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: Roy F Chemaly, Andrew J Ullmann, Susanne Stoelben, Marie Paule Richard, Martin Bornhäuser, Christoph Groth, Hermann Einsele, Margarida Silverman, Kathleen M Mullane, Janice Brown, Horst Nowak, Katrin Kölling, Hans P Stobernack, Peter Lischka, Holger Zimmermann, Helga Rübsamen-Schaeff, Richard E Champlin, Gerhard Ehninger, AIC246 Study Team
• Journal: The New England journal of medicine (N Engl J Med) Vol. 370 Issue 19 Pg. 1781-9 (May 08 2014) ISSN: 1533-4406 [Electronic] United States
• PMID: 24806159 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Acetates
• Antiviral Agents
• Quinazolines
• letermovir

Topics

• Acetates (administration & dosage, adverse effects)
• Adult
• Antiviral Agents (administration & dosage, adverse effects)
• Cytomegalovirus Infections (prevention & control)
• Dose-Response Relationship, Drug
• Double-Blind Method
• Hematopoietic Stem Cell Transplantation
• Humans
• Immunocompromised Host
• Incidence
• Kaplan-Meier Estimate
• Opportunistic Infections (prevention & control)
• Quinazolines (administration & dosage, adverse effects)
• Transplantation, Homologous
• Treatment Failure