A Mortality Analysis of the Cytomegalovirus (CMV) Infection Letermovir Prophylaxis Trial in CMV-Seropositive Recipients of Allogeneic Hematopoietic Cell Transplantation (HCT)
Authors: Maertens Johan , Schmitt Michael , Marty Francisco M , Ljungman Per , Chemaly Roy F , Kartsonis Nicholas A , Butterton Joan , Wan Hong , Teal Valerie L , Sarratt Kendra , Murata Yoshihiko , Leavitt Randi Y , Badshah Cyrus 
Published: October 2017

Abstract

Background
In a Phase III randomized, double-blind, placebo-controlled study of CMV-seropositive HCT recipients, letermovir prophylaxis significantly reduced the incidence of clinically significant CMV infections (CS-CMVi) through 24 weeks post-HCT. We investigated the impact of letermovir prophylaxis on mortality through Week 48 post-HCT.

Methods
Adult CMV-seropositive allogeneic HCT recipients with undetectable plasma CMV DNA at screening who could initiate treatment by Week 4 post-HCT were eligible. Subjects stratified by high or low CMV disease risk were randomized 2:1 to letermovir dosed at 480 mg/d (240 mg/d if on cyclosporine) or placebo PO or IV through Week 14 post-HCT. Time to all-cause mortality and non-relapse mortality (defined as death due to any reason other than the indication for HCT) through Week 48 post-HCT are presented using Kaplan–Meier (KM) plots censored at study discontinuation for reasons other than death/non-relapse death or upon study completion. Distribution of time to mortality endpoints was tested by stratified log-rank tests using two-sided P-values.

Results
This analysis included all 565 patients randomized and treated with ≥1 dose of study drug. Subjects began study drug a median of 9 days post-HCT; 36.5% started post-engraftment. The observed KM event rate for all-cause mortality was lower in the letermovir group (10.6%) than the placebo group (15.5%) at Week 24 post-HCT, and remained lower through Week 48 post-HCT (21.4% vs. 26.2%) (Figure 1). The observed K–M event rate for all-cause mortality in subjects who developed CS-CMVi was also lower in the letermovir group (4.6%) than the placebo group (17.1%) at Week 48 post-HCT. The observed KM event rate for non-relapse mortality was lower in the letermovir group (6.9%) vs. the placebo group (11.2%) at Week 24 post-HCT, and remained lower in the letermovir group (13.9%) than the placebo group (17.5%) through Week 48 post-HCT (Figure 2).

Conclusion
All-cause and non-relapse mortality were reduced in the letermovir group compared with the placebo group through Week 48 post-HCT (relative risk reduction ~18% and ~21%, respectively). These results are consistent with a clinically meaningful survival benefit for letermovir prophylaxis.

Disclosures
J. Maertens, MSD: Consultant and Investigator, Consulting fee, Research grant and Speaker honorarium. M. Schmitt, MSD: Consultant and Investigator, Consulting fee. F. M. Marty, Merck & Co., Inc.: Consultant, Grant Investigator and Scientific Advisor, Consulting fee and Grant recipient. P. Ljungman, Merck & Co., Inc.: Consultant and Investigator, Consulting fee, Research grant and Speaker honorarium. R. F. Chemaly, Merck & Co., Inc.: Consultant and Investigator, Consulting fee, Research grant and Speaker honorarium. N. A. Kartsonis, Merck & Co., Inc.: Employee, Salary and stock/stock options. J. Butterton, Merck & Co., Inc.: Employee, Salary and stock, stock options. H. Wan, Merck & Co., Inc.: Employee, Salary and stock, stock options.V. L. Teal, Merck & Co., Inc.: Employee, Salary and Stock/stock options. K. Sarratt, Merck & Co., Inc.: Employee, Salary and stock & stock options. Y. Murata, Merck & Co., Inc.: Employee, Salary and stock and stock options. R. Y. Leavitt, Merck & Co., Inc.: Employee, Salary and stock, stock options. C. Badshah, Merck & Co., Inc.: Employee, Salary and stock, stock options