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ilgrastim (r-metHuG-CSF) was approved in the Unitedtates in 1991 for use in decreasing the incidence of

nfection, as manifested by febrile neutropenia, in pa-ients with nonmyeloid malignancies treated with myelo-uppressive chemotherapy. Colony-stimulating factorsuch as filgrastim are a significant advance in the support-ve care of patients with cancer. However, because of itshort half-life, filgrastim requires daily dosing by injectiono maintain its effects on the bone marrow. PegfilgrastimNeulasta; Amgen, Thousand Oaks, CA) is a longer-act-ng, self-regulating form of filgrastim created by the co-alent linkage of a 20-kd polyethylene glycol molecule tohe N-terminal of the filgrastim molecule. The molecularharacteristics of pegfilgrastim result in a longer terminalalf-life, making once-per-chemotherapy-cycle adminis-ration possible. The results from two randomized dou-le-blind phase III clinical trials in patients with breastancer treated with myelosuppressive chemotherapyhowed that a single dose of pegfilgrastim provides neu-rophil support comparable with that provided by anverage of 11 daily injections of filgrastim. Pegfilgrastimas also been shown to be comparable to filgrastim ineducing neutropenic complications in patients treatedith chemotherapy for lymphoma. Data from three clin-

cal trials have been presented: a randomized controlledrial in elderly patients treated with CHOP (cyclophos-hamide/doxorubicin/vincristine/prednisone) for re-

apsed or refractory non-Hodgkin’s lymphoma; a ran-omized controlled trial in patients treated with ESHAPetoposide/methylprednisolone/cisplatin/cytarabine) forelapsed or refractory lymphoma; and a study in patientsith newly diagnosed non-Hodgkin’s lymphoma. The

afety profile of pegfilgrastim is comparable to that oflgrastim in the clinical settings studied to date. Thence-per-cycle administration of pegfilgrastim may im-rove patient quality of life because it is less disruptive toatients and caregivers, and increase adherence becauseo doses are missed, thus further advancing the manage-ent of chemotherapy-induced neutropenia and its con-

equences.emin Oncol 30 (suppl 13):24-30. © 2003 Elsevier Inc. Allights reserved.

From the Department of Medicine, Duke University Medicalenter, Durham, NC.Dr Crawford receives grant or research support from, is a con-

ultant to, and is on the speakers bureau of Amgen.Address reprint requests to Jeffrey Crawford, MD, Duke Com-

rehensive Cancer Center, Duke University Medical Center,urham, NC 27710.© 2003 Elsevier Inc. All rights reserved.0093-7754/03/3004-1305$30.00/0

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

4

PEGFILGRASTIM: RATIONALE ANDMOLECULAR CHARACTERISTICS

Filgrastim was approved in 1991 to decrease thencidence of infection and febrile neutropeniaFN) in patients with nonmyeloid malignanciesreated with myelosuppressive chemotherapy.ince that time, several million patients treatedith chemotherapy for cancer have benefited from

t. The availability of filgrastim markedly changedhe treatment of patients with cancer, for whomhe prevailing attitude had been the acceptance ofreatment with potentially life-threatening toxic-ty. Filgrastim has been proven effective in reduc-ng myelosuppression and the incidence of FN, asell as increasing adherence to the chemotherapyose and schedule.1-4 The pharmacokinetic profilef filgrastim is characterized by a short half-life,pproximately 3.5 hours, which necessitates dailyosing until neutrophil recovery. The requirementor daily injections can create additional difficul-ies for patients who are already burdened by aiagnosis of cancer and require treatment withyelosuppressive chemotherapy.A form of filgrastim with a duration of action of

ays rather than hours could substantially benefitatients by reducing the number of injections perycle of chemotherapy, thereby possibly improvingreatment scheduling and patient adherence and re-ucing health care expenditures. Such a moleculeas been developed through pegylation technology,

n which a polyethylene glycol (PEG) molecule isonjugated to filgrastim, creating a new moleculenown as pegfilgrastim (Neulasta; Amgen, Thou-ands Oaks, CA).5 The modification of therapeuticgents by the addition of PEG has been shown tolter the pharmacokinetic and pharmacodynamicroperties of the parent molecule, resulting in agentsith several advantages over the unmodified agent.egylated agents have been shown to have a longeralf-life, greater physical and thermal stability,reater resistance to enzymatic degradation, more-table plasma concentrations, and less immunogenic-ty and antigenicity.6-8 The longer duration of activ-ty afforded by pegylation makes extended dosingntervals possible, which has the potential to im-

