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N Engl J Med. 2014 May 8;370(19):1781-9. doi: 10.1056/NEJMoa1309533.

Letermovir for cytomegalovirus prophylaxis in hematopoietic-cell transplantation.

Author information

1
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.).

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.).

PMID:
24806159
DOI:
10.1056/NEJMoa1309533
[Indexed for MEDLINE]
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