Effects of vascular endothelial growth factor (VEGF) signaling inhibition on human erythropoiesis

Abstract

3575 Background: In rodents, inhibition of VEGF signaling increases production of red blood cells. Major clinical trials of VEGF signaling inhibitors have not reported on these effects in human patients (pts). Methods: To determine whether disruption of VEGF signaling in humans is associated with increased erythropoiesis, we analyzed red blood cell (RBC) and hemoglobin (Hgb) measurements in pts at a single institution enrolled in a phase II trial of axitinib in advanced thyroid cancers (16 pts), a study of sorafenib in advanced solid tumors (57 pts), and a randomized phase II trial of concomitant fluorouracil, hydroxyurea, and radiation with (14 pts) or without bevacizumab (8 pts) for locally advanced cancers of the head and neck. In the axitinib and sorafenib trials, no pt received red cell transfusions (Tf) or erythropoiesis stimulating agents (ESAs). Three pts in the chemoradiotherapy study received Tf or ESAs and were excluded from further analysis. Erythropoietin (EPO) plasma concentrations were measured only on pts in the sorafenib study at baseline, and days 8 and 35. Mixed models with random intercept were used to determine the effect of VEGF signaling inhibitors on RBC and Hgb. Repeated measures analysis of variance was used to examine whether EPO levels changed over time. Results: Over the first 84 day interval of treatment RBC increased for each day on axitinib (4 K/mcl [95% CI 2, 7], p < 0.001) or sorafenib (3K/mcl [2, 4], p < 0.001). Similar results were detected for Hgb. For the first 68 day interval of chemoradiotherapy alone, the RBC declined over time (-13K/mcl/day [-16, -10]) but less so (-7K/mcl [-10, -5]) with added bevacizumab (interaction p = 0.003). EPO levels changed with sorafenib exposure, most notably, increasing by 38% between days 8 and 35 (p < 0.001 by Wilcoxon signed rank test). Conclusions: VEGF signaling inhibition is associated with increased RBC and EPO production. This effect might contribute to positive and negative clinical consequences of exposure to VEGF signaling inhibitors. [Table: see text]