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Randomized, Multicenter, Open-Label Study of Pegfilgrastim Compared With Daily Filgrastim After Chemotherapy for Lymphoma

From the University of Nebraska Medical Center, Omaha, NE; Princess Margaret Hospital, Toronto, Canada; University Hospitals of Cleveland, Cleveland, OH; University of California Los Angeles Medical Center, Los Angeles, and Amgen Inc, Thousand Oaks, CA; New England Medical Center, Boston, MA; Duke University Medical Center, Durham, NC; and University of Maryland Medical Center and Johns Hopkins Hospital, Baltimore, MD.

Address reprint requests to Julie M. Vose, MD, Department of Internal Medicine, University of Nebraska Medical Center, 987680 Nebraska Medical Center, Omaha, NE 68198; email: jmvose{at}unmc.edu.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Purpose: The primary objective was to assess the duration of grade 4 neutropenia (neutrophil count < 0.5 x 10⁹/L) after one cycle of chemotherapy with etoposide, methylprednisolone, cisplatin, and cytarabine in patients randomly assigned to receive one dose of pegfilgrastim or daily filgrastim after chemotherapy. Febrile neutropenia, neutrophil profiles, time to neutrophil recovery, pharmacokinetics, and safety were also assessed.

Patients and Methods: An open-label, randomized, phase II study was designed to compare the effects of a single subcutaneous injection of pegfilgrastim (sustained-duration filgrastim) 100 µg/kg per chemotherapy cycle (n = 33) with daily subcutaneous injections of filgrastim 5 µg/kg (n = 33) in patients receiving salvage chemotherapy for relapsed or refractory Hodgkin’s or non-Hodgkin’s lymphoma.

Results: The incidence of grade 4 neutropenia in the pegfilgrastim and filgrastim groups was 69% and 68%, respectively. In addition, the mean duration of grade 4 neutropenia was similar in both groups (2.8 and 2.4 days, respectively). The results for the two groups were also not significantly different for febrile neutropenia, neutrophil profile, time to neutrophil recovery, or toxicity profile. A single subcutaneous injection of pegfilgrastim 100 µg/kg produced a sustained serum concentration relative to daily subcutaneous injections of filgrastim. Filgrastim-treated patients received a median of 11 injections per cycle.

Conclusion: Pegfilgrastim was safe and well tolerated in this patient population. A single injection of pegfilgrastim per chemotherapy cycle provided neutrophil support with safety and efficacy similar to that provided by daily injections of filgrastim. Once-per-cycle administration of pegfilgrastim simplifies the management of neutropenia and may have important clinical benefits for patients and healthcare providers.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
ALTHOUGH NON-HODGKIN’S lymphoma (NHL) is considered a chemotherapy-responsive tumor, 20% to 50% of patients who achieve a complete response may ultimately relapse and need additional therapy.^1,2 The prognosis for patients with intermediate-grade or high-grade NHL who relapse after initial therapy is generally poor with conventional salvage regimens.^3,4 However, the use of high-dose chemotherapy and autologous hematopoietic stem-cell transplantation in relapsed patients has demonstrated an improved disease-free survival compared with salvage chemotherapy alone.⁵ In preparation for transplantation, patients often need conventional chemotherapy to reduce the tumor bulk and to test for chemotherapy sensitivity.^6,7 Many such chemotherapy regimens cause neutropenia and/or thrombocytopenia that might result in serious toxicities or lead to delays in the next cycle of chemotherapy.

Similarly, patients with Hodgkin’s disease (HD) who fail their induction chemotherapy are often candidates for salvage chemotherapy followed by high-dose chemotherapy and hematopoietic stem-cell transplantation.^8,9 Patients with NHL or HD who relapse receive salvage chemotherapy to prepare them for peripheral-blood progenitor cell transplantation or, if they are not candidates for transplantation, to provide them with continuing treatment of their tumor. Filgrastim as an adjunct to cancer chemotherapy is often incorporated into both front-line and salvage chemotherapy regimens to decrease the incidence and duration of severe neutropenia and its sequelae, and to allow full-dose chemotherapy to continue.^10–12