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rove patient adherence and quality of life and lower

Seminars in Oncology, Vol 30, No 4, Suppl 13 (August), 2003: pp 24-30

treatment costs. A number of pegylated agents havebeen approved for use in oncology, including pegy-lated interferon alfa-2a, which is administered onceweekly for the treatment of renal cell carcinoma, andpegylated liposomal doxorubicin, which appears tobe more effective and less cardiotoxic than unmod-ified or liposome-encapsulated doxorubicin.9 Pegy-lated products are likely to be more convenient forpatients than traditional dosage forms, and their im-proved pharmacokinetics increase the clinical utilityof these agents.10

The pegfilgrastim conjugate was bioengineeredaccording to structure-function analysis to main-tain the biologic activity of the filgrastim moleculewhile providing better pharmacokinetic and phar-macodynamic properties. In the creation of pegfil-grastim, a 20-kd linear PEG molecule is covalentlyattached to the N-terminal methionine residue ofthe filgrastim parent, a site distal to the receptor-binding site. Thus, the pharmacologic profile isunchanged from that of filgrastim.11 The resultingpegylated molecule has a molecular weight of39,000, approximately twice that of filgrastim. Thegreater molecular size exceeds the limit for renalclearance; therefore, neutrophil-mediated clear-ance becomes the predominant route of elimina-tion of pegfilgrastim. The rate of clearance of peg-filgrastim is directly related to the number ofcirculating neutrophils. As a result, the serum lev-els of pegfilgrastim are maintained during the neu-trophil nadir and rapidly decline at the onset ofneutrophil recovery after myelosuppressive che-motherapy. This pharmacokinetic profile is appro-priately characterized as “patient-specific” and“self-regulating,” because elimination depends oneach patient’s unique neutrophil recovery. Theself-regulating property of pegfilgrastim suggeststhat a single injection after chemotherapy mayprovide sufficient support in a variety of chemo-therapy regimens that produce neutropenia of var-ious durations. The characteristics of pegfilgrastimpredict a therapeutic profile similar to that of fil-grastim, but with the benefit of less frequent ad-ministration.5-11

CLINICAL TRIAL DATA

Phase I Studies in Healthy Volunteers and PatientsWith Cancer

The pharmacokinetics of pegfilgrastim given bythe subcutaneous route have been studied both in

healthy adult volunteers and in adult patients withcancer.5,12 In 32 adult volunteers, pegfilgrastimadministered as a single subcutaneous dose rangingfrom 30 to 300 �g/kg was well tolerated and pro-duced dose-dependent increases in the absoluteneutrophil count (ANC).5 The neutrophil countsincreased from the pretreatment value in a dose-and time-dependent fashion, producing medianpeak values of 30.4 � 109/L in the 30-�g/kg co-hort and 50.8 � 109/L in the 300-�g/kg cohort.The peak ANC and duration of response were alsodose-related. The median duration of response wasabout 6 days in the 30-�g/kg group and more than8 days in the other groups, consistent with reducedrenal clearance.

A phase I-II dose-escalation study in patientswith non–small cell lung cancer compared treat-ment with filgrastim 5 �g/kg/d and single-injec-tion pegfilgrastim 30, 100, or 300 �g/kg, given 2weeks before and again 24 hours after treatmentwith carboplatin and paclitaxel.12 The prechemo-therapy ANC increased in a dose-dependent fash-ion, and the duration of the effect was also dose-dependent in the pegfilgrastim groups. Thepostchemotherapy ANC nadirs were similar withpegfilgrastim 30 �g/kg and filgrastim 5 �g/kg/d,and the ANC nadirs were higher in the two otherpegfilgrastim cohorts. The ANC nadir occurred atapproximately day 7 after the chemotherapy andwas identical with pegfilgrastim 30 �g/kg and fil-grastim 5 �g/kg/d (0.1 � 109/L) and higher withpegfilgrastim 100 �g/kg (0.65 � 109/L) and 300�g/kg (0.7 � 109/L). As predicted, the serumlevels of pegfilgrastim remained elevated through-out the ANC nadir and rapidly declined duringneutrophil recovery, indicating neutrophil-medi-ated clearance.12

