Impact of Letermovir Primary Cytomegalovirus Prophylaxis on 1-Year Mortality After Allogeneic Hematopoietic Cell Transplantation: A Retrospective Cohort Study

Abstract

Background: Cytomegalovirus (CMV)-seropositive (R+) hematopoietic cell transplant (HCT) recipients have a survival disparity compared with CMV-seronegative recipient/donor (R-D-) pairs. We hypothesized that primary letermovir prophylaxis (LET) may abrogate this disparity. We investigated the relationship between LET and mortality at 1 year post-HCT.

Methods: In this retrospective cohort study, we included adult R-D- or R+ patients who received HCT pre-LET (between 1 January 2013 through 15 December 2017) and post-LET (between 16 December 2017 through December 2019). R+ were categorized by LET receipt as R+/LET or R+/no-LET. Cox proportional hazard models were used to estimate the association of LET with all-cause mortality at 1 year after transplantation.

Results: Of 848 patients analyzed, 305 were R-D-, 364 R+/no-LET, and 160 R+/LET. Because of similar mortality (adjusted hazard ratio [aHR], 1.29 [95% confidence interval {CI}, .76-2.18]; P = .353]) between pre-LET/R-D- and post-LET/R-D-, R-D- were combined into 1 group. Compared with R-D-, the aHR for mortality was 1.40 (95% CI, 1.01-1.93) for R+/no-LET and 0.89 (95% CI, .57-1.41) for R+/LET. Among R+, LET was associated with decreased risk of death (aHR, 0.62 [95% CI, .40-.98]); when conventional HCT and T-cell depleted HCT were analyzed separately, the aHR was 0.86 (95% CI, .51-1.43) and 0.21 (95% CI, .07-.65), respectively.

Conclusions: At 1 year post-HCT, LET was associated with closing the mortality disparity between R-D- and R+. Among all R+, LET was associated with decreased mortality, driven by 79% reduced incidence of death in T-cell depleted HCT.

Keywords: CMV; HCT; allogeneic hematopoietic cell transplant; cytomegalovirus; letermovir; mortality; prevention.

Conflict of interest statement

Potential conflicts of interest. S. G. has received research funding from Miltenyi Biotec, Takeda, Celgene, Amgen, Sanofi, Johnson & Johnson, and Actinium Pharmaceuticals, and is on the advisory boards for Kite Pharmaceuticals, Celgene, Sanofi, Novartis, Johnson & Johnson, Amgen, Takeda, Jazz Pharmaceuticals, and Actinium Pharmaceuticals. M.-A. P. has received institutional research support for clinical trials from Incyte, Kite/Gilead, Miltenyi Biotec, and Novartis; has received honoraria from AbbVie, Bellicum, Bristol-Myers Squibb, Incyte, Merck, Novartis, Nektar Therapeutics, Celgene, Equilium, Karyopharm, Kite/Gilead, Miltenyi Biotec, MorphoSys, Omeros, OrcaBio, VectivBio AG, Vor Biopharma, and Takeda; has served on data and safety monitoring boards for Servier, Cidara Therapeutics, Sallas Life Sciences, and Medigene and scientific advisory boards for MolMed and NexImmune; and holds ownership interests in NexImmune and Omeros. G. P. has served as an investigator for Merck & Co and Shire/Takeda; has received research grant support from Merck & Co; has received consulting and other fees from Chimerix, Astellas, Merck, Cidara, Amplyx, AlloVir, Takeda/Shire, Behring, Octapharma, SymBio, Shionogi, Partners Therapeutics, ADMA Biologics, Vera, and Siemens Healthineers; has received payment and honoraria for continuing medical education programs from PeerView, PeerVoice, Vindico, and Medscape; has received speaker’s fees from Merck & Co; and has served as a data safety and monitoring committee (DSMC) member for Amplyx and Vera, DCSM chair for AlloVir, Endpoint Adjudication Committee (EAC) Chair for Octapharma, and advisory board member for ADMA Biologics, Astellas Pharma, Cidara, Octapharma, Partners Therapeutics, Shionogi, Behring, Takeda, and Siemens Healthineers. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

Figures

Figure 1.

