Pharmacodynamic Monitoring Predicts Outcomes of CCR5 Blockade as Graft-versus-Host Disease Prophylaxis

Abstract

Blocking lymphocyte trafficking after allogeneic hematopoietic stem cell transplantation is a promising strategy to prevent graft-versus-host disease (GVHD) while preserving the graft-versus-tumor response. Maraviroc, a CCR5 antagonist, has shown promise in clinical trials, presumably by disrupting the migration of effector cells to GVHD target organs. We describe a phosphoflow assay to quantify CCR5 blockade during treatment with maraviroc and used it to evaluate 28 patients in a phase II study. We found that insufficient blockade of CCR5 was associated with significantly worse overall survival (HR, 10.6; 95% CI, 2.2 to 52.0; P = .004) and higher rates of nonrelapse mortality (HR, 146; 95% CI, 1.0 to 20,600; P = .04) and severe acute GVHD (HR, 12; 95% CI, 1.9 to 76.6; P = .009). In addition, we found that pretransplant high surface expression of CCR5 on recipient T cells predicted higher nonrelapse mortality and worse GVHD- and relapse-free survival. Our results demonstrate that pharmacodynamic monitoring of CCR5 blockade unravels interpatient variability in the response to therapy and may serve as a clinically informative biomarker.

Keywords: Chemokine receptor blockade; GVHD; Maraviroc.