Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8430136 | Biology of Blood and Marrow Transplantation | 2018 | 22 Pages |
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,â10.6; 95% CI, 2.2 to 52.0; Pâ=â.004) and higher rates of nonrelapse mortality (HR,â146; 95% CI, 1.0 to 20,600; Pâ=â.04) and severe acute GVHD (HR,â12; 95% CI, 1.9 to 76.6; Pâ=â.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.
Related Topics
Life Sciences
Biochemistry, Genetics and Molecular Biology
Cancer Research
Authors
Austin P. Huffman, Lee P. Richman, Lisa Crisalli, Alex Ganetsky, David L. Porter, Robert H. Vonderheide, Ran Reshef,