Novel strategies for granulocyte colony-stimulating factor treatment of severe prolonged neutropenia suggested by mathematical modeling.

Abstract

To improve the effectiveness of granulocyte colony-stimulating factor (G-CSF) treatment in high-risk neutropenic patients. 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 microg/kg/d), single pegylated (pegG; pegfilgrastim 100 microg/kg), and continuous infusion (CG; filgrastim 10 microg/kg/d). The interpatient variability is studied by Monte-Carlo simulation of pegG compared with SG and placebo. 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 (< or =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. 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.