Pegfilgrastim: the promise of pegylation fulfilled

J. Crawford

Division of Medical Oncology and Transplantation, Duke Comprehensive Cancer Center, Duke University Medical Center, Durham, NC, USA

The laboratory and clinical investigation of hematopoietic growth factors has had a profound impact on the practice of oncology and the care of cancer patients [1]. In studies with these agents, we have learnt not only about the biological effects these agents have on the hematopoietic system, but also about the clinical benefit that occurs by reducing treatment-related anemia, neutropenia and thrombocytopenia. With regard to the colony-stimulating factors (G-CSF, GM-CSF) our knowledge base continues to grow and guidelines for clinical use continue to undergo revision [2]. In addition to reducing the toxicity of myelosuppressive chemotherapy for millions of cancer patients, these agents have also been integral to the study of chemotherapy dose intensity and dose density. The science of stem cells has been heavily dependent on the study of the hematopoietic cytokines and their regulation and interaction. As a result, the application of high-dose chemotherapy with CSF-mobilized progenitor-cell support has become a standard of care in selected patients with hematological malignancies, while dose-dense chemotherapy approaches are showing promising results in both hematological malignancies and solid tumors, particularly breast cancer [3].

It is remarkable that all of this has occurred over the last decade since the initial approval of filgrastim (G-CSF) [4]. While much work remains to further our understanding of the biology and clinical applications of G-CSF, a major advance has occurred by the redesign of the molecule as pegfilgrastim [5]. Filgrastim, a low molecular weight protein (18 800 kDa), is freely filtered by the kidney leading to rapid clearance of the molecule and a half-life of ~3 h after subcutaneous dosing, necessitating daily injections. The addition of a 20 kDa polyethylene glycol moiety to filgrastim changes the pharmacokinetic properties to virtually eliminate renal clearance. The major remaining mode of clearance of pegfilgrastim is the neutrophil itself through a ‘self-regulating’ mechanism [6].

The initial clinical study of this molecule demonstrated that a single dose of pegfilgrastim after chemotherapy led to a steady state serum concentration of this cytokine during the post chemotherapy period, through the neutrophil nadir until subsequent neutrophil recovery [7]. Pegfilgrastim stimulates the expansion of early myeloid precursors and the more rapid maturation and differentiation of neutrophils. As adequate neutrophil recovery occurs, these cells clear pegfilgrastim from the serum through G-CSF receptor–ligand binding over a rapid time course of 24–48 h. The early clinical studies, as well as other preclinical work, suggested that the pharmacokinetic/pharmacodynamic benefit of pegfilgrastim compared with filgrastim occurs with equivalent effects on cell proliferation, receptor binding, neutrophil response and neutrophil function [57].

Of course, proof that pegfilgrastim is equal in clinical benefit to filgrastim can only come through randomized clinical trials. In this issue of the Annals of Oncology, Green et al. present the results of such a study in women with breast cancer receiving doxorubicin 60 mg/m2 and docetaxel 75 mg/m2 every 3 weeks for four cycles [8]. This regimen is associated with an average duration of grade IV neutropenia of 4 days, in the absence of growth factors. Thus, patients were randomized to receive a single subcutaneous dose of pegfilgrastim 24 h after chemotherapy administration and repeated with each cycle versus daily filgrastim injections at 5 µg/kg per day. This same design was also used in another phase III trial published by Holmes et al. [9]. The major difference in the design of the two trials was that the Holmes study used a per weight dosing of pegfilgrastim at 100 µg/kg, while the Green trial used a fixed dose of 6 mg. This dose was computed from the phase II data where comparisons with filgrastim showed similar rates of neutrophil recovery.

