Effect of Sirolimus Exposure on the Need for Preemptive Antiviral Therapy for Cytomeglovirus Infection after Allogeneic Hematopoietic Stem Cell Transplantation

Beatriz Guglieri-Lopez, Alejandro Perez-Pitarch, Irene Garcia-Cadenas, Estela Gimenez, Pere Barba, Nuria Rabella, Juan Carlos Hernandez-Boluda, Laura Fox, David Valcarcel, Albert Esquirol, Rafael Ferriols-Lisart, Jorge Sierra, Carlos Solano, David Navarro, Rodrigo Martino, José Luis Piñana

Research output: Contribution to journalArticleResearch

4 Citations (Scopus)

Abstract

© 2019 American Society for Blood and Marrow Transplantation The current study evaluates the clinical effect of sirolimus exposure on the occurrence of cytomegalovirus (CMV)DNAemia necessitating preemptive antiviral therapy. A total of 167 consecutive recipients of reduced-intensity conditioning (RIC)allogeneic hematopoietic stem cell transplantation (allo-HSCT)who received sirolimus- and tacrolimus-based graft-versus-host disease (GVHD)prophylaxis and whose CMV serostatus was positive for donors and/or recipients were included in this multicenter retrospective study. A parametric model with consecutive sirolimus blood levels describing the time to CMV DNAemia-RAT was developed using NONMEM version 7.4. Overall, 122 of 167 patients (73%)were allografted from an unrelated donor, and the donor CMV-serostatus was negative in 51 cases (31%). Fifty-six recipients (34%)developed CMV DNAemia necessitating preemptive therapy, with a cumulative incidence of 36% at a median follow-up of 25 months. Time to CMV DNAemia necessitating preemptive therapy was best described using a Gompertz function. CMV DNAemia necessitating preemptive therapy-predicting factors were antithymocyte globulin-based conditioning regimen (hazard ratio [HR], 2.2; 95% confidence interval [CI], 1.1 to 4.1; P <.01)and sirolimus concentration (HR,.94; 95% CI,.87 to.99; P <.01). The risk of CMV DNAemia-RAT decreased by 6% for each 1 ng/mL increase in sirolimus trough concentration. In conclusion, we provide evidence on the association between sirolimus blood concentration and incidence of CMV DNAemia necessitating preemptive therapy in allo-HSCT recipients. Moreover, this study presents the first predictive model describing the time to CMV DNAemia necessitating preemptive antiviral therapy as a function of sirolimus drug concentration.
Original languageEnglish
Pages (from-to)1022-1030
JournalBiology of Blood and Marrow Transplantation
Volume25
DOIs
Publication statusPublished - 1 May 2019

Keywords

  • Allogeneic hematopoietic stem cells transplantation
  • Cytomegalovirus disease
  • Cytomegalovirus DNAemia
  • Cytomegalovirus infection
  • Mechanistic target of rapamycin inhibitor
  • PK/PD
  • Preemptive antiviral therapy
  • Quantitative PCR
  • Sirolimus
  • Sirolimus exposure
  • Time-to-event analysis

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