Pegfilgrastim comprises the protein filgrastim to which a 20-kDa polyethylene glycol (PEG) molecule is bound covalently to the N-terminal methionine residue.^13,14 The addition of the PEG molecule increases the serum half-life of pegfilgrastim. This study was designed to investigate whether pegfilgrastim, administered as a single subcutaneous injection of 100 µg/kg, would result in a duration of grade 4 neutropenia similar to that provided by daily subcutaneous injections of filgrastim of 5 µg/kg in patients with relapsed NHL or HD receiving etoposide, methylprednisolone, cisplatin, and cytarabine (ESHAP) chemotherapy.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patients
Patients who were diagnosed with relapsed or persistent HD or NHL and who were at least 18 years of age were eligible for enrollment if they met the other eligibility requirements. Patients with NHL were eligible if they relapsed from or were refractory to first-line chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). HD patients were eligible if they had experienced treatment failure from at least one prior chemotherapy regimen. All patients were required to have an Eastern Cooperative Oncology Group performance status 2, an absolute neutrophil count (ANC) 1.5 x 10⁹/L, a platelet count 100 x 10⁹/L, and adequate renal function. Patients were excluded if they had an active infection or had used antimicrobials within 72 hours before chemotherapy administration, if they had received prior bone marrow or peripheral-blood progenitor cell transplantation or received radiotherapy within 4 weeks of study enrollment, or if they had been exposed to more than two separate courses of chemotherapy for their malignancy.

The protocol was approved by the institutional review boards of all participating institutions, and all patients gave written informed consent before any study-related tests were performed. In addition, the protocol was approved by the scientific review committees of the institutions per standard procedure.

Study Design and Statistical Analysis
This study was a multicenter, randomized, phase II study to compare the safety, efficacy, and pharmacokinetics of once-per-cycle pegfilgrastim with daily filgrastim administered after ESHAP chemotherapy in cycle 1. Subjects were randomly assigned, in a 1:1 ratio without stratification, to one of the following two groups: filgrastim 5 µg/kg/d until ANC 10 x 10⁹/L postnadir or for 12 days, whichever came first; or pegfilgrastim 100 µg/kg single administration. The planned sample size was 52 patients (26 per treatment group). The study enrolled 33 patients per treatment group to account for an anticipated dropout rate of between 15% and 20%. Although not designed as a formal noninferiority study, based on an expected SD of 2.1 days, the planned sample size of 26 patients per treatment group in cycle 1 was calculated to provide statistical power of 51% to detect a 1-day difference between the two treatment groups in the duration of grade 4 neutropenia and a power of 95% to detect a 2-day difference in the duration of grade 4 neutropenia.

Mean and median ANCs were analyzed by treatment group and cycle, and the medians were plotted over time. Descriptive statistics were used to summarize the duration of grade 4 neutropenia, time to ANC recovery, and ANC nadir by cycle for each group. The cumulative incidence of febrile neutropenia (cycles 1 and 2) was tabulated by treatment. Ninety-five percent confidence intervals were calculated for treatment group differences in mean duration of grade 4 neutropenia, the mean time to ANC recovery, the mean ANC nadir, and the percent of patients with febrile neutropenia. Incidence of adverse events was summarized by cycle, treatment group, body system, and preferred term. The pharmacokinetic parameters of pegfilgrastim were calculated for cycle 1 by noncompartmental analysis. Results of antipegfilgrastim antibody assays were tabulated for samples collected before study drug exposure, during treatment, and during follow-up.

Study Drugs
Filgrastim and pegfilgrastim are produced by recombinant DNA technology and are expressed in Escherichia coli. Pegfilgrastim comprises the protein filgrastim to which a 20-kDa PEG molecule is covalently bound.

Study drug (pegfilgrastim or filgrastim) was administered on day 6, 1 day after completion of chemotherapy. Patients randomized to pegfilgrastim received a single subcutaneous 100 µg/kg injection per chemotherapy cycle; patients randomized to filgrastim received daily subcutaneous injections of 5 µg/kg/d for 12 days or until an ANC 10 x 10⁹/L after the chemotherapy-induced ANC nadir, whichever occurred first.

Treatment Procedures
Blood samples for complete blood counts were collected on day 1 before chemotherapy administration, daily during the treatment period beginning on day 6, and at follow-up visits. Blood samples were collected for a chemistry profile at the beginning of each chemotherapy cycle.

Chemotherapy was repeated every 3 weeks. ESHAP chemotherapy consisted of etoposide 40 mg/m², methylprednisolone 500 mg, cisplatin 25 mg/m²/d, and cytarabine 2,000 mg/m², all administered intravenously. Etoposide and cytarabine were decreased by 20% and 50%, respectively, for a platelet count less than 20 x 10⁹/L. Cisplatin was decreased 25% for a creatinine of 1.5 to 2.0 mg/dL and 50% for a creatinine of 2.1 to 3.0 mg/dL, and was maintained for a creatinine of more than 3.0 mg/dL.