A phase II dose-finding study compared a singleinjection of pegfilgrastim 30, 60, or 100 �g/kg anddaily filgrastim 5 �g/kg in patients with breastcancer treated with four cycles of doxorubicin anddocetaxel.13 Treatment with pegfilgrastim and fil-grastim began 24 hours after the administration ofthe chemotherapy. A single 100-�g/kg dose ofpegfilgrastim per cycle produced an ANC recoveryprofile similar to that with filgrastim 5 �g/kg/dafter chemotherapy (Fig 1).14 The time to ANCrecovery and the incidence and duration of grade4 neutropenia in cycle 1 and subsequent cycleswere also similar. Patients treated with a singledose of pegfilgrastim 100 �g/kg or an average of 11

PEGFILGRASTIM IN THE MANAGEMENT OF CIN 25

injections of filgrastim 5 �g/kg were given morethan 90% of the chemotherapy doses on time, andthe planned dose (ie, � 80% of the planned dosein cycle 1) was delivered in all cycles.13 The safetyprofiles of the two drugs were similar, with mild tomoderate bone pain being the most frequentlyreported adverse event. The results of the studyshow that pegfilgrastim 100 �g/kg administeredonce per chemotherapy cycle provides neutrophilsupport similar to that with daily filgrastim 5 �g/kg. Moreover, this study shows that pegfilgrastim isas safe as filgrastim over several cycles of chemo-therapy.

Phase III Registration Trials

The phase I and II dose-ranging studies helpeddetermine the appropriate dose of pegfilgrastim forthe pivotal registration trials. In these phase I andII studies, a weight-based dose of pegfilgrastim 100�g/kg produced the optimal ANC response acrossseveral patient populations.12,13 To further in-crease the ease of dosing, a 6-mg fixed dose wasproposed on the basis of pharmacokinetic andpharmacodynamic modeling. In addition, datafrom the phase II study in patients with breastcancer were analyzed to evaluate the outcome bythe size of the total dose of pegfilgrastim, indepen-dent of the weight-based dose size (30, 60, or 100�g/kg per cycle). Patients were grouped into thefollowing total-dose cohorts: 4, 6, and 8 mg (� 1mg), and the analysis found that a 6-mg total doseproduced outcomes most similar to those in thefilgrastim group.15 Thus, the 6-mg dose was se-

lected as the fixed dose to take forward in a pivotalstudy.

Two randomized phase III clinical trials wereconducted to support the registration of pegfilgras-tim (Fig 2). The design of the trials was identicalexcept that one assessed a weight-based dose ofpegfilgrastim 100 �g/kg and the other assessed a6-mg fixed dose. Filgrastim 5 �g/kg/d was the com-parator in both studies, and both studies wereconducted in patients given doxorubicin anddocetaxel for up to four cycles as adjuvant treat-ment for breast cancer. The trials were designed toshow the noninferiority of pegfilgrastim. The pri-mary endpoint was the duration of severe neutro-penia (DSN) in cycle 1, defined as ANC �0.5 �109/L, and secondary endpoints were the DSN incycles 2 through 4, depth of the ANC nadir, timeto ANC recovery, and incidence of FN.

A total of 310 patients were enrolled in thephase III weight-based dosing trial.15 Pegfilgrastim100 �g/kg was found to be comparable with fil-grastim 5 �g/kg/d with respect to the primary endpoint, the DSN in cycle 1 (mean [SD], 1.7 [1.5]days and 1.8 [1.4] days, respectively). In cycles 2through 4 the differences in DSN were statisticallysignificant in favor of pegfilgrastim (Table 1).15

The mean time to ANC recovery, defined as thetime from the administration of chemotherapy un-til the ANC had increased to 2 � 109/L after thenadir, was 9.3 days with pegfilgrastim and 9.7 dayswith filgrastim.15 In addition, the overall inci-dence of FN was significantly lower with pegfil-grastim (9% v 18%; P � .029).15

Fig 1. Neutrophil recovery profiles with pegfilgrastim and filgrastim in patients with breast cancer. ANC, absolute neutrophilcount. (Reprinted with permission.14)

26 JEFFREY CRAWFORD

A total of 130 patients were randomized in thesmaller, fixed-dose phase III randomized trial.16

