A Phase III, Randomized, Double-Blind, Placebo-Controlled Comparative Trial of Pegfilgrastim Versus Filgrastim after Autologous Peripheral Blood Stem Cell Transplantation (PBSCT).

Introduction: Myeloid colony stimulating factors accelerate engraftment and shorten hospital stay following PBSCT. Pegfilgrastim (Peg-G), a pegylated granulocyte colony-stimulating factor is equivalent to filgrastim (G) when used to hasten neutrophil recovery after conventional chemotherapy. While small non-randomized trials suggest that Peg-G could be used in lieu of G to speed hematopoietic reconstitution after PBSCT, no large Phase III trial data exist. This phase III, randomized, double-blind, placebo controlled comparative trial of Peg-G vs G After autologous PBSCT compared the efficacy, costs and safety of the two treatments.

Methods: Consented adult patients undergoing an autologous PBSCT at our institution were eligible if they had collected > 2 × 10⁶ CD34/kg for transplant. Patients were randomized to either fixed-dose Peg-G at 6 mg SQ x1 dose plus daily G-placebo or daily G at 5 mg/kg/day plus Peg-G placebo × 1, all starting on day +1 posttransplant. G or G-placebo continued until sustained engraftment, defined as neutrophils > 5000/ml × 3 days, or 10,000/ml × 1 day, or through day +25 posttransplant. They were stratified based on prep regimen (TBI vs other) and CD34 cell dose/kg (< 5 vs ≥ 5 × 10⁶/kg). The primary endpoint was time to neutrophil engraftment of >500/ml × 3 days. Patients not engrafting to this level by day +19 were permitted to receive open label G. Analysis of infectious complications and cytokine costs as defined by the number of days of G vs the cost of Peg-G plus any rescue doses of G was determined.

Results: We enrolled 78 patients who underwent myeloablative autologous PBSCT for myeloma, lymphoma, testicular, or ovarian carcinoma between 11/03 and 5/07 of whom 39 were randomized to each group. The mean CD34 doses were 4.1 and 4.7 × 10⁶/kg (p = .68) for the Peg-G and G groups respectively. The groups were matched for age, sex, weight, and underlying disease. The median time to neutrophil engraftment was 9 and 10 days respectively for the Peg-G and G groups (p = 0.15). No patient required rescue G to achieve engraftment. The median time to an ANC of 1500/ml × 3 or 5000/ml × 1 was the same in both groups (12 days), but only 45% vs 97% of patients reached a WBC of 5000/ml × 3 or 10,000/ml × 1 (p < .0001) in the Peg-G vs G groups. For the Peg-G vs G groups there were no differences in: platelet engraftment (11 vs. 13 days, p = 0.29), the number of platelet transfusions (5 vs. 4, p = 0.3), incidence of positive cultures for bacterial pathogens (23 vs. 15%, p = 0.39), days of fever (1 vs 2, p = 0.2) or duration of hospital stay (19 vs 19 days). There was 1 death in each group prior to engraftment each due to sepsis. The number of days of G given to that arm to reach an ANC of 1500/ml × 3 or 5000/ml × 1 was 12. Considering the Average Wholesale Price for the actual doses used in this trial for the two groups there was a per-patient savings of $961 for the Peg-G group compared to the G-group using this engraftment endpoint (p < .001).

Conclusions: This Phase III study demonstrated equivalency between Peg-G and G in the ability to achieve prompt neutrophil recovery post PBSCT. There was no difference in infectious complications and the use of Peg-G did achieve a significant cost savings over G.