Safety Measurements
The safety end points of the study were the incidence of adverse events, deaths on study, and the production of antibodies against pegfilgrastim or filgrastim. Serum samples for antipegfilgrastim antibody analyses were collected at the beginning of each chemotherapy cycle and during the 3-month follow-up visit.

Efficacy Measurements
The primary efficacy end point was the duration of grade 4 neutropenia, defined as an ANC less than 0.5 x 10⁹/L, during cycle 1. Secondary efficacy end points were the duration of grade 4 neutropenia in subsequent cycles, ANC profiles, and the time to ANC recovery. Rates of febrile neutropenia (defined as ANC < 0.5 x 10⁹/L and temperature 38.2°C) were assessed cumulatively for cycles 1 and 2.

Pharmacokinetic Measurements
Serum samples for pharmacokinetic analyses were collected daily beginning on day 6 before administration of study drug, during cycle 1 only. The pharmacokinetic end points measured in cycle 1 were the observed peak serum concentration, the time to observed peak serum concentration, the terminal half-life, the area under the serum concentration time curve from time zero to infinity, and the serum clearance of pegfilgrastim.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patients
A total of 66 patients were enrolled onto this study at 17 institutions; 33 patients were randomly assigned to pegfilgrastim and 33 to filgrastim. Six patients withdrew before receiving study drug because of neuropathy (n = 2), progressive disease (n = 2), hemolytic anemia (n = 1), or pneumonia (n = 1), and one patient withdrew because of disease progression after receiving study drug but before the period of expected severe neutropenia. Twenty-nine pegfilgrastim and 31 filgrastim patents received at least one dose of study drug in cycle 1. Patients receiving study drug seemed generally well matched with respect to physical characteristics and baseline blood counts (Table 1 and Table 2). A higher percentage of patients receiving filgrastim had more advanced disease compared with patients receiving pegfilgrastim; 87% of filgrastim-treated patients were diagnosed with stage III or stage IV disease, whereas only 66% of pegfilgrastim-treated patients were diagnosed with stage III or stage IV disease (Table 1). The baseline ANC, platelet, and hemoglobin levels were also similar between randomization arms (Table 2).

Study Drug Administration
Patients treated with pegfilgrastim received a single subcutaneous injection of study drug per chemotherapy cycle. The median number of injections administered to patients treated with filgrastim was 11 in both cycles 1 and 2.

Chemotherapy Administration
No chemotherapy dose delays or reductions were attributable to neutropenia. When they did occur, chemotherapy dose delays were infrequent and were similar between treatment groups. Dose delays were reported in cycle 2 because of delayed platelet recovery (one patient in each treatment group) and anemia with thrombocytopenia (one pegfilgrastim-treated patient). Two pegfilgrastim-treated patients experienced delays in initiating chemotherapy cycles 2 and 3 because of adverse events related to disease or to chemotherapy.

Chemotherapy dose was reduced in cycle 2 for two filgrastim-treated and four pegfilgrastim-treated patients because of elevated creatinine and/or severe thrombocytopenia in cycle 1. This extent of chemotherapy dose reduction is not unexpected in patients receiving ESHAP.

Safety
Adverse events. All patients reported at least one adverse event, but most events were attributable to complications arising from myelosuppressive cytotoxic chemotherapy or the primary disease. No patterns or trends indicative of specific pegfilgrastim-related toxicity were noted. The frequency of most adverse events was similar between the two treatment groups, and adverse events were generally associated with bone pain. Bone pain was reported in nine (29%) of 31 filgrastim-treated patients and 11 (38%) of 29 pegfilgrastim-treated patients (P = not significant). The most common nonhematologic toxicity that was believed to represent a severe adverse event was fatigue, which was noted in six (19%) of 31 of patients randomized to filgrastim and four (14%) of 29 patients randomized to pegfilgrastim (Table 3). Most events were considered mild to moderate in severity and usually required treatment only with nonnarcotic analgesia.

Antibody formation. All samples from patients receiving pegfilgrastim were analyzed for antipegfilgrastim antibodies at baseline, after therapy, and at the 3-month follow-up. No evidence of neutralizing antibodies was observed. All patients had ANC recovery to more than 1.0 x 10⁹/L during the follow-up period.

Efficacy
Duration of grade 4 neutropenia for cycle 1. The incidence of grade 4 neutropenia was similar for both treatment groups, 69% and 68% for the pegfilgrastim and filgrastim groups, respectively (Fig 1). The mean duration of grade 4 neutropenia was 2.8 and 2.4 days for the pegfilgrastim and filgrastim groups, respectively. The observed difference was 0.43 (95% confidence limits, -0.95, 1.81) (Table 4).

