in patients with Hodgkin’s and non-Hodgkin’s lymphoma after conditioning with high-dose BEAM followed by autologous peripheral blood stem cell transplantation (APBSCT) compared with filgrastim. Methods: We reviewed patient charts and our prospective transplantation database for clinical data from the post-transplant period. An integrated cost analysis, including the use of blood products and length of hospital stay, was also performed. Results: Fourteen (26%) patients with Hodgkin’s lymphoma and 40 (74%) patients with non-Hodgkin’s lymphoma were analyzed. Thirty-four (68%) patients received single-dose pegfilgrastim (6 mg), and 20 (32%) patients received daily filgrastim (5 µg/kg) after APBSCT. No differences were observed regarding duration of neutropenia grade 4 (pegfilgrastim median 7 days/filgrastim median 8 days; p = 0.13), thrombocytopenia grade 4 (7/9.5 days, respectively; p = 0.21), fever (4.5/2 days; p = 0.057), intravenous antibiotic treatment (11/10 days; p = 0.75) or length of hospital stay (16.5/16 days; p = 0.27) between the groups. The use of pegfilgrastim resulted in 12% higher treatment-related costs when compared to filgrastim, without reaching statistical significance (p = 0.38). Conclusion: Pegfilgrastim appears to be equivalent to filgrastim after high-dose BEAM followed by APBSCT in the treatment of lymphoma patients.

Effects of pegylated G-CSF on immune cell number and function in patients with gynecological malignancies

BackgroundPegylated granulocyte colony-stimulating factor (G-CSF; pegfilgrastim) is a longer-acting form of G-CSF, whose effects on dendritic cell (DC) and regulatory T cell (Treg) mobilization, and on the in vivo and ex vivo release of immune modulating cytokines remain unexplored.MethodsTwelve patients with gynecological cancers received carboplatin/paclitaxel chemotherapy and single-dose pegfilgrastim as prophylaxis of febrile neutropenia. Peripheral blood was collected prior to pegfilgrastim administration (day 0) and on days +7, +11 and +21, to quantify immunoregulatory cytokines and to assess type 1 DC (DC1), type 2 DC (DC2) and Treg cell mobilization. In vitro-differentiated, monocyte-derived DC were used to investigate endocytic activity, expression of DC maturation antigens and ability to activate allogeneic T-cell proliferation.ResultsPegfilgrastim increased the frequency of circulating DC1 and DC2 precursors. In contrast, CD4+FoxP3+ bona fide Treg cells were unchanged compared with baseline. Serum levels of hepatocyte growth factor and interleukin (IL)-12p40, but not transforming growth factor-β1 or immune suppressive kynurenines, significantly increased after pegfilgrastim administration. Interestingly, pegfilgrastim fostered in vitro monocytic secretion of IL-12p40 and IL-12p70 when compared with unconjugated G-CSF. Finally, DC populations differentiated in vitro after clinical provision of pegfilgrastim were phenotypically mature, possessed low endocytic activity, and incited a robust T-cell proliferative response.ConclusionsPegfilgrastim induced significant changes in immune cell number and function. The enhancement of monocytic IL-12 secretion portends favorable implications for pegfilgrastim administration to patients with cancer, a clinical context where the induction of immune deviation would be highly undesirable.

Pegfilgrastim reduces the length of hospitalization and the time to engraftment in multiple myeloma patients treated with melphalan 200 and auto-SCT compared with filgrastim