There were no significant differences betweengroups in cycle 1 in either the mean [SD] DSN(1.8 [1.4] days with pegfilgrastim and 1.6 [1.1] dayswith filgrastim) or the overall incidence of severeneutropenia (84% and 83%, respectively). Recov-ery of the ANC was similar with pegfilgrastim 6mg and filgrastim 5 �g/kg/d.16 Over the entire

study, 13% of pegfilgrastim-treated patients expe-rienced FN compared with 20% in the filgrastimgroup (Table 2). However, the sample size in thistrial was smaller, and the study was not designedwith sufficient power to detect significant differ-ences in FN. In addition, to further assess theadequacy of the 6-mg fixed dose, the primary end-point (the DSN in cycle 1) was analyzed in patientsubsets by pretreatment weight (Fig 3). The resultsof the analysis suggest that all weight groups wereadequately protected with a single 6-mg dose of

Fig 2. Design of the pivotal phase III clinical trials of pegfilgrastim. Patients were stratified by weight and prior chemotherapy.Filgrastim was given daily to ANC >10 � 109/L or 14 doses, whichever occurred first.14,16

Table 1. Results in a Phase III Clinical TrialComparing a Single Dose of Pegfilgrastim 100 �g/kg

and Filgrastim 5 �g/kg/d in Patients WithBreast Cancer15

Pegfilgrastim Filgrastim

Patients with grade 4neutropenia, cycle 1 77% 79%

Mean (SD) DSN in days, cycle 1 1.7 (1.5) 1.8 (1.4)Mean (SD) DSN in days, cycle 2 0.7 (0.9) 1.1* (1.1)Mean (SD) DSN in days, cycle 3 0.6 (0.9) 1.2* (1.4)Mean (SD) DSN in days, cycle 4 0.9 (1.2) 1.3* (1.5)Patients with FN, cycle 1 7% 12%Patients with FN, all cycles 9% 18%†

Abbreviations: DSN, duration of severe neutropenia; FN,febrile neutropenia.

*P � .025.†95% CI for the difference between groups, �16.8% to

�1.1%; P � .029.

Table 2. Results of a Phase III Clinical TrialComparing a Single Dose of Pegfilgrastim 6 mg WithFilgrastim 5 �g/kg/d in Patients With Breast Cancer16

Pegfilgrastim Filgrastim

Patients with grade 4neutropenia, cycle 1 84% 83%

Mean (SD) DSN in days, cycle 1 1.8 (1.4) 1.6 (1.1)Mean (SD) DSN in days, cycle 2 1.1 (1.2) 0.9 (1.0)Mean (SD) DSN in days, cycle 3 1.1 (1.2) 0.9 (1.1)Mean (SD) DSN in days, cycle 4 1.0 (1.1) 1.0 (1.3)Patients with FN, cycle 1 9% 15%Patients with FN, all cycles 13% 20%*

Abbreviations: DSN, duration of severe neutropenia; FN,febrile neutropenia.

*95% CI for the difference between groups, �19% to �5%.

PEGFILGRASTIM IN THE MANAGEMENT OF CIN 27

pegfilgrastim. Finally, as in the weight-based dos-ing trial, both treatments were generally well tol-erated. Thus, this study confirms that a fixed-dose,once-per-cycle injection of pegfilgrastim providessafe and effective support in patients at risk forchemotherapy-induced neutropenia, across a widerange of body weights.16

The results of the phase III clinical trials showthat a single dose of pegfilgrastim given once perchemotherapy cycle is as effective as repeated dailyinjections of filgrastim (average of 11 daily injec-tions) with respect to DSN, the depth of the ANCnadir, and time to ANC recovery. Furthermore, asingle 6-mg fixed dose of pegfilgrastim providesequivalent protection from neutropenic complica-tions, eliminating the need for dosing based onbody weight. Moreover, the studies confirm that

the side-effect profiles of pegfilgrastim and filgras-tim are comparable, with mild to moderate bonepain being the most common adverse event. Fi-nally, the lower incidences of FN in the pegfilgras-tim groups in each study are a provocative findingthat warrants further investigation.

Additional Efficacy Analyses

Because of the comparability of the design ofthe two pivotal trials, the efficacy data were pooledfor further analysis.17,18 Pooled analysis increasesthe sample size, which can be of particular benefitin subset analyses. Pooled efficacy data from 448patients were evaluated in the first study.18 Theincidence of FN, use of intravenous anti-infec-tives, and rates of hospitalization were comparedin the pegfilgrastim and filgrastim groups. Over allcycles, the incidence of FN was lower with pegfil-grastim (11% v 19%), which translates into a 44%reduction in the risk for the development ofFN (RR, 0.56; 95% CI, 0.35 to 0.89). The ratesof hospitalization and intravenous anti-infectiveuse were also lower with pegfilgrastim than withfilgrastim (19% v 23% and 19% v 21%, respec-tively).

