Novel Strategies for Granulocyte Colony-Stimulating Factor Treatment of Severe Prolonged Neutropenia Suggested by Mathematical Modeling

Purpose: To improve the effectiveness of granulocyte colony-stimulating factor (G-CSF) treatment in high-risk neutropenic patients. Experimental Design: We study G-CSF effects on chemotherapy-induced neutropenia by expanding a simple mathematical model of neutrophil dynamics in the blood. The final model is fitted and validated using published clinical data of neutrophil response to chemotherapy and standard s.c. G-CSF protocol (SG; filgrastim 5 mu g/kg/cl), single pegylated (pegG; pegfilgrastim 100 mu g/kg), and continuous infusion (CG; filgrastim 10 mu g/kg/d). The interpatient variability is studied by Monte-Carlo simulation of pegG compared with SG and placebo. Results: The effect G-CSF support on neutropenia depends on the neutrophil count at the nadir. Three distinct neutropenia grades are identified: G1 (300 x 10(3)-500 x 10(3) cells/mL), G2 (50 x 10(3)-300 x 10(3) cells/mL), and G3 (<= 50 x 10(3) cells/mL). For many G2 patients, the G-CSF levels required for recovery are not attainable by the standard regimen, whereas the sustained pegG and CG seem to be significantly more effective. For G3 patients, G-CSF support alone is not sufficient and additional clinical approaches should be considered. The results presented here are robust and are only slightly affected by population variability. Conclusions: The model captures the G-CSF-neutrophil dynamics of severe chemotherapy-induced neutropenia. Our results clarify and complement the current American Society of Clinical Oncology recommendations for G-CSF administration in neutropenia: High sustained G-CSF levels are needed to treat severe neutropenia and may be achieved by either CG or pegG. The potential effect of sustained G-CSF on severe neutropenia should be studied within a framework of a prospective randomized clinical trial.