To reduce the duration of neutropenia after conditioning chemotherapy and autologous peripheral blood stem cell transplantation (APBSCT), granulocyte-colony stimulating factors (G-CSF) are commonly administered. We retrospectively evaluated the impact of pegfilgrastim compared to filgrastim on neutrophil engraftment, hospital stay, and supportive measures in patients with multiple myeloma after conditioning with Melphalan 200 (Mel200) followed by APBSCT. Ninety-two APBSCT after Mel200 treatment were performed in 72 patients between January 2006 and December 2009 at our institution. Patients received either single-dose pegfilgrastim (n = 46; 50%), or daily filgrastim (n = 46; 50%) after APBSCT (median duration of filgrastim use, 9 days; range, 3-14 days). Duration of neutropenia grade IV was shorter with pegfilgrastim compared with filgrastim (median, 5 days (range, 3-14 days) versus 6 days (range, 3-9 days), p = 0.0079). The length of hospitalization differed significantly (pegfilgrastim (median, 14.5 days; range, 11-47 days) versus filgrastim (median, 15.5 days; range, 12-64 days), p = 0.024). Pegfilgrastim-treated patients had less red blood cell transfusions (median, 0 transfusions (range, 0-10) versus 0.5 transfusions (range, 0-9), p = 0.00065). Pegfilgrastim was associated with reduced cost of the treatment procedure compared with filgrastim (p = 0.031). Pegfilgrastim appears to be at least equivalent to filgrastim without additional expenditure in myeloma patients treated with Mel200 and APBSCT.

Pegfilgrastim Appears Equivalent to Daily Dosing of Filgrastim to Treat Neutropenia After Autologous Peripheral Blood Stem Cell Transplantation in Patients With Non-Hodgkin Lymphoma

Filgrastim decreases the time to neutrophil recovery after autologous peripheral blood stem cell transplantation (PBSCT). We hypothesized that single-dose pegfilgrastim would mimic multiple daily doses of filgrastim, resulting in an equivalent shortening of post-PBSCT neutropenia. Patients who were eligible for PBSCT and aged >or= 18 years were identified before high-dose chemotherapy, after the harvesting and cryopreservation of peripheral blood progenitor cells (ie, > 2.5 x 10(6) CD34-positive cells/kg). Eligible patients received either standard carmustine/etoposide/cytarabine/melphalan (BEAM) or carmustine/etoposide/cytarabine/cyclophosphamide (BEAC) high-dose chemotherapy. Before high-dose chemotherapy, patients were randomly assigned to receive pegfilgrastim 6 mg on day 1 (arm A) or weight-based, dose-adjusted filgrastim beginning on day 1 (arm B) after transplantation until neutrophil engraftment. One-hundred and one patients were enrolled between April 2003 and April 2007. Three patients were not treated. Demographics were well-balanced in terms of stage at diagnosis, Eastern Cooperative Oncology Group performance status, histology, and lines of previous therapy. Results (arm A/arm B) pertained to mean doses received (1.0/12.6), mean absolute neutrophil count recovery days (9.3/9.8), red blood cell transfusions (1.7/1.9), red blood cell transfusion units (3.1/3.8), platelet transfusions (3.1/2.8), positive blood culture rate (18%/29.2%), febrile neutropenia (FN; 18%/16.7%), and duration of FN (days; 7.1/6.9). Transplantation-related mortality and grade 3 or 4 adverse events were comparable between arms. Pegfilgrastim after PBSCT appears equivalent to multiple daily doses of filgrastim. This approach might be considered in lieu of filgrastim, thus obviating the need for multiple daily injections.

A single dose pegfilgrastim for supporting neutrophil recovery in patients treated for high-risk acute myeloid leukemia by the EMA 2000 schedule

Dose intensity has been demonstrated to be one determinant for treatment efficacy in younger adults with high-risk (relapsed and refractory) acute myelogenous leukemia. Between 2000 and 2006, 56 patients entered the EMA 2000 study and received timed sequential reinduction chemotherapy. From 2004, chemotherapy was also followed by one subcutaneous dose of pegfilgrastim. Thirty-six patients reached a complete remission, while nine obtained a partial remission. Median time to granulocyte and platelet recovery was 34 and 38 days respectively. The major non-hematologic toxicities were severe infections but despite this 23 remitters could proceed to their post-remission treatment, although 13 did not because of severe toxicity or early relapse. The median overall survival was 9·3 months. The EMA 2000 regimen is a highly effective treatment with a response rate of 64% and a low early death rate. The period of critical neutropenia was relatively short in both phases and the supportive use of pegfilgrastim, although showing a trend toward reduced neutropenic period, did not appear to reduce the risk of infection in this group and may not be a critical requirement for reducing the risk of treatment-related toxicity.

Safety and efficacy of pegfilgrastim in pediatric solid tumor patients (pts).

e20007 Background: Progressive intensification of chemo-radiotherapy regimens has led to improved outcome of children with solid tumors. Marrow toxicity and neutropenia have become the main dose-limiting toxicities, often resulting in life-threatening infectious complications. Hematopoietic growth factors were introduced into clinical practice to minimize these complications. Recently Pegfilgrastim, a PEG-conjugated form of r-metHuG-CSF (filgrastim) with much longer serum half-life and a comparable safety and efficacy profile in adults has become available. We describe our retrospective institutional experience with Pegfilgrastim after myelosuppressive chemotherapy in children with solid tumours. Methods: Pts received a single subcutaneous injection of Pegfilgrastim, administered 72-96 hours after the completion of chemotherapy, at the dose of 100 μ g/kg (in children < 40 kg of weight) or 6 mg flat dose (in pts > 40 kg). Diagnoses were: CNS tumours (3), neuroblastoma (6), rhabdomyosarcoma (3), Ewing sarcoma (6), renal cancer (1) and other solid tumors (3). We analyzed: incidence and duration of grade IV neutropenia, presence and length of fever, incidence of bacteremia, absolute neutrophil count (ANC) nadir, number of platelet (Plt) and packed red blood cell (PRBC) transfusions, PBSC harvests and incidence of adverse events. Results: Between February 2008 and April 2009, 22 patients, M/F 13/9, median age 70 months (range 26-191), median body weight 19.2 kg (range 14-60.5) received 80 doses. We observed: grade IV neutropenia in 86% of courses, median ANC nadir of 0.03×109/L (range 0- 3.360×109/L), median recovery time of 14 days (range 8-30) and median duration of grade IV neutropenia of 4 days (range 0-16). Febrile neutropenia occurred in 58% of courses, with 7 cases of documented sepsis; patients received 88 PRBC transfusions and 148 Plt transfusions. 83% of PBSC harvests were successful, with a median harvest of 6,7 × 106 CD34+ cells/kg (range 2.16-60); no significant adverse events were recorded. Conclusions: A single dose of pegfilgrastim per chemotherapy course is as safe and effective as daily filgrastim in children with solid malignancies both in enhancing neutrophil recovery and in CD34+ mobilization. No significant financial relationships to disclose.

Retrospective comparison of the effects of filgrastim and pegfilgrastim on the pace of engraftment in auto-SCT patients

The high doses of chemotherapy used for the preparatory regimens before autologous blood or marrow stem cell transplantation leave patients at risk for neutropenic complications. The administration of filgrastim post transplant reduces the time to neutrophil recovery and therefore has become a standard practice at many institutions. In 2006, we implemented a practice change from filgrastim to pegfilgrastim. We present data on 164 consecutive patients (82 patients who received filgrastim compared with 82 patients who received pegfilgrastim) who received an auto-SCT between January 2006 and November 2007. Patients who received pegfilgrastim had faster engraftment (9.6 days compared with 10.9 days, P<0.0001), a lower incidence of febrile neutropenia (59% compared with 78%, P=0.015), as well as shorter hospital stay, fewer days of treatment with i.v. antibiotics (6.3 days compared with 9.6 days, P=0.006), and fewer radiographic tests, which translated to an estimated total cost savings of over $8000 per patient. Overall, there were no differences in toxicity with these two agents. We conclude that a single dose of pegfilgrastim is a safe and efficacious alternative to daily injections of filgrastim and can be a cost-effective approach in auto-SCT patients.

Randomized Phase III Trial of Pegfilgrastim versus Filgrastim after Autologus Peripheral Blood Stem Cell Transplantation

Nonrandomized trials suggest that pegfilgrastim, a pegylated granulocyte colony-stimulating factor, could be used in lieu of filgrastim after autologus peripheral blood stem cell transplantation. This phase III, randomized, double-blinded, placebo-controlled trial compared the efficacy, costs, and safety of single-dose pegfilgrastim (single 6 mg dose) versus daily filgrastim (5 microg/kg/day) for this indication. Seventy-eight patients, matched for age, sex, underlying disease, stage, and CD34/kg transplant dose were enrolled. Cytokines were started on day +1 posttransplant and continued to an absolute neutrophil count (ANC) of 5x10(9)/L for 3 days or 10x10(9)/L for 1 day. The median time to neutrophil engraftment (ANC >1.5x10(9)/L for 3 days or 5x10(9)/L for 1 day) was the same in both groups (12 days). No differences in platelet engraftment (11 versus 13 days), number of platelet transfusions (5 versus 4), percent with positive cultures for bacterial pathogens (23% versus 15%), days of fever (1 versus 2), deaths prior to engraftment (1 versus 1), or duration of hospital stay (19 versus 19 days) were seen between the pegfilgrastim and filgrastim groups, respectively. Using the average wholesale price for doses used in this trial, there was a per-patient savings of $961 for the pegfilgrastim group (P < .001). This phase III study failed to demonstrate a difference in time to neutrophil engraftment or any clinical sequelae between pegfilgrastim and filgrastim when given post-APBSCT, with pegfilgrastim achieving a cost savings over filgrastim.

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.

A comparative study of single-dose pegfilgrastim versus daily filgrastim in patients with acute myeloid leukemia

e18005 Background: Prophylactic treatment with recombinant human granulocyte colony stimulating factor (rhGCSF) is used to decrease the severity and duration of neutropenia in patients receiving myelosupressive chemotherapy. It can be used during induction and consolidation chemotherapy in acute myeloid leukemia (AML). Mechanism of action of pegylated GCSF is the same as filgrastim except for delayed clearance. Few studies addressed the use of pegylated filgrasim in AML. Methods: After 24 hours of consolidation chemotherapy, 8 patients in the study arm received single dose of subcutaneous 6 mg pegfilgrastim. The control group received daily filgrastim at a dose of 5 microgram per kg.until absolute neutroophil count of 2 ×109 cells/μL for 2 consecutive days. The neutrophil recovery time, febrile neutropenia and its duration, duration of hospitalization and safety profiles were compared. Results: There were 20 episodes of pegfilgrastim administration. The median age was 41 years in pegfilgrastim arm and 39 years in filgrastim arm. Medium time to neutrophil recovery was 14 days for pegfilgrastim arm and 17 days for filgrastim arm. In the pegfilgrastim arm 12 (60%) episodes of febrile neutropenia occurred compared to 11 (55%) in filgrastim arm. The median duration of febrile neutropenia was 3 days in pegfilgrastim arm versus 4 days in filgrastim arm. The median duration of hospitalization was 15 days in pegfilgrastim arm and 18 days in filgrastim arm. Safety profile and complete remission status did not differ between the two groups. Conclusions: The present study showed favorable profile of pegfilgrastim for netrophil recovery, duration of neutropenia and hospital stay. There was no difference with regard to safety or response to treatment. No significant financial relationships to disclose.

Pegfilgrastim for PBSC mobilization and autologous haematopoietic SCT

To date, G-CSF is the most favoured cytokine administered for PBSC mobilization because of its great efficacy and lack of serious toxicity. Recently, a pegylated filgrastim (pegfilgrastim) has been introduced. Attachment of the polyethylene glycol (PEG) moiety reduces renal excretion and masks proteolytic cleavage sites resulting in elevated G-CSF serum levels for up to 14 days after a single injection. As single-dose pegfilgrastim had similar effects in the prophylaxis of chemotherapy-induced neutropenia as the daily administration of the unconjugated drug, its capability for the mobilization of haematopoietic stem and progenitor cells has been assessed and presented to be at least equal to that of conventional G-CSF. Administration of pegfilgrastim following high-dose therapy and autologous blood SCT (BSCT) shortened the time to myeloid recovery as seen in conventional G-CSF. Plasma G-CSF levels were about 1 log higher with pegfilgrastim, but in the setting of autologous BSCT this did not translate into a faster haematopoietic recovery. Only few data exist on the biological effects of pegfilgrastim. Still, these data suggest that pegfilgrastim-stimulation results in different functional properties of haematopoietic stem and progenitor cells compared with G-CSF.

Single-dose pegfilgrastim is comparable to daily filgrastim in mobilizing peripheral blood stem cells: a case-matched study in patients with lymphoproliferative malignancies

Pegfilgrastim (PEGFIL) has been found to be comparable to daily filgrastim (FIL) in managing chemotherapy-induced neutropenia. In the present study, we evaluated the ability of PEGFIL to mobilize stem cells in 38 consecutive patients with lymphoproliferative diseases (multiple myeloma, n = 18; lymphomas, n = 15; chronic lymphocytic leukemia, n = 5). Patients were mobilized using PEGFIL (6-18 mg as a single dose) during 2005-2006; 32 then received high-dose chemotherapy followed by autologous stem cell transplantation. PEGFIL-mobilized patients were matched by age, disease, and treatment line at a ratio of 1:2 to historical FIL-mobilized controls. The primary study endpoint was the blood CD34(+) concentration at onset of leukapheresis. Leukapheresis began a median of 10 days from the beginning of mobilization chemotherapy in both groups. At the onset of leukapheresis, median blood CD34(+) cell counts did not differ significantly in the FIL group compared with the PEGFIL group (79 x 10(6)/L vs 64 x 10(6)/L, respectively; p = 0.44). In the different disease categories, the respective CD34(+) cell counts after FIL and PEGFIL mobilization were 72 x 10(6)/L vs 123 x 10(6)/L (p = 0.08) in myeloma, 51 x 10(6)/L vs 62 x 10(6)/L (p = 0.6) in lymphomas, and 27 x 10(6)/L vs 30 x 10(6)/L (p = 0.62) in CLL, respectively. The target CD34(+) cell yield was harvested with one leukapheresis in 53% of PEGFIL-mobilized patients. Engraftment after autografting did not differ significantly in the two groups. Stem cell mobilization with a single dose of PEGFIL was, therefore, comparable to that achieved using daily FIL in patients with lymphoproliferative diseases. PEGFIL is a more practical way to mobilize stem cells than daily FIL.

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

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.

Efficient mobilization of peripheral blood stem cells following CAD chemotherapy and a single dose of pegylated G-CSF in patients with multiple myeloma

High-dose chemotherapy followed by autologous blood stem cell transplantation is the standard treatment for myeloma patients. In this study, CAD (cyclophosphamide, adriamycin, dexamethasone) chemotherapy and a single dose of pegfilgrastim (12 mg) was highly effective in mobilizing peripheral blood stem cells (PBSCs) for subsequent transplantation, with 88% of patients (n = 26) achieving the CD34+ cell harvest target of > or = 7.50 x 10(6) CD34+ cells/kg body weight, following a median of two apheresis procedures (range 1-4) and with first apheresis performed at a median day 13 after CAD application (range 10-20). Patients treated with pegfilgrastim showed a reduced time to first apheresis procedure from mobilization compared with filgrastim-mobilized historical matched controls (n = 52, P = 0.015). The pegfilgrastim mobilization regimen allowed for transplantation of a median of 3.58 x 10(6) CD34+ cells/kg body weight while leaving sufficient stored cells for a second high-dose regimen and back-ups in most patients. Engraftment following transplantation was comparable to filgrastim, with a median time of 14 days to leucocyte > or =1.0 x 10(9)/l (range 10-21) and 11 days to platelets > or = 20 x 10(9)/l (range 0-15). The results of this study thus provide further support for the clinical utility of pegfilgrastim for the mobilization of PBSC following chemotherapy in cancer patients scheduled for transplantation.

Mobilisation of Autologous Stem Cells Using a Single Fixed Dose Injection of Pegfilgrastim; Feasibility in Extensively Pre-Treated Lymphoma and Myeloma Patients.

In patients with multiple myeloma and refractory or relapsed lymphoma consolidation high-dose chemotherapy combined with stem cell rescue is an established therapy in chemosensitive disease. A commonly used approach to mobilise CD34+ haematopoietic stem cells is the administration of granulocyte colony-stimulating factor following a course of chemotherapy. Pegylation of filgrastim decreases renal clearance of the molecule. Pegfilgrastim is subject to a distinct method of clearance compared to filgrastim. The clearance therefore depends almost solely on a neutrophil receptor mediated process. This means clearance is self-regulated and increases when the number of neutrophils with G-CSF receptors augments in the blood. In earlier series of patients, pegfilgrastim showed to be effective in mobilising blood progenitor cells in single fixed doses of 6 mg. as well as 12 mg. The optimal dose and scheduling of the injection and apheresis is not completely established in various patients groups with diverse extents of chemotherapeutic pre-treatment. In this study we compared the mobilisation kinetics of patients with different haematological malignancies using either filgrastim or one injection of pegfilgrastim in two different doses. 58 patients with various indications for autologous stem cell transplantation were studied. The transplantation indications were multiple myeloma, NHL and Hodgkin's lymphoma. Patients received a single dose of either 6 mgs or 12 mgs of pegfilgrastim; a third group of patients was treated with filgrastim daily. Filgrastim administration was stopped as soon as sufficient numbers of stem cells were harvested. Harvesting in both groups started as soon as an absolute CD 34+ count of >1 × 107 per litre was reached. The required number of stem cells was 3 × 106/kg bodyweight (6 × 106/kg in multiple myeloma patients). Mobilisation kinetics and apheresis results were compared in the three groups. The one-way analysis of variance (ANOVA) was used to compare the data.26 Patients received a single dose of 6 mgs pegfilgrastim and 10 patients received a dose of 12 mgs of pegfilgrastim. 22 Patients, matched for disease type and pre-treatment regimens, age and gender received filgrastim daily. The filgrastim was administered in an average total dose of 4,2 mgs. (7,7 m gr./kg/day). Table 1 shows results of the apheresis. Of 26 patients who received pegfilgrastim 6 mgs, 5 patients showed a failure mobilising stemcells (21%). In 2 of those 5 patients harvesting succeeded eventually after additional stimulation with filgrastim and another 2 patients were mobilised in a later stage after additional chemopriming and filgrastim in high dosage. One of the patients receiving 12 mgs. of pegfilgrastim also needed additional filgrastim administration. None of the filgrastim mobilisation procedures failed. The results indicate that a single dose pegfilgrastim of 6 mgs is not capable of mobilising sufficient peripheral blood stem cells in all patients. In this study, both doses of pegfilgrastim showed a reduced CD34 cells harvest and less efficient apheresis procedures.Table 1:Results Apheresispegfilgrastimpegfilgrastimfilgrastim6 mg (n=26)12 mg (n=10)(n=22)day 1st apheresis, mean (SD) *12.2 (1.4)12.1 (0.9)13.5 (2.4)max. blood CD34+ count (×107/L), mean (SD)8.6 (7,7)7.9 (6,6)11.6 (10)number CD34+ cells (×106/kg), mean (SD)8.2 (4.6)8 (2,5)11 (6,2)number CD34+ cells (×106/kg)per litre proc. volume, mean (SD) *440 (290)461 (350)797 (650)failure apheresis510* p<0,05

Efficacy of single dose pegfilgrastim in enhancing the mobilization of CD34+ peripheral blood stem cells in aggressive lymphoma patients treated with cisplatin-aracytin-containing regimens

Systematic data on the ability of pegfilgrastim to mobilize stem cells after chemotherapy are scarce. We evaluated the efficacy of a single 6 mg dose of pegfilgrastim for mobilizing peripheral blood stem cells (PBSC) in aggressive lymphoma patients. Between July 2004 and October 2005, 17 aggressive non-Hodgkin's lymphoma and 11 poor-risk Hodgkin's lymphoma were treated with cycles containing cisplatin-aracytin. At the end of chemotherapy, the patients received 6 mg of pegfilgrastim. Duration of grade 4 neutropenia, adverse events, time to neutrophil recovery, peak and harvest of CD34+ cells were recorded. Twenty-seven out of 28 patients harvested a median of 17.3 x 10(6)/CD34+ cells (range 2.5-28.9) after a median of 9 days (range 8-12 days), with a single apheresis procedure in 25 cases. All patients had grade 3-4 neutropenia, median duration 3 days. The only adverse event was mild bone pain. To date, 13 patients have been autografted with a median of 15.4 x 10(6) CD34+ pegfilgrastim-mobilized cells per kg (range 2.5-28.9) with rapid and sustained engraftment. Mobilization, harvesting and autografting of pegfilgrastim-mobilized PBC can be successfully achieved in pretreated patients with aggressive lymphoma.

Efficacy of single‐dose pegfilgrastim after chemotherapy for the mobilization of autologous peripheral blood stem cells in patients with malignant lymphoma or multiple myeloma

A single injection of pegfilgrastim has been shown to be equivalent to daily filgrastim in enhancing neutrophil recovery after chemotherapy, whereas the experiences with pegfilgrastim in mobilization of peripheral blood progenitor cells (PBPCs) are limited. Forty unselected patients with lymphoma or multiple myeloma were treated with different chemotherapy regimens followed by 6 mg of pegfilgrastim for mobilization of autologous PBPCs. Patients with an inadequate mobilization (blood CD34+ cells <or= 10/microL after nadir) were given additional daily doses of 10 microg per kg unconjugated filgrastim. A median blood CD34+ peak concentration of 81 per microL (range, 10-565/microL) was found in 30 patients, who had only received pegfilgrastim, compared to 13 per microL (median, range 4-71/microL; p < 0.001) in 10 poor mobilizing patients with additional filgrastim. The median yield of CD34+ cells was 9.8 x 10(6) per kg (range, 1.5-88.1) after pegfilgrastim only versus 2.5 x 10(6) (range, 1.7-7.0) in poor mobilizers. Patients who needed additional cytokine administration were those with a more extensive previous antineoplastic treatment and mobilizing regimens containing PBPC toxic agents. The results confirm the efficacy and feasibility of PBPC mobilization with chemotherapy and single-dose pegfilgrastim in patients with lymphoproliferative malignacies. In less heavily pretreated patients, 6 mg of pegfilgrastim after chemotherapy induced an adequate mobilization, whereas dose and schedule in patients after numerous cytotoxic regimens need further investigation.

Randomized trial and pharmacokinetic study of pegfilgrastim vs. filgrastim in children and young adults with newly diagnosed sarcoma treated with dose intensive chemotherapy

9020 Background: Daily subcutaneous (SC) filgrastim reduces the duration of severe neutropenia in children receiving dose intensive chemotherapy. A single SC dose of pegfilgrastim may be as efficacious. Methods: We conducted a randomized, non-inferiority trial comparing neutrophil recovery, tolerability, and pharmacokinetics of pegfilgrastim (100 mcg/kg SC once/cycle) to filgrastim (5 mcg/kg SC daily until post nadir ANC &gt;10,000) in children and young adults with newly diagnosed sarcoma treated with vincristine, doxorubicin, and cyclophosphamide (VDC) for cycles 1, 2, 5, 9, 11, 13 alternating with etoposide and ifosfamide (IE) for cycles 3, 4, 6–8, 10, 12, 14. Local control with radiation or surgery was initiated after cycle 5. Serum GCSF concentrations were monitored during cycle 1 and measured by ELISA. Complete blood counts were monitored thrice weekly during cycles 1–4. Cycle duration was collected for all cycles. Results: Accrual has been completed. 34 patients (median age 19 y, range 3–25 y) were enrolled, 28 have completed 4 cycles, and 26 have completed therapy. Growth factor associated toxicity included reversible transaminase elevation and arthralgias and was similar on the 2 treatment arms. For filgrastim (n=13) the median (range) GCSF Cmax was 12 ng/mL (4–16 ng/mL), Css was 7 ng/mL (2–9 ng/mL) and Tmax was 6 h (4–8 h). For pegfilgrastim (n=13), the median (range) GCSF Cmax was 69 ng/mL (11–235 ng/mL), Css was 43 ng/mL (7–151 ng/mL) and Tmax was 28 h (4–168 h). Median (range) neutrophil recovery and cycle duration are presented in the table. Conclusion: Pegfilgrastim was well tolerated. Peak and steady state serum GCSF concentrations were higher in patients receiving pegfilgrastim but more variable. The number of days of severe neutropenia and the cycle duration with single dose pegfilgrastim appear to be at least equivalent to daily filgrastim. [Table: see text] No significant financial relationships to disclose.