Letermovir Primary Prophylaxis in High-Risk Hematopoietic Cell Transplant Recipients: A Matched Cohort Study

Abstract

Background: Real-life data on the administration of letermovir as cytomegalovirus (CMV) primary prophylaxis after allogeneic hematopoietic cell transplantation (HCT) remain limited. Methods: We conducted a retrospective single-center matched cohort study, comparing consecutive high-risk allogeneic HCT recipients (cases) receiving primary prophylaxis with letermovir and untreated matched historical controls, during a study period of 180 days. The primary outcome was the incidence of clinically significant (cs) CMV infection. Secondary outcomes included duration and costs of CMV-antiviral treatments, hospital resource utilization, hematology and laboratory parameters. Results: Letermovir prophylaxis decreased csCMV infection incidence from 82.7% (controls) to 34.5% (cases; p-value < 0.0001). Controls were more likely to have >1 episode of csCMV infection (59.6%) compared to cases (11.5%; p-value < 0.0001). Letermovir was associated with: shorter overall CMV-associated treatment duration (49 days vs. 77.8 days; p-value: 0.02) and a trend for lower costs of CMV-associated treatments ($4096 vs. $9736; p-value: 0.07) and reduced length of stay (44.8 days vs. 59.8 days; p-value: 0.16). Letermovir administration was associated with significantly shorter duration (27.3 days vs. 57.1 days; p-value: 0.008) and lower costs ($1089 vs. $2281; p-value: 0.008) of valganciclovir treatment. Compared to controls, higher platelet counts were observed in cases (138 G/L vs. 92 G/L; p-value: 0.03) and renal function was improved (94 mL/min/1.73 m2 vs. 74 mL/min/1.73 m2; p-value: 0.006). Conclusions: Primary anti-CMV letermovir prophylaxis decreased the incidence of csCMV infection and the administration of CMV-associated treatments and costs, particularly those associated with valganciclovir. An effect of letermovir on platelet reconstitution and renal function of csCMV post-HCT was observed and needs further investigation.

Therapeutic Drug Monitoring of Orally Administered Letermovir Prophylaxis in Allogeneic Hematopoietic Stem Cell Transplant Recipients

“…Monitoring and preemptive treatment of CMV DNAemia at our institution have been previously described ( 11 ). Briefly, plasma CMV qPCR is performed once weekly at our institution in allogeneic HSCTR during the first 3 months post-HSCT with the COBAS CMV for Cobas 6800 test (Roche Diagnostics, Indianopolis, IN, USA) with a limit of detection of 21 IU/mL and limit of quantification of 25 IU/mL.…”

“…Briefly, plasma CMV qPCR is performed once weekly at our institution in allogeneic HSCTR during the first 3 months post-HSCT with the COBAS CMV for Cobas 6800 test (Roche Diagnostics, Indianopolis, IN, USA) with a limit of detection of 21 IU/mL and limit of quantification of 25 IU/mL. Until December 31, 2020, primary letermovir CMV-prophylaxis was administered to (i) all CMV donor-negative (D−)/R-positive (R+) patients from day (D) 1 to D100 post-HSCT and (ii) CMV HSCTR+ with early (during the first 6 months post-HSCT) grade ≥2 acute GvHD requiring corticosteroid treatment at ≥1 mg/kg/day and until tapering to <10 mg/day of prednisone equivalent ( 11 ). Starting January 1, 2021, all CMV HSCTR+ received primary CMV prophylaxis with letermovir between days 1 and 100 post-HSCT.…”

“…In May 2019, administration of letermovir-based primary CMV-prophylaxis was initiated in high-risk allogeneic HSCTR at our institution with a breakthrough csCMV rate of 27% ( 11 , 12 ). Due to nationwide shortage in IV letermovir, only PO letermovir was used.…”

New trends in the management of cytomegalovirus infection after allogeneic hematopoietic cell transplantation: a survey of the Infectious Diseases Working Party of EBMT

“…On the other hand, several factors may have slowed down this policy such as the variable time interval for the authorization of letermovir prescription at different European countries, the costs of the drug prophylaxis and the need for every allogeneic-HCT unit to reformulate the annual budget and approve the costs for letermovir, and the attitude of the centres and hematologists to utilise in the routine practice the indications coming from a clinical trial. Retrospective data from "real world" use and cost-effectiveness model analysis, con rmed that anti-CMV primary prophylaxis with letermovir is associated with a reduction of CMV infections, shorter hospitalizations, reduced costs and improvement of hematological and renal parameters [21][22][23] . In this regard, our interpretation of existing data support that a broader use of letermovir primary prophylaxis in the next future may result into an improvement of the overall transplant outcomes, as suggested by a post-hoc analysis on overall mortality conducted on the patient recruited in the phase III trial of letermovir versus placebo 24 .…”

Cytomegalovirus as an Uninvited Guest in the Response to Vaccines in People Living with HIV

“…Classical anti-CMV agents are associated with significant toxicities, as ganciclovir-mediated myelosuppression or foscarnet-associated nephrotoxicity, limiting their use to life-threatening clinically-significant CMV infections. However, the safe and effective anti-CMV drug letermovir, acting as a terminase inhibitor, has been recently developed and was approved by the FDA in 2017 for primary prophylaxis in adult CMV-seropositive allogeneic transplantation recipients [ 79 , 80 , 81 ]. Although the indications of this new drug remain strictly limited for now, the development of this new molecule may well be a game changer in the understanding and management of CMV infection.…”