Letermovir for cytomegalovirus prophylaxis in hematopoietic-cell transplantation
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Letermovir for cytomegalovirus prophylaxis in hematopoietic-cell transplantation. / Chemaly, Roy F; Ullmann, Andrew J; Stoelben, Susanne; Richard, Marie Paule; Bornhäuser, Martin; Groth, Christoph; Einsele, Hermann; Silverman, Margarida; Mullane, Kathleen M; Brown, Janice; Nowak, Horst; Kölling, Katrin; Stobernack, Hans P; Lischka, Peter; Zimmermann, Holger; Rübsamen-Schaeff, Helga; Champlin, Richard E; Ehninger, Gerhard; AIC246 Study Team.
in: NEW ENGL J MED, Jahrgang 370, Nr. 19, 08.05.2014, S. 1781-9.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Letermovir for cytomegalovirus prophylaxis in hematopoietic-cell transplantation
AU - Chemaly, Roy F
AU - Ullmann, Andrew J
AU - Stoelben, Susanne
AU - Richard, Marie Paule
AU - Bornhäuser, Martin
AU - Groth, Christoph
AU - Einsele, Hermann
AU - Silverman, Margarida
AU - Mullane, Kathleen M
AU - Brown, Janice
AU - Nowak, Horst
AU - Kölling, Katrin
AU - Stobernack, Hans P
AU - Lischka, Peter
AU - Zimmermann, Holger
AU - Rübsamen-Schaeff, Helga
AU - Champlin, Richard E
AU - Ehninger, Gerhard
AU - AIC246 Study Team
AU - Kröger, Nicolaus-Martin
PY - 2014/5/8
Y1 - 2014/5/8
N2 - 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.).
AB - 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.).
KW - Acetates
KW - Adult
KW - Antiviral Agents
KW - Cytomegalovirus Infections
KW - Dose-Response Relationship, Drug
KW - Double-Blind Method
KW - Hematopoietic Stem Cell Transplantation
KW - Humans
KW - Immunocompromised Host
KW - Incidence
KW - Kaplan-Meier Estimate
KW - Opportunistic Infections
KW - Quinazolines
KW - Transplantation, Homologous
KW - Treatment Failure
U2 - 10.1056/NEJMoa1309533
DO - 10.1056/NEJMoa1309533
M3 - SCORING: Journal article
C2 - 24806159
VL - 370
SP - 1781
EP - 1789
JO - NEW ENGL J MED
JF - NEW ENGL J MED
SN - 0028-4793
IS - 19
ER -
