title: Higher tacrolimus concentrations early after transplant reduce the risk of acute GvHD in reduced-intensity allogeneic stem cell transplantation.
abstract: There is significant variability in the serum concentrations of tacrolimus attained early post transplant due to drug interactions and genomic variation. We evaluated whether tacrolimus concentrations early post transplant correlated with incidence of acute GvHD in 120 consecutive patients allografted with a uniform reduced-intensity conditioning regimen. All patients received standard prophylaxis with oral tacrolimus and IV methotrexate. The primary variable of interest was mean weekly tacrolimus concentrations in the initial 4 weeks post transplant. In multivariate analysis, week 1 tacrolimus concentration was an independent predictor of acute grade 2-4 GvHD (hazard ratio (HR), 0.90; 95% confidence interval (CI), 0.84-0.97; P<0.01). This association was driven by a lower risk of acute grade 2-4 GvHD in patients with week 1 tacrolimus concentrations >12 ng/mL (HR, 0.47; 95% CI, 0.25-0.88; P=0.02). Week 1 tacrolimus concentrations were not associated with chronic GvHD, relapse or overall survival. Lower tacrolimus concentrations at weeks 2, 3 and 4 were not associated with a higher incidence of GvHD. In summary, we found that higher tacrolimus concentrations during the first week after allografting with a reduced-intensity conditioning regimen were associated with significantly reduced risk of acute grade 2-4 GvHD without increasing risk of relapse.
authors.affiliation: Department of Pharmacy, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Ganetsky
authors.affiliation: Department of Pharmacy, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Shah
authors.affiliation: Center for Pharmacoepidemiology Research and Training, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: T A
authors.initials: TA
authors.lastname: Miano
authors.affiliation: Department of Biostatistics and Epidemiology, Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: W-T
authors.initials: WT
authors.lastname: Hwang
authors.affiliation: Department of Biostatistics and Epidemiology, Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: J
authors.initials: J
authors.lastname: He
authors.affiliation: Blood and Marrow Transplantation Program, Abramson Cancer Center and the Division of Hematology and Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: A W
authors.initials: AW
authors.lastname: Loren
authors.affiliation: Blood and Marrow Transplantation Program, Abramson Cancer Center and the Division of Hematology and Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: E O
authors.initials: EO
authors.lastname: Hexner
authors.affiliation: Blood and Marrow Transplantation Program, Abramson Cancer Center and the Division of Hematology and Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: N V
authors.initials: NV
authors.lastname: Frey
authors.affiliation: Blood and Marrow Transplantation Program, Abramson Cancer Center and the Division of Hematology and Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: D L
authors.initials: DL
authors.lastname: Porter
authors.affiliation: Blood and Marrow Transplantation Program and Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, New York, NY, USA.
authors.forename: R
authors.identifier: http://orcid.org/0000-0003-2185-9546
authors.initials: R
authors.lastname: Reshef
mesh_terms: D000208:Acute Disease; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D064591:Allografts; D005260:Female; D006086:Graft vs Host Disease / Q000097:blood / Q000401:mortality / Q000517:prevention & control; D006402:Hematologic Diseases / Q000097:blood / Q000401:mortality / Q000628:therapy; D006801:Humans; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000493:pharmacokinetics; D008875:Middle Aged; D033581:Stem Cell Transplantation; D016559:Tacrolimus / Q000008:administration & dosage / Q000493:pharmacokinetics; D013997:Time Factors; D019172:Transplantation Conditioning
chemical_list: D016559:Tacrolimus; D008727:Methotrexate