Once-per-cycle pegfilgrastim (Neulasta) for the management of chemotherapy-induced neutropenia

doi:10.1016/S0093-7754(03)00314-2

Seminars in Oncology

Volume 30, Supplement 13, August 2003, Pages 24-30

https://doi.org/10.1016/S0093-7754(03)00314-2 Get rights and content

Abstract

Filgrastim (r-metHuG-CSF) was approved in the United States in 1991 for use in decreasing the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies treated with myelosuppressive chemotherapy. Colony-stimulating factors such as filgrastim are a significant advance in the supportive care of patients with cancer. However, because of its short half-life, filgrastim requires daily dosing by injection to maintain its effects on the bone marrow. Pegfilgrastim (Neulasta; Amgen, Thousand Oaks, CA) is a longer-acting, self-regulating form of filgrastim created by the covalent linkage of a 20-kd polyethylene glycol molecule to the N-terminal of the filgrastim molecule. The molecular characteristics of pegfilgrastim result in a longer terminal half-life, making once-per-chemotherapy-cycle administration possible. The results from two randomized double-blind phase III clinical trials in patients with breast cancer treated with myelosuppressive chemotherapy showed that a single dose of pegfilgrastim provides neutrophil support comparable with that provided by an average of 11 daily injections of filgrastim. Pegfilgrastim has also been shown to be comparable to filgrastim in reducing neutropenic complications in patients treated with chemotherapy for lymphoma. Data from three clinical trials have been presented: a randomized controlled trial in elderly patients treated with CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone) for relapsed or refractory non-Hodgkin’s lymphoma; a randomized controlled trial in patients treated with ESHAP (etoposide/methylprednisolone/cisplatin/cytarabine) for relapsed or refractory lymphoma; and a study in patients with newly diagnosed non-Hodgkin’s lymphoma. The safety profile of pegfilgrastim is comparable to that of filgrastim in the clinical settings studied to date. The once-per-cycle administration of pegfilgrastim may improve patient quality of life because it is less disruptive to patients and caregivers, and increase adherence because no doses are missed, thus further advancing the management of chemotherapy-induced neutropenia and its consequences.

Section snippets

Pegfilgrastim: rationale and molecular characteristics

Filgrastim was approved in 1991 to decrease the incidence of infection and febrile neutropenia (FN) in patients with nonmyeloid malignancies treated with myelosuppressive chemotherapy. Since that time, several million patients treated with chemotherapy for cancer have benefited from it. The availability of filgrastim markedly changed the treatment of patients with cancer, for whom the prevailing attitude had been the acceptance of treatment with potentially life-threatening toxicity. Filgrastim

Phase I studies in healthy volunteers and patients with cancer

The pharmacokinetics of pegfilgrastim given by the subcutaneous route have been studied both in healthy adult volunteers and in adult patients with cancer.5, 12 In 32 adult volunteers, pegfilgrastim administered as a single subcutaneous dose ranging from 30 to 300 μg/kg was well tolerated and produced dose-dependent increases in the absolute neutrophil count (ANC).5 The neutrophil counts increased from the pretreatment value in a dose- and time-dependent fashion, producing median peak values of

Conclusion

The commercial availability of pegfilgrastim, a newer colony-stimulating factor with a sustained duration of action, is an advance in neutrophil growth factors. Pegfilgrastim was created by the covalent attachment of a PEG molecule to the filgrastim parent protein in a process known as pegylation. Unlike filgrastim, which undergoes predominantly renal elimination, pegfilgrastim is of sufficient size to minimize renal elimination. Data in patients with cancer show that the primary route of

