| Autor: |
McCune JS; City of Hope, Department of Population Sciences, Duarte, California 91010, United States.; City of Hope, Department of Hematology & HCT, Duarte, California 91010, United States., McKiernan JS; City of Hope, Department of Population Sciences, Duarte, California 91010, United States., van Maarseveen E; Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht University, 3584 CS Utrecht, The Netherlands., Huitema ADR; Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht University, 3584 CS Utrecht, The Netherlands.; Department of Pharmacy & Pharmacology, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands., Randolph TW; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, United States., Deeg HJ; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, United States.; Department of Medicine, University of Washington, Seattle, Washington 98195, United States., Nakamura R; City of Hope, Department of Hematology & HCT, Duarte, California 91010, United States., Baker KS; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, United States.; Department of Pediatrics, University of Washington, Seattle, Washington 98195, United States. |
| Abstrakt: |
Busulfan-based conditioning is the most commonly used high-dose conditioning regimen for allogeneic hematopoietic cell transplant (HCT). The alkylating agent busulfan has a narrow therapeutic index, with busulfan doses personalized to a target plasma exposure (targeted busulfan). Using a global pharmacometabonomics approach, we sought to identify novel biomarkers of relapse or acute graft versus host disease (GVHD) in a cohort of 84 patients receiving targeted busulfan before allogeneic HCT. A total of 763 endogenous metabolomic compounds (EMCs) were quantitated in 230 longitudinal blood samples before, during, and shortly after intravenous busulfan administration. We performed both univariate linear regression and pathway enrichment analyses using global testing. The cysteine/methionine pathway and the glycine, serine, and threonine metabolism pathway were most associated with relapse. The latter be explained by the fact that glutathione S -transferases conjugate both busulfan and glutathione, which contains glycine as a component. The d-arginine and d-ornithine metabolism pathway and arginine and proline metabolism pathway were most associated with acute GVHD. None of these associations were significant after correcting for false discovery rate (FDR) with a strict cutoff of FDR-adjusted p < 0.1. Although larger studies are needed to substantiate these findings, the results show that EMCs may be used as predictive biomarkers in HCT patients. |
