title: Possible correlation of sirolimus plasma concentration with sinusoidal obstructive syndrome of the liver in patients undergoing myeloablative allogeneic hematopoietic cell transplantation.
abstract: OBJECTIVE
  To determine the frequency of sinusoidal obstructive syndrome (SOS) in patients undergoing allogeneic hematopoietic cell transplantation who received graft-versus-host disease (GVHD) prophylaxis with sirolimus and tacrolimus, and to assess whether the occurrence of SOS correlates with immunosuppressant levels.
  
  
  METHODS
  Retrospective cohort study.
  
  
  METHODS
  Hematopoietic cell transplant unit at an academic medical center.
  
  
  METHODS
  Fifty-nine adults who received myeloablative preparative regimens for transplantation of any hematologic malignancy and received sirolimus and tacrolimus for GVHD prophylaxis between January 1, 2007, and May 1, 2009; all donors and transplant recipients were human leukocyte antigen (HLA) matched for at least HLA-A, -B, -C, and -DRB1.
  
  
  RESULTS
  The primary outcome was the occurrence of SOS after hematopoietic cell transplantation. Plasma concentrations of sirolimus and tacrolimus and the summative levels of sirolimus and tacrolimus were then compared in patients who developed SOS with those who did not develop SOS. Trough levels were measured from blood samples collected 30-60 minutes before the morning doses of sirolimus and tacrolimus on days 0-35, or until the development of SOS. Of the 59 patients, 12 (20%) developed SOS. The mean sirolimus level was significantly higher in patients who developed SOS relative to those who did not develop SOS (10.5 vs 8.7 ng/ml, p=0.003). The mean summative trough level of sirolimus and tacrolimus was also significantly higher in those who developed SOS compared with those who did not (19.7 vs 17.1 ng/ml, p=0.003). The mean ± SD time to the occurrence of SOS was 28 ± 8.7 days. The median time to death was 101 days for patients who developed SOS compared with 433 days for patients who did not develop SOS (p=0.002).
  
  
  CONCLUSIONS
  Sirolimus plasma concentration may correlate with the development of delayed SOS; however, further research is needed to prospectively evaluate the role of sirolimus exposure in the pathogenesis of SOS.
authors.affiliation: Department of Pharmacy, Indiana University Simon Cancer Center, Indianapolis, Indiana 46202, USA. pkiel@iuhealth.org
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Kiel
authors.forename: Craig A
authors.initials: CA
authors.lastname: Vargo
authors.forename: Gourang P
authors.initials: GP
authors.lastname: Patel
authors.forename: Lindsay L
authors.initials: LL
authors.lastname: Rosenbeck
authors.forename: Shivani
authors.initials: S
authors.lastname: Srivastava
mesh_terms: D000328:Adult; D015331:Cohort Studies; D005260:Female; D006086:Graft vs Host Disease / Q000517:prevention & control*; D018380:Hematopoietic Stem Cell Transplantation; D006504:Hepatic Veno-Occlusive Disease / Q000097:blood / Q000139:chemically induced* / Q000453:epidemiology; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood* / Q000627:therapeutic use; D019172:Transplantation Conditioning / Q000379:methods*; D014184:Transplantation, Homologous; D016896:Treatment Outcome
chemical_list: D007166:Immunosuppressive Agents; D020123:Sirolimus