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Chemotherapy-induced neutropenia and emerging agents for prevention and treatment: A review
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Citation Excerpt :
PEGylation, which increases the size of the molecule and prevents renal excretion, has been most successful [42]. PEGylation increases the serum half-life of G-CSF by up to 42 h, enabling the dosing schedule to be 1 dose per cycle [43]. The first PEGylated G-CSF agent approved for use was pegfilgrastim in 2002 [44].
Polymer-drug conjugates: Design principles, emerging synthetic strategies and clinical overview
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Adagen, an enzyme replacement treatment for adenosine deaminase deficiency, was the first protein-polymer conjugate to be approved in early 1990 s. Post this regulatory approval, numerous polymeric drugs and polymeric nanoparticles have entered the market as advanced or next-generation polymer-based therapeutics, while many others have currently been tested clinically. The polymer conjugation to therapeutic moiety offers several advantages, like enhanced solubilization of drug, controlled release, reduced immunogenicity, and prolonged circulation. The present review intends to highlight considerations in the design of therapeutically effective polymer-drug conjugates (PDCs), including the choice of linker chemistry. The potential synthetic strategies to formulate PDCs have been discussed along with recent advancements in the different types of PDCs, i.e., polymer-small molecular weight drug conjugates, polymer-protein conjugates, and stimuli-responsive PDCs, which are under clinical/preclinical investigation. Current impediments and regulatory hurdles hindering the clinical translation of PDC into effective therapeutic regimens for the amelioration of disease conditions have been addressed.
Nanomedicines accessible in the market for clinical interventions
2021, Journal of Controlled Release
Citation Excerpt :
It was synthesized by PEGylation of parent recombinant protein molecule NEUPOGEN® (Filgrastim) [87]. It is indicated for the treatment of febrile neutropenic patients who underwent myelosuppressive chemotherapy for non-myeloid malignancies [145]. Neulasta® is produced by covalent interaction of PEG with filgrastim, which is a recombinant human Granulocyte-colony stimulating factor (G-CSF) produced from E. coli that leads to a bulky molecule.
Nanomedicines refers to nanotechnology inspired pharmaceutical products often referred to as ‘nanopharmaceuticals.’ It has displayed commendable potential in enhancing therapeutic efficacy as well as in reducing the side effects associated with conventional drug counterpart. Recent years have monitored the entry of a large amount of nanomedicine in the market with an appreciable market share to date. Despite this, the development of nanomedicine is posing challenges (i.e., safety, regulatory hurdles, cost, scale-up issues, etc.) that need to be resolved for their market entry. This review presents a cross-sectional discussion on the nanomedicine-derived products available in the market for both clinical and diagnostic applications. An overview of its market potential, market size, and the products that are currently in the clinical stages is also provided. The review also expounds on the challenges faced by nano-drug products at the time of their commercialization.
Side effects of using granulocyte-colony stimulating factors as prophylaxis of febrile neutropenia in cancer patients: A systematic review
2021, Critical Reviews in Oncology/Hematology
Citation Excerpt :
Even if the real prevalence of bone pain due to G-CSF is difficult to assess, given the difference in chemotherapy and G-CSF used, overall it could be estimated to range between 25 % and 38 % (Lambertini et al., 2014). This type of pain is generally described as mild or moderate (Biganzoli et al., 2004; Frampton and Keating, 2005; Aapro et al., 2010b; Renwick et al., 2009; Crawford, 2003; Jakubowski and Gabrilove, 1996), involving mainly the sternal, lumbosacral and sacroiliac regions (Van Ryckeghem et al., 2019) and it usually does not lead to the interruption of treatment with G-CSF (Biganzoli et al., 2004). Short-term bone pain is the most frequent adverse effect also in the pediatric setting.
We systematically reviewed the literature regarding short- and long-term safety and tolerability of prophylactic use of Granulocyte-Colony Stimulating Factor (G-CSF) for chemotherapy-related febrile neutropenia (FN).
730 pertinent records published from 1994 to 2020 were identified. Exclusion criteria included no assessment of safety or Quality of life (QOL).
Among 88 full-texts included, most studies were conducted during or shortly after G-CSF administration. Mild-to-moderate medullary bone pain was the most reported side effect, usually responsive to anti-inflammatory drugs although potentially impactful on daily functioning. Transient leukocytosis, thrombocytopenia and alterations in biochemistry were also commonly reported. Short-term improvements in patient-reported outcomes were observed as a result of reduction of FN and secondary complications. Secondary myeloid neoplasms were the only reported late effect. No studies evaluated the long-term impact on QOL.
G-CSF seem safe and well-tolerated, although few data are available on long-term impact of use of G-CSF.
Comparative analysis of neutropenia in children with cancer treated with chemotherapy and granulocyte colony-stimulating factor or its pegylated form
2012, Pediatria Polska