Cumulative incidence of clinically significant cytomegalovirus infection (cs-CMVi) and use of cytomegalovirus (CMV) antivirals by receipt of letermovir prophylaxis (LET). A, Patients were censored at days 180 post–hematopoietic cell transplant or last follow-up, whichever occurred first. Death was treated as competing risk event. Univariable Fine-Gray subdistribution hazard model was used to compare the cumulative incidence of cs-CMVi between groups. B, Bars show estimated total days on antivirals per 1000 person-days across relevant groups. No-LET: CMV-seropositive recipients who did not receive LET. LET: CMV-seropositive recipients who received LET. Abbreviations: CI, confidence interval; CMV, cytomegalovirus; cs-CMVi, clinically significant cytomegalovirus infection; HCT, hematopoietic cell transplant; HR, hazard ratio; LET, letermovir prophylaxis; PET, preemptive therapy.

Figure 2.

Adjusted cumulative incidence of all-cause and nonrelapse mortality by study timeframe and cytomegalovirus (CMV) serostatus. Adjusted cumulative incidences of all-cause mortality (A) and nonrelapse mortality (B) through 1 year post–hematopoietic cell transplant (HCT) by study timeframe and CMV serostatus. Patients were censored at 1 year post-HCT or last follow-up, whichever occurred first. For nonrelapse mortality, second transplant, relapse, and progression of disease were treated as competing risk events. The adjusted all-cause and nonrelapse mortality were calculated from multivariable Cox proportional hazard model and multivariable Fine-Gray subdistribution hazard model, respectively. Acute graft-vs-host disease grade was treated as a time-dependent variable in multivariable models. Pre-LET: prior to implementation of letermovir (from 1 January 2013 to 15 December 2017). Post-LET: after implementation of letermovir (from 16 December 2017 to 31 December 2019). Abbreviations: aHR, adjusted hazard ratio; CI, confidence interval; HCT, hematopoietic cell transplant; LET, letermovir prophylaxis; R–D–, cytomegalovirus-seronegative recipient/donor; R+, cytomegalovirus-seropositive recipient.

Figure 3.

Adjusted cumulative incidence of all-cause and nonrelapse mortality for letermovir prophylaxis (LET) and no-LET groups compared with cytomegalovirus (CMV)–seronegative recipient/donor (R–D–; reference). Adjusted cumulative incidence of all-cause mortality (A) and nonrelapse mortality (B) through 1 year post– hematopoietic cell transplant recipient (HCT) by receipt of LET and CMV serostatus. Patients were censored at 1 year post-HCT or last follow-up, whichever occurred first. For nonrelapse mortality, second transplant, relapse, and progression of disease were treated as competing risk events. The adjusted all-cause and nonrelapse mortality were calculated from multivariable Cox proportional hazard model and multivariable Fine-Gray subdistribution hazard model, respectively. Acute graft-vs-host disease grade was treated as a time-dependent variable in multivariable models. No-LET: CMV-seropositive recipient without LET. LET: CMV-seropositive recipient with LET. Abbreviations: aHR, adjusted hazard ratio; CI, confidence interval; HCT, hematopoietic cell transplant recipient; LET, letermovir prophylaxis; R–D–, cytomegalovirus-seronegative recipient/donor.

Figure 4.

Results from multivariable models evaluating receipt of letermovir prophylaxis (LET) as a risk factor for all-cause and nonrelapse mortality in cytomegalovirus (CMV)–seropositive (R+) recipients. Number (%) of death from all causes (A) and death without second transplant, relapse, or progression of disease Adjusted hazard ratio (aHR) of all-cause mortality and nonrelapse mortality through 1 year post–hematopoietic cell transplant by receipt of LET among R+ patients. Patients were censored at 1 year post-HCT or last follow-up, whichever occurred first. For nonrelapse mortality, second transplant, relapse, and progression of disease were treated as competing risk events. Multivariable Cox proportional hazard models and Fine-Gray subdistribution hazard models were performed to assess aHR for all-cause and nonrelapse mortality, respectively. Acute graft-vs-host disease grade and clinically significant CMV infection were treated as a time-dependent variable in multivariable models. No-LET was treated as reference group. Bars show percentage; points show aHR and whiskers show 95% confidence interval. Abbreviations: CI, confidence interval; CMV, cytomegalovirus; R+, cytomegalovirus-seropositive recipient.