Another report analyzed the pooled data to as-sess the comparability of pegfilgrastim and filgras-tim in younger (� 65 years) and older patients (�65 years).17 Data were compared on the DSN incycle 1 and the all-cycle incidence of FN, grade 4neutropenia, intravenous anti-infective use, andhospitalization (Table 3). The mean DSN did notdiffer significantly between younger and older pa-tients (1.8 days and 1.7 days with pegfilgrastim and1.6 days and 2.1 days with filgrastim, respectively).The rates of FN were similar by age group and were

Fig 3. Duration of severe neutropenia after a single dose ofpegfilgrastim 6 mg or filgrastim 5 �g/kg/d in chemotherapycycle 1, by pretreatment weight.16 Black bar, pegfilgrastim6-mg fixed dose; gray bar, filgrastim 5 �g/kg/d. DSN, durationof severe neutropenia.

Table 3. Efficacy of Pegfilgrastim and Filgrastim in Patients With Breast Cancer, by Age <65 and >65 Years

�65 years �65 years

Pegfilgrastim(n � 200)

Filgrastim(n � 193)

Pegfilgrastim(n � 27)

Filgrastim(n � 32)

Mean DSN (days), cycle 1 1.8 1.6 1.7 2.1Patients with FN 10% 18% 15% 22%Patients with anti-infective use 19% 20% 26% 34%Patients hospitalized for FN 18% 23% 22% 25%

Abbreviations: DSN, duration of febrile neutropenia; FN, febrile neutropenia.Reprinted with permission.19

28 JEFFREY CRAWFORD

lower with pegfilgrastim in both age groups, with arelative risk of 0.57 (95% CI, 0.36 to 0.90). Theincidence of intravenous antibiotic use and hospi-talization were lower with pegfilgrastim in bothage groups. In conclusion, the results show thatpegfilgrastim is at least as safe and effective asfilgrastim in elderly patients with breast cancer.17

Efficacy in Non-Hodgkin’s Lymphoma

Pegfilgrastim has also been shown to be compa-rable to filgrastim in reducing neutropenic compli-cations in patients treated with chemotherapy forlymphoma. Data from three clinical trials havebeen presented.19-21 An open-label randomizedcontrolled trial in elderly patients treated withcyclophosphamide, doxorubicin, vincristine, andprednisone (CHOP) for relapsed or refractorynon-Hodgkin’s lymphoma (NHL) compared a sin-gle dose of pegfilgrastim 60 or 100 �g/kg and dailyfilgrastim 5 �g/kg.19 In an intent-to-treat analysis,the outcomes were similar in the treatment groups,including the mean DSN and the incidence of FN.The pegfilgrastim 100-�g/kg dose most closely re-sembled filgrastim in terms of efficacy. The inci-dences and types of adverse events were also com-parable in the groups, indicating that pegfilgrastimand filgrastim produce similar outcomes in patientswith NHL treated with chemotherapy.

Similar protection against chemotherapy-in-duced neutropenia was seen in patients with NHLor Hodgkin disease who were given a single dose ofpegfilgrastim 100 �g/kg (n � 29) or filgrastim 5�g/kg/d (n � 31) beginning 24 hours after ESHAP(etoposide, methylprednisolone, cisplatin, and cyt-arabine) chemotherapy.20 The incidence of grade4 neutropenia in the first cycle of chemotherapywas 69% and 68% with pegfilgrastim and filgras-tim, respectively. In the second cycle, grade 4neutropenia occurred in 23% and 36% of thepegfilgrastim and filgrastim recipients, respec-tively. The mean (SD) DSN was 2.8 (2.6) daysand 2.4 (2.7) days with pegfilgrastim and filgras-tim, respectively, in the first cycle and 0.4 (0.9)and 0.6 (1.1) days, respectively, in the secondcycle.20