W onkologii stosuje się czynnik wzrostu kolonii granulocytarnych (filgrastim) celem przyspieszenia odnowy granulocytarnej. Pegfilgrastim jest jego pegylowaną postacią o znacznie przedłużonym czasie działania.
Analiza porównawcza skuteczności działania filgrastimu i pegfilgrastimu zastosowanych po chemioterapii u dzieci z chorobami nowotworowymi.
Retrospektywnej analizie poddano przebieg neutropenii po chemioterapii oraz towarzyszących jej objawów u 18 pacjentów otrzymujących filgrastim i u 12 otrzymujących pegfilgrastim.
Nie stwierdzono istotnych różnic w przebiegu klinicznym pomiędzy obiema grupami pacjentów. Jednakże u pacjentów otrzymujących pegfilgrastim czas trwania ciężkiej neutropenii byt znamiennie krótszy niż u pacjentów otrzymujących filgrastim (4,5 vs 7,5 dnia, p=0,017), a różnica czasu trwania bardzo ciężkiej neutropenii oraz czasu trwania ciężkiej leukopenii byty bliskie znamienności statystycznej. Wśród pacjentów otrzymujących pegfilgrastim częstość występowania gorączki neutropenicznej byfa znamiennie niższa (10/22 vs 23/26, tj. 45% vs88%, p=0,003), jednak mediana czasu trwania gorączki byfa wyższa w tej grupie (3 vs2 dni, p=0,008). Pacjenci nie zgłaszali dolegliwości związanych ze stosowaniem filgrastimu lub pegfilgrastimu.
Pegylowaną postać filgrastimu o przedłużonym działaniu jest lekiem bezpiecznym i dobrze tolerowanym przez dzieci z chorobami nowotworowymi po chemioterapii. W porównaniu z filgrastimem zastosowanie pegfilgrastimu stwarza możliwości skrócenia czasu ciężkiej neutropenii i redukcji częstości występowania gorączki neutropenicznej.
Granulocyte colony stimulating factor (G-CSF, filgrastim) is used in oncology to accelerate granulocyte recovery. Pegfilgrastim is its pegylated derivative with prolonged activity.
Comparative analysis of effectiveness of pegfilgrastim or filgrastim applied after chemotherapy in children with cancer.
A total number of 18 patients receiving filgrastim and 12 patients receiving pegfilgrastim were enrolled into analysis.
There were no significant differences in clinical course between the two groups of patients. However, duration of severe neutropenia was significantly shorter for patients receiving pegfilgrastim than those receiving filgrastim (4.5 vs 7.5 days, p=0.017), and the difference in the duration of very severe neutropenia and duration of severe leukopenia almost reached statistical significance. Among patients receiving pegfilgrastim, incidence of febrile neutropenia was significantly Iower (10/22 vs 23/26, ie 45% vs 88%, p=0.003), but the median duration of fever was higher in this group (3 vs 2 days, p=0.008). Patients did not report adverse symptoms associated with the use of pegfilgrastim or filgrastim.
Pegylated form of filgrastim with prolonged activity, is a safe drug and well tolerated by children with cancer after chemotherapy. In comparison with filgrastim, the application of pegfilgrastim gives the possibility to reduce the severe neutropenia and reduce the incidence of febrile neutropenia.
Emergency granulopoiesis promotes neutrophil-dendritic cell encounters that prevent mouse lung allograft acceptance
2011, Blood
Citation Excerpt :
Accordingly, in our present studies, G-CSF was administered as a single bolus at the time of transplantation to better model the kinetics of G-CSF expression in Ext CI lung recipients. In contrast, when G-CSF is used to mobilize hematopoietic progenitors, it is generally given over the course of up to 5 days or it is PEGylated to increase stability, potentiating prolonged exposure to T cells within the blood and BM.35,36 Therefore, it remains likely that during lung transplantation, direct G-CSF exposure to T cells is relatively transient compared with its use as an agent to promote hematopoietic progenitor isolation.
The mechanisms by which innate immune signals regulate alloimmune responses remain poorly understood. In the present study, we show by intravital 2-photon microscopy direct interactions between graft-infiltrating neutrophils and donor CD11c⁺ dendritic cells (DCs) within orthotopic lung allografts immediately after reperfusion. Neutrophils isolated from the airways of lung transplantation recipients stimulate donor DCs in a contact-dependent fashion to augment their production of IL-12 and expand alloantigen-specific IFN-γ⁺ T cells. DC IL-12 expression is largely regulated by degranulation and induced by TNF-α associated with the neutrophil plasma membrane. Extended cold ischemic graft storage enhances G-CSF–mediated granulopoiesis and neutrophil graft infiltration, resulting in exacerbation of ischemia-reperfusion injury after lung transplantation. Ischemia reperfusion injury prevents immunosuppression-mediated acceptance of mouse lung allografts unless G-CSF–mediated granulopoiesis is inhibited. Our findings identify granulopoiesis-mediated augmentation of alloimmunity as a novel link between innate and adaptive immune responses after organ transplantation.

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¹: Dr Crawford receives grant or research support from, is a consultant to, and is on the speakers bureau of Amgen.

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Once-per-cycle pegfilgrastim (Neulasta) for the management of chemotherapy-induced neutropenia

Abstract

Section snippets

Pegfilgrastim: rationale and molecular characteristics

Phase I studies in healthy volunteers and patients with cancer

Conclusion

Blood

Eur J Cancer

Exp Hematol

Cancer Treat Rev

Cancer Treat Rev

Cancer Treat Rev

Cancer Treat Rev

Ann Oncol

Ann Oncol

Filgrastim (r-metHuG-CSF) in the chemotherapy setting