View larger version (27K): [in this window] [in a new window]   Fig 1. Percentage of patients with severe neutropenia. The percentage of patients with severe neutropenia (absolute neutrophil count < 0.5 x 109/L) after etoposide, methylprednisolone, cisplatin, and cytarabine chemotherapy in cycles 1 and 2 by randomization arm.

ANC profiles. The geometric mean ANC nadir was 0.208 x 10⁹/L for filgrastim-treated patients and 0.161 x 10⁹/L for pegfilgrastim-treated patients (Table 4). The 95% confidence interval of 0.326 to 1.839 was based on the ratio of the pegfilgrastim geometric mean to the filgrastim geometric mean, such that a value of 1 would indicate the nadir values were equal. The median ANC patterns over time in cycle 1 suggest that the treatment group medians were comparable when chemotherapy (day 1) and study drug (day 6) were initiated, with no observable differences within the expected period of grade 4 neutropenia until day 15 (Fig 2). On day 15, the median ANC in both treatment groups was more than 2.0 x 10⁹/L; however, the median ANC of filgrastim-treated patients increased at a rapid rate to a median ANC of 19.3 x 10⁹/L on day 18. This continued rapid increase after ANC recovery to within the normal range is a result of the daily administration of filgrastim for up to 12 days or until a postnadir ANC of 10 x 10⁹/L, whichever occurred first. In contrast, the median ANC of pegfilgrastim patients increased to 5.3 x 10⁹/L on day 18. At the scheduled conclusion of the cycle (day 21), the median ANC in both treatment groups was comparable, with both exceeding respective baseline values (Fig 2). The median ANC patterns in cycle 2 were similar to those in cycle 1.

View larger version (20K): [in this window] [in a new window]   Fig 2. Median absolute neutrophil counts (ANCs) in cycle 1. The median ANC for patients randomized to filgrastim or pegfilgrastim after cycle 1 of etoposide, methylprednisolone, cisplatin, and cytarabine chemotherapy.

Febrile neutropenia.
The cumulative incidence of febrile neutropenia was reported only for cycles 1 and 2 because of the small number of patients who continued with treatment in cycles 3 and 4. Twenty-one percent of pegfilgrastim-treated patients and 19% of filgrastim-treated patients developed febrile neutropenia. The observed difference was 1.3%, and the 95% confidence limits were -19.4, 22.0.

Pharmacokinetics
The pharmacokinetic profile was defined for cycle 1 in 21 of 29 pegfilgrastim-treated patients and 28 of 31 filgrastim-treated patients. A single injection of pegfilgrastim resulted in a sustained serum concentration relative to filgrastim. The maximum pegfilgrastim concentration was achieved approximately 33 hours after administration of study drug. Pegfilgrastim concentrations were sustained until ANC nadir occurred. As ANC recovered, pegfilgrastim concentration declined rapidly, consistent with a neutrophil-mediated clearance mechanism. Pegfilgrastim concentrations were higher and were sustained longer in some patients who experienced grade 4 neutropenia than in patients who did not. No significant relationships between pharmacokinetic parameters and demographic variables or between ANC and the area under the serum concentration time curve from time zero to infinity were observed.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Hematologic toxicity associated with possible neutropenic complications is a major dose-limiting toxicity of cancer chemotherapy. The cloning and purification of hematopoietic growth factors such as granulocyte-macrophage colony-stimulating factor (rHuGM-CSF) and granulocyte colony-stimulating factor (rHuG-CSF) have allowed testing of these molecules in an attempt to modify the neutrophil nadir associated with chemotherapy.^15,16 One of the first large randomized studies of filgrastim involved 211 patients receiving combination chemotherapy for small-cell lung cancer.¹⁷ In this study, filgrastim was well tolerated and led to reductions in the incidence of fever with neutropenia and culture-confirmed infections, as well as the incidence, duration, and severity of grade 4 neutropenia.¹⁷

The chemotherapy regimens used for patients with lymphoma are often dose intensive with high rates of associated neutropenic-related morbidity and occasional mortality.^18–20 Both rHuGM-CSF and rHuG-CSF have been tested in phase III randomized trials for patients receiving combination chemotherapy for NHL.^21,22 In a study by Pettengell et al,²¹ 80 patients with NHL were randomized to receive vincristine, etoposide, doxorubicin, prednisolone, cyclophosphamide, and bleomycin with or without filgrastim administered as a daily subcutaneous dose of 230 µg/m². Neutropenia, defined as an ANC less than 1,000/µL, occurred in 15 (37%) of 41 filgrastim-treated patients and in 33 (85%) of 39 controls (P < .00001).²¹ In addition, febrile neutropenia (temperature 37.5°C and ANC < 0.1 x 10⁹/L) occurred in nine (22%) of 41 filgrastim-treated patients and 17 (44%) of 39 controls (P = .04). With either rHuG-CSF or rHuGM-CSF, daily administration is required for 7 to 14 days to alter the nadir of neutropenia in such patients.

Pegfilgrastim was recently synthesized by adding a PEG molecule to the N terminus of filgrastim.^13,14 PEG-conjugated proteins have displayed decreased plasma clearance, with a resultant increase in half-life.¹³ This decreased plasma clearance potentially can translate into enhanced clinical efficacy. In preclinical studies, pegfilgrastim was administered to nonneutropenic animals, and these animals had dose-dependent increases in both peak ANCs and the duration of ANC increases over baseline values. In mice made neutropenic by injection of fluorouracil and then treated with pegfilgrastim or standard filgrastim, both demonstrated a more rapid return to baseline than a control group of mice that received no growth factor.²³

With this preclinical information, the first clinical trial was designed to determine the pharmacokinetics, safety, and preliminary efficacy profiles of pegfilgrastim in non–small-cell lung cancer patients receiving myelosuppressive chemotherapy. In the study by Johnston et al,²⁴ 13 patients with non–small-cell lung cancer were randomly assigned to receive daily filgrastim or a single injection of pegfilgrastim (30, 100, or 300 µg/kg) 2 weeks before chemotherapy and again 24 hours after administration of carboplatin and paclitaxel. After chemotherapy, median ANC nadirs were similar in the filgrastim cohort and the cohort receiving pegfilgrastim 30 µg/kg, with higher nadirs seen in the cohorts receiving 100 or 300 µg/kg.²⁴

Subsequently, pegfilgrastim was tested in two larger phase III randomized trials in patients receiving four cycles of doxorubicin and docetaxel for high-risk stage II to IV breast cancer. In one trial,²⁵ 77 patients were randomly assigned to receive 5 µg/kg of filgrastim after the chemotherapy, and 80 patients were randomly assigned to receive a single dose of 6 mg of pegfilgrastim followed by daily placebo injections after chemotherapy. The percentages of patients with febrile neutropenia (ANC < 0.5 x 10⁹/L and temperature > 38.2°C) in at least one cycle were similar in both arms (20% of patients in the filgrastim arm and 13% in the pegfilgrastim arm; P = not significant). In the second double-blind trial,²⁶ 310 patients were randomly assigned to receive 5 µg/kg daily of filgrastim (n = 156) or a single 100 µg/kg dose of pegfilgrastim (n = 154) after chemotherapy. The percentage of patients with febrile neutropenia in at least one cycle was 18% in the filgrastim arm and 9% in the pegfilgrastim arm (difference in percentages, -9%; two-sided 95% confidence limits, -16.8%, -1.1%; P = .029).

The study in this open-label, phase II, randomized trial evaluated filgrastim compared with pegfilgrastim for the alteration or prevention of neutropenia in patients receiving ESHAP chemotherapy for recurrent or refractory HD or NHL. With salvage chemotherapy such as ESHAP, a high percentage of patients experience neutropenia and, in some cases, febrile neutropenia. Therefore, an agent that could modify this incidence and yet be more convenient for the patient, with one subcutaneous injection per cycle, would be ideal. Consistent with the findings from the phase III studies, this study demonstrated that one injection of pegfilgrastim per cycle was as effective as 11 daily injections of filgrastim for modifying the neutropenia associated with ESHAP chemotherapy. Other less-intense salvage regimens may require fewer than 11 doses of filgrastim.

The prolonged pharmacokinetic and pharmacodynamic effects of pegfilgrastim have raised the concern that this agent might have more toxicities compared with filgrastim. However, the toxicities reported in the two arms of this trial were similar and were those expected to be seen in patients receiving ESHAP chemotherapy. This information, along with that of the previous trials that also demonstrated similar toxicities of pegfilgrastim to filgrastim, seems to indicate that the overall toxicity profiles of the two agents are similar. With the convenience of once-per-cycle dosing, pegfilgrastim has potential therapeutic advantages over standard filgrastim and may become the standard of care in the future.

	ACKNOWLEDGMENTS

 
Bing-Bing Yang, PhD, assisted with the pharmacokinetic studies; Beth Kin, RN, and Diane Dunford, RN, assisted with the safety monitoring. MaryAnn Foote, PhD, assisted in the preparation of the manuscript.

	REFERENCES

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Submitted March 8, 2002; accepted October 11, 2002.

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