What clinical trials and/or guidelines exist regarding the use of letermovir for CMV prophylaxis specifically in allogeneic HCT recipients?

Comment by InpharmD Researcher

Letermovir is recommended for prophylaxis of cytomegalovirus (CMV) infection in high-risk allogeneic hematopoietic cell transplant recipients, with guidelines supporting extension of primary prophylaxis up to day 200 post-transplant in patients with mismatched or haploidentical donors, umbilical cord transplants, T-cell depletion, or recent high-dose prednisone exposure. Based on available clinical trials, with limitations, it reduces the incidence of clinically significant CMV infection during prophylaxis, though infection rates may converge by one year. Letermovir can also be used for secondary prophylaxis in patients with prior CMV infection once viral load is low or undetectable, with low rates of breakthrough infection and minimal adverse events. Low-level CMV DNAemia may