The primary end point of the current trial, the mean duration of grade IV neutropenia, was 1.8 days for the pegfilgrastim group and 1.6 days for the filgrastim group in the first cycle [8]. These differences were not significant by the prospective non-inferiority criteria of the trial. The duration of grade IV neutropenia in later cycles of treatment was again comparable between the pegfilgrastim group and filgrastim group. Importantly, no difference was seen in the duration of grade IV neutropenia across the weight quartiles comparing the fixed dose of pegfilgrastim to the per weight dosed filgrastim patients. In addition, adverse events between the two groups were similar with bone pain as the predominant adverse event. Examination by weight quartile showed no variation by weight in the reporting of bone pain.

Interestingly, despite comparable degrees of neutropenia, there was less febrile neutropenia in the pegfilgrastim group compared with the filgrastim patients, 13 versus 20% [8]. While this didn’t reach statistical significance in the trial [8], in the Holmes study [9], the reduction in the rate of febrile neutropenia from 18 to 9% was significant. Febrile neutropenia was a secondary end point of these trials, so these results must be taken cautiously, but they suggest that further studies to assess the possible clinical superiority of pegfilgrastim are warranted.

The Green trial [8] confirms the findings of the Holmes trial [9] and extends the equivalence of pegfilgrastim from a per weight dosing to a fixed-dose schedule. Based on these data and the convenience of a fixed-dose regimen, regulatory agents around the world have utilized these results in approval of pegfilgrastim in the management of chemotherapy-induced neutropenia. In the USA, the indication for pegfilgrastim is "to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia" [10]. As with the initial approval of G-CSF, this is a broad clinical indication that is derived from the phase II and III data available to the FDA for patients with thoracic malignancies [6], lymphoma [11] and breast cancer [89].

Clinical trials are needed to further define the role of pegfilgrastim with other chemotherapy regimens and in other disease settings, particularly to explore more dose-dense regimens of every 2 weeks or even weekly chemotherapy. Although previous trials have administered pegfilgrastim 24 h after chemotherapy, there is interest in examining the dosing of pegfilgrastim on the same day as chemotherapy. At the moment, this is outside the recommended ASCO guidelines for the other CSFs [2], but clinical trials in this area are clearly indicated. Because of the data suggesting an increased yield of CD34+ cells in the dose–response studies of pegfilgrastim [7], studies of pegfilgrastim in stem-cell mobilization will also be performed.

Furthermore, to take advantage of the self-regulating properties of pegfilgrastim, studies of this agent in the setting of prolonged neutropenia such as the post-transplant setting and acute myeloid leukemia, are of particular interest. The hypothesis would be that despite prolonged neutropenia, of potentially weeks in duration, a single dose of pegfilgrastim may still be adequate to enhance neutrophil recovery, but this requires testing. The dosing interval in other neutropenic settings, such as severe chronic neutropenia or myelodysplasia, would also need to be defined. While the fixed-dose schedule seems adequate for most adults, studies of the optimal dose in the pediatric setting are ongoing.

Lastly and very importantly, the availability of a new cytokine to enhance neutrophil recovery will allow investigators to re-explore areas that perhaps were not as well studied as they could have been in the past. Trials are underway to evaluate the impact of neutropenia and febrile neutropenia on quality of life end points, utilizing tools developed by Calhoun et al. that were not available previously [12]. Our understanding of the impact of febrile neutropenia in the cancer patient is expanding substantially through the work of Dr G. H. Lyman, Dr D. Dale and others in the ANC Study Group. Among other observations this group has made is the continuing high mortality rates, as well as cost of care, in cancer patients with febrile neutropenia, the large majority of whom did not receive growth factor support as a preventive strategy [13]. A major focus of this group is risk stratification for the development of neutropenia and its complications based on patient characteristics, such as age and comorbidity, rather than just disease state and chemotherapy regimen [14, 15]. The evaluation of pegfilgrastim in prospective prevention trials based on patient risk statification is eagerly awaited.

J. Crawford

Division of Medical Oncology and Transplantation, Duke Comprehensive Cancer Center, Duke University Medical Center, Durham, NC, USA (E-mail: crawf006@mc.duke.edu)

References

1. Crawford JC, Blackwell S. Hematopoietic growth factors. In Perry MC (ed): The Chemotherapy Source Book, 3rd edition. Philadelphia, PA: Lippincott Williams and Wilkins 2001; 94–105.