The third trial was an open-label multicenterstudy that evaluated the pharmacokinetics andefficacy of a single 6-mg fixed dose of pegfilgrastimin 30 patients with newly diagnosed NHL treatedwith CHOP chemotherapy.21 The serum concen-tration of pegfilgrastim was maximal at 24 hours

after dosing. Recovery of the ANC was evident byday 11, after which the serum concentrations ofpegfilgrastim declined linearly, with a median ter-minal half-life of approximately 42 hours. Theserum levels of pegfilgrastim declined concurrentwith a rising ANC, consistent with neutrophil-mediated, self-regulating clearance. Grade 4 neu-tropenia occurred in 43% of patients, and FN in11%. The mean DSN was 1 day (� 1.4 days), andmedian time to ANC recovery was 10 days. Thisstudy shows that in patients with NHL treatedwith CHOP, a single 6-mg dose of pegfilgrastimper chemotherapy cycle provides adequate drugexposure for neutrophil support in all subjects,irrespective of body weight.21

CONCLUSION

The commercial availability of pegfilgrastim, anewer colony-stimulating factor with a sustainedduration of action, is an advance in neutrophilgrowth factors. Pegfilgrastim was created by thecovalent attachment of a PEG molecule to thefilgrastim parent protein in a process known aspegylation. Unlike filgrastim, which undergoespredominantly renal elimination, pegfilgrastim isof sufficient size to minimize renal elimination.Data in patients with cancer show that the pri-mary route of elimination of pegfilgrastim is clear-ance through neutrophil-receptor binding. The se-rum level of pegfilgrastim decreases as the ANCincreases. Therefore, the pharmacokinetics of peg-filgrastim are characterized as patient-specific andself-regulating.

A single dose of pegfilgrastim given 24 hoursafter the completion of a cycle of chemotherapyhas been shown to provide ANC support similar tothat of daily filgrastim in patients with breast can-cer, NHL, and non–small cell lung cancer. Clini-cal data from two large phase III comparative trialsshow that pegfilgrastim is as effective as filgrastimin reducing the DSN in the first and subsequentcycles of chemotherapy. Pegfilgrastim has alsobeen studied in patients with lymphoma, in whichit was shown to be comparable with filgrastim inreducing neutropenic complications in patientstreated with various chemotherapy regimens.Across all clinical studies conducted to date, thesafety profile of pegfilgrastim has been comparablewith that of filgrastim. Manageable mild-to-mod-erate bone pain is the most frequent adverse eventwith both pegfilgrastim and filgrastim.

PEGFILGRASTIM IN THE MANAGEMENT OF CIN 29

The simplified dosing regimen of pegfilgrastimmay improve patient adherence and reduce treat-ment costs by reducing the frequency of injectionsand office visits for injections in the days afterchemotherapy. Additional studies are under wayto further assess the benefits of pegfilgrastim, anewer colony-stimulating factor that provides theefficacy of filgrastim with a single dose per chemo-therapy cycle.

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15. Yang BB, Lum P, Renwick J, et al: Pharmacokineticrationale for a fixed-dose regimen of a sustained-duration formof filgrastim in cancer patients. Blood 96:157b, 2000 (abstr4384)

16. Green MD, Koelbl H, Baselga J, et al: A randomizeddouble-blind multicenter phase III study of fixed-dose single-administration pegfilgrastim versus daily filgrastim in patientsreceiving myelosuppressive chemotherapy. Ann Oncol 14:29-35, 2003

17. Shogan J, Koelbl H, Holmes FA: Pegfilgrastim showssafety and efficacy similar to filgrastim in elderly patients withbreast cancer. Proc Am Soc Clin Oncol 21:66a, 2002 (abstr260)

18. Siena S, Piccart MJ, Holmes FA, et al: A combinedanalysis of two pivotal randomized trials of a single dose ofpegfilgrastim per chemotherapy cycle and daily filgrastim inpatients with stage II-IV breast cancer. Oncol Rep 10:715-724,2003

19. Hiddemann W, Grigg A, Solal-Celigny P, et al: Anopen-label, randomized parallel, dose-ranging study of singleadministration SD/01 vs daily filgrastim as an adjunct to che-motherapy in elderly patients with non-Hodgkin’s lymphoma.Haematol J 1:184, 2001 (abstr 685)

20. Vose JM, Crump M, Lazarus H, et al: Randomized,multicenter, open-label study of pegfilgrastim compared withdaily filgrastim after chemotherapy for lymphoma. J Clin Oncol21:514-519, 2003

21. George S, Yunus F, Yang BB, et al: Pharmacokineticprofiles of fixed dose single pegfilgrastim administration inpatients with non-Hodgkin’s lymphoma. Blood 98:27b, 2001(abstr 3700)

30 JEFFREY CRAWFORD