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

Authors' Affiliation: Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot, Israel

Requests for reprints: Eliezer Shochat, Iatromatics, 50/12 Ben Yehuda St. Netanya 42305, Israel. Phone/Fax: 972-9-834-2939; E-mail: eliezer.shochat{at}iatromatics.com or Vered Rom-Kedar, Computer Science and Applied Mathematics, Weizmann Institute of Science, P.O. Box 26, Rehovot 76100, Israel, E-mail: vered.rom-kedar{at}weizmann.ac.il.

Abstract

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 µg/kg/d), single pegylated (pegG; pegfilgrastim 100 µg/kg), and continuous infusion (CG; filgrastim 10 µg/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 10³–500 x 10³ cells/mL), G2 (50 x 10³–300 x 10³ cells/mL), and G3 (50 x 10³ 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.