2. Ozer H, Armitage JO, Bennett CL et al. 2000 update of recommendations for the use of hematopoietic colony-stimulating factors: evidence-based, clinical practice guidelines. J Clin Oncol 2000; 18: 3558–3585.[Free Full Text]

3. Citron M, Beery D, Cirrincione C et al. Superiority of dose-dense (DD) over conventional scheduling (CS) and equivalence of sequential (SC) vs combination adjuvant chemotherapy (CC) for node-positive breast cancer (CALGFB 9741, INT C9741). Paper presented at 25th Annual San Antonio Breast Cancer Symposium, 12 December 2002, San Antonio, TX (Abstr 15).

4. Crawford J, Ozer H, Stoller R et al. Reduction in the incidence of chemotherapy-induced febrile neutropenia in patients with small cell lung cancer by granulocyte colony-stimulating factor (R-metG-CSF). N Engl J Med 1991; 325: 164–171.[Abstract]

5. Crawford J. Pegfilgrastim administered once per cycle reduces incidence of chemotherapy-induced neutropenia. Drugs 2002; 62 (Suppl 1): 79–88.[ISI][Medline]

6. Roskos LK, Yang B, Schwab G et al. A cytokinetic model of r-metHuG-CSF-SD/01 (SD/01) mediated granulopoiesis and the "self-regulation" of SD/01 elimination in non-small cell lung cancer (NSCLC) patients. Blood 1998; 92 (Suppl 1): 507a (Abstr).[ISI]

7. Johnston E, Crawford J, Blackwell S et al. Randomized dose-escalation study of SD/01 compared with daily filgrastim in patients receiving chemotherapy. J Clin Oncol 2000; 18: 2522–2528.[Abstract/Free Full Text]

8. Green MD, Koelbl H, Baselga J et al. A randomized double-blind multicenter phase III study of fixed-dose single-administration pegfilgrastim versus daily filgrastim in patients receiving myelosuppressive chemotherapy. Ann Oncol 2003; 14: 29–35.[Abstract/Free Full Text]

9. Holmes FA, O’Shaughnessy J, Vukelja S et al. Blinded, randomized, multicenter study to evaluate single administration pegfilgrastim once per cycle versus daily filgrastim as an adjunct to chemotherapy in patients with high-risk stage II or stage III/IV breast cancer. J Clin Oncol 2002; 20: 727–731.[Abstract/Free Full Text]

10. Pegfilgrastim prescribing information. Thousand Oaks, CA: Amgen 2002.

11. Vose JM, Crum M, Lazarus H et al. Single dose pegfilgrastim (SD/01) is as effective as daily filgrastim following ESHAP chemotherapy for subjects with non-Hodgkin’s lymphoma or Hodgkin’s disease: results of a randomized, open label study. Blood 2001; 98: 799a (Abstr 3322).[CrossRef]

12. Calhoun EA, Change C-H, Welshman EE et al. A neutropenia-specific quality of life instrument: rationale for the development of the FACT-N. Proc Am Soc Clin Oncol 2002; 21: 375a (Abstr 1498).

13. Kuderer NM, Cosler L, Crawford J et al. Cost and mortality associated with febrile neutropenia in adult cancer patients. Proc Am Soc Clin Oncol 2002; 21: 250a (Abstr 998).

14. Lyman GH, Lyman CH, Ogboola Y. Risk models for the prediction of chemotherapy-induced neutropenia. Neutropenia Oncol 2001; 1: 2–7, 12.

15. Lyman GH, Kuderer NM, Balducci L. Cost-benefit analysis of granulocyte colony-stimulating factor in the management of elderly cancer patients. Curr Opin Hematol 2002; 9: 207–214.[CrossRef][ISI][Medline]





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