Randomized trial and pharmacokinetic study of pegfilgrastim versus filgrastim after dose-intensive chemotherapy in young adults and children with sarcomas

Abstract

Purpose: To compare the effectiveness, tolerance, and pharmacokinetics of a single dose of pegfilgrastim to daily filgrastim in children and young adults with sarcomas treated with dose-intensive combination chemotherapy.

Experimental design: Patients were randomized to receive a single dose of 100 mcg/kg of pegfilgrastim s.c. or 5 mcg/kg/day of filgrastim s.c., daily until neutrophil recovery after two treatment cycles with vincristine, doxorubicin, and cyclophosphamide (VDC) and two cycles of etoposide and ifosfamide (IE). The duration of severe neutropenia (absolute neutrophil count, < or =500/mcL) during cycles 1 to 4 and cycle duration for all cycles were compared. Pharmacokinetics of pegfilgrastim and filgrastim and CD34+ stem cell mobilization were studied on cycle 1. Growth factor-related toxicity, transfusions, and episodes of fever and neutropenia and infections were collected for cycles 1 to 4.

Results: Thirty-four patients (median age, 20 years; range 3.8-25.8) were enrolled, and 32 completed cycles 1 to 4. The median (range) duration of absolute neutrophil count of <500/mcL was 5.5 (3-8) days for pegfilgrastim and 6 (0-9) days for filgrastim (P = 0.76) after VDC, and 1.5 (0-4) days for pegfilgrastim and 3.75 (0-6.5) days for filgrastim (P = 0.11) after IE. More episodes of febrile neutropenia and documented infections occurred on the filgrastim arm. Serum pegfilgrastim concentrations were highly variable. Pegfilgrastim apparent clearance (11 mL/h/kg) was similar to that reported in adults.

Conclusion: A single dose per cycle of pegfilgrastim was well tolerated and may be as effective as daily filgrastim based on the duration of severe neutropenia and number of episodes of febrile neutropenia and documented infections after dose-intensive treatment with VDC and IE.

Fig 1

The number of days of severe neutropenia in patients treated with pegfilgrastim compared to patients treated with filgrastim during (A) cycles 1 and 2 of V₃DC and (B) cycles 3 and 4 of IE. Symbols represents the average days of severe neutropenia during cycle 1 and 2 or 3 and 4 for each patient; the line is the median for each group.

Fig 1

The number of days of severe neutropenia in patients treated with pegfilgrastim compared to patients treated with filgrastim during (A) cycles 1 and 2 of V₃DC and (B) cycles 3 and 4 of IE. Symbols represents the average days of severe neutropenia during cycle 1 and 2 or 3 and 4 for each patient; the line is the median for each group.

Fig 2

Absolute neutrophil counts (ANC) during cycles 1 and 2 of V₃DC on the pegfilgrastim arm (A) and the filgrastim arm (B) and cycles 3 and 4 of IE on the pegfilgrastim arm (C) and the filgrastim arm (D) for all patients. Geometric mean serum G-CSF concentration for patients receiving pegfilgrastim is presented for cycle 1 in panel A.

Fig 2

Absolute neutrophil counts (ANC) during cycles 1 and 2 of V₃DC on the pegfilgrastim arm (A) and the filgrastim arm (B) and cycles 3 and 4 of IE on the pegfilgrastim arm (C) and the filgrastim arm (D) for all patients. Geometric mean serum G-CSF concentration for patients receiving pegfilgrastim is presented for cycle 1 in panel A.

Fig 2

Absolute neutrophil counts (ANC) during cycles 1 and 2 of V₃DC on the pegfilgrastim arm (A) and the filgrastim arm (B) and cycles 3 and 4 of IE on the pegfilgrastim arm (C) and the filgrastim arm (D) for all patients. Geometric mean serum G-CSF concentration for patients receiving pegfilgrastim is presented for cycle 1 in panel A.

Fig 2

Absolute neutrophil counts (ANC) during cycles 1 and 2 of V₃DC on the pegfilgrastim arm (A) and the filgrastim arm (B) and cycles 3 and 4 of IE on the pegfilgrastim arm (C) and the filgrastim arm (D) for all patients. Geometric mean serum G-CSF concentration for patients receiving pegfilgrastim is presented for cycle 1 in panel A.