A systematic literature review of the efficacy, effectiveness, and safety of filgrastim

David C Dale, Jeffrey Crawford, Zandra Klippel, Maureen Reiner, Timothy Osslund, Ellen Fan, Phuong Khanh Morrow, Kim Allcott, Gary H Lyman, David C Dale, Jeffrey Crawford, Zandra Klippel, Maureen Reiner, Timothy Osslund, Ellen Fan, Phuong Khanh Morrow, Kim Allcott, Gary H Lyman

Abstract

Purpose: Filgrastim (NEUPOGEN®) is the originator recombinant human granulocyte colony-stimulating factor widely used for preventing neutropenia-related infections and mobilizing hematopoietic stem cells. This report presents findings of a systematic literature review and meta-analysis of efficacy and safety of originator filgrastim to update previous reports.

Methods: A literature search of electronic databases, congress abstracts, and bibliographies of recent reviews was conducted to identify English-language reports of clinical trials and observational studies evaluating filgrastim in its US-approved indications up to February 2015. Two independent reviewers assessed titles/abstracts and full texts of publications, and extracted data from studies that compared originator filgrastim vs placebo or no treatment. For outcomes with sufficient homogeneous data reported across studies, meta-analysis was performed and relative risk (RR) determined. Data were summarized descriptively for all other evaluated outcomes.

Results: A total of 1194 unique articles evaluating originator filgrastim were identified, with 25 meeting eligibility criteria for data extraction: 18 randomized controlled trials, 2 nonrandomized clinical trials, and 5 observational studies. In chemotherapy-induced neutropenia (CIN), filgrastim vs placebo or no treatment significantly reduced febrile neutropenia incidence (RR 0.63, 95% CI 0.53-0.75) and grade 3 or 4 neutropenia incidence (RR 0.50, 95% CI 0.37-0.68). The most commonly reported adverse event (AE) with filgrastim was bone pain (RR 2.61, 95% CI 1.29-5.27 in CIN). Additional efficacy and safety outcomes are described within indications.

Conclusions: This systematic literature review and meta-analysis confirms and updates previous reports on the efficacy and safety of originator filgrastim. Bone pain was the commonly reported AE associated with filgrastim use.

Keywords: Absolute neutrophil count; Granulocyte colony-stimulating factor; Meta-analysis; NEUPOGEN®; Neutropenia; Systematic review.

Conflict of interest statement

David Dale has received research support from and is a consultant for Amgen Inc. Jeffrey Crawford has received research support from Amgen Inc., AstraZeneca, Bayer, Clovis, and GTx; has been a scientific advisor for Merck, Novartis, and Pfizer; and has participated as a member of a data and safety monitoring board for Celgene, G1 Therapeutics, Janssen, Merrimack, and Roche. Zandra Klippel, Maureen Reiner, Timothy Osslund, Ellen Fan, and Phuong Khanh Morrow are employees of and own stock in Amgen Inc. Kim Allcott is an employee of Oxford PharmaGenesis Ltd., which has received project funding from Amgen Inc. and Amgen (Europe) GmbH. Gary Lyman has received research support from Amgen Inc.

Figures

Fig. 1
Fig. 1
PRISMA flow diagram. AML = acute myeloid leukemia; ARS = acute radiation syndrome; BMT = bone marrow transplantation; CIN = chemotherapy-induced neutropenia; G-CSF = granulocyte colony-stimulating factor; NCT = nonrandomized clinical trial; PBPC = peripheral blood progenitor cell; RCT = randomized controlled trial; SCN = severe chronic neutropenia
Fig. 2
Fig. 2
Risk estimates in CIN for (a) FN incidence (2197 total patients; filgrastim, n = 1130; placebo or no treatment, n = 1067) and (b) grade 3 or 4 neutropenia incidence (1409 total patients; filgrastim, n = 714; placebo or no treatment, n = 695). Random effects meta-analysis was performed for the outcomes to compare data from clinical trials for filgrastim vs placebo or no treatment and relative risk determined. Note: filgrastim = originator filgrastim (NEUPOGEN®). aData for patients who received CHOP (filgrastim, n = 101; no filgrastim, n = 104) and those who received CNOP (filgrastim, n = 103; no filgrastim, n = 100) in the Osby et al. [27] study were analyzed separately. bData for patients with NSCLC (filgrastim, n = 24; no filgrastim, n = 9) and those with NHL (filgrastim, n = 10; no filgrastim, n = 5) in the Blayney et al. [30] study were analyzed separately. Chemotherapy regimens: CHOP = cyclophosphamide, doxorubicin, vincristine, prednisone; CNOP = cyclophosphamide, mitoxantrone, vincristine, prednisone. CIN = chemotherapy-induced neutropenia; FN = febrile neutropenia; NSCLC = non-small cell lung cancer; NHL = non-Hodgkin’s lymphoma
Fig. 3
Fig. 3
Risk estimates for bone pain incidence in CIN (1078 total patients; filgrastim, n = 540; placebo or no treatment, n = 538). Random effects meta-analysis was performed and relative risk determined. Note: filgrastim = originator filgrastim (NEUPOGEN®). Studies with missing reports of events for the placebo or no treatment arm (therefore, events not assumed to be 0) were not included in the analysis. aReported 0 events in the placebo or no treatment arm; 0.5 events added to each arm for an adjusted event rate. bData for patients who received CHOP (filgrastim, n = 101; no filgrastim, n = 104) and those who received CNOP (filgrastim, n = 103; no filgrastim, n = 100) in the Osby et al. [27] study were analyzed separately. Chemotherapy regimens: CHOP = cyclophosphamide, doxorubicin, vincristine, prednisone; CNOP = cyclophosphamide, mitoxantrone, vincristine, prednisone. CIN = chemotherapy-induced neutropenia

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