title: Letermovir for cytomegalovirus prophylaxis in hematopoietic-cell transplantation.
abstract: BACKGROUND
  Cytomegalovirus (CMV) infection is a leading cause of illness and death in patients who have undergone allogeneic hematopoietic-cell transplantation. Available treatments are restricted by clinically significant toxic effects and drug resistance.
  
  
  METHODS
  In this phase 2 study, we evaluated the effect of letermovir (also known as AIC246), a new anti-CMV drug with a novel mechanism of action, on the incidence and time to onset of prophylaxis failure in CMV-seropositive recipients of allogeneic hematopoietic-cell transplants from matched related or unrelated donors. From March 2010 through October 2011, we randomly assigned 131 transplant recipients in a 3:1 ratio to three sequential study cohorts according to a double-blind design. Patients received oral letermovir (at a dose of 60, 120, or 240 mg per day, or matching placebo) for 12 weeks after engraftment. The primary end point was all-cause prophylaxis failure, defined as discontinuation of the study drug because of CMV antigen or DNA detection, end-organ disease, or any other cause. Patients underwent weekly surveillance for CMV infection.
  
  
  RESULTS
  The reduction in the incidence of all-cause prophylaxis failure was dose-dependent. The incidence of prophylaxis failure with letermovir, as compared with placebo, was 48% versus 64% at a daily letermovir dose of 60 mg (P=0.32), 32% at a dose of 120 mg (P=0.01), and 29% at a dose of 240 mg (P=0.007). Kaplan-Meier time-to-onset profiles for prophylaxis failure showed a significant difference in the comparison of letermovir at a dose of 240 mg per day with placebo (P=0.002). The safety profile of letermovir was similar to placebo, with no indication of hematologic toxicity or nephrotoxicity.
  
  
  CONCLUSIONS
  Letermovir, as compared with placebo, was effective in reducing the incidence of CMV infection in recipients of allogeneic hematopoietic-cell transplants. The highest dose (240 mg per day) had the greatest anti-CMV activity, with an acceptable safety profile. (Funded by AiCuris; ClinicalTrials.gov number, NCT01063829.).
authors.affiliation: From the University of Texas M.D. Anderson Cancer Center, Houston (R.F.C., R.E.C.); University Medical Center (A.J.U.) and private statistical consultation (H.N.), Mainz, AiCuris, Wuppertal (S.S., M.P.R., K.K., H.P.S., P.L., H.Z., H.R.-S.), Medizinische Klinik und Poliklinik I, Universitatsklinikum Dresden, Dresden (M.B., G.E.), Universitatsklinikum Münster, Münster (C.G.), and Department of Internal Medicine II, Julius-Maximilians-University, Würzburg (H.E.) - all in Germany; University of Iowa, Iowa City (M.S.); University of Chicago Medical Center, Chicago (K.M.M.); and Stanford University Hospital, Stanford, CA (J.B.).
authors.forename: Roy F
authors.initials: RF
authors.lastname: Chemaly
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Ullmann
authors.forename: Susanne
authors.initials: S
authors.lastname: Stoelben
authors.forename: Marie Paule
authors.initials: MP
authors.lastname: Richard
authors.forename: Martin
authors.initials: M
authors.lastname: Bornhäuser
authors.forename: Christoph
authors.initials: C
authors.lastname: Groth
authors.forename: Hermann
authors.initials: H
authors.lastname: Einsele
authors.forename: Margarida
authors.initials: M
authors.lastname: Silverman
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Mullane
authors.forename: Janice
authors.initials: J
authors.lastname: Brown
authors.forename: Horst
authors.initials: H
authors.lastname: Nowak
authors.forename: Katrin
authors.initials: K
authors.lastname: Kölling
authors.forename: Hans P
authors.initials: HP
authors.lastname: Stobernack
authors.forename: Peter
authors.initials: P
authors.lastname: Lischka
authors.forename: Holger
authors.initials: H
authors.lastname: Zimmermann
authors.forename: Helga
authors.initials: H
authors.lastname: Rübsamen-Schaeff
authors.forename: Richard E
authors.initials: RE
authors.lastname: Champlin
authors.forename: Gerhard
authors.initials: G
authors.lastname: Ehninger
mesh_terms: D000085:Acetates / Q000008:administration & dosage* / Q000009:adverse effects; D000328:Adult; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000009:adverse effects; D003586:Cytomegalovirus Infections / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D016867:Immunocompromised Host; D015994:Incidence; D053208:Kaplan-Meier Estimate; D009894:Opportunistic Infections / Q000517:prevention & control*; D011799:Quinazolines / Q000008:administration & dosage* / Q000009:adverse effects; D014184:Transplantation, Homologous; D017211:Treatment Failure
chemical_list: D000085:Acetates; D000998:Antiviral Agents; D011799:Quinazolines; C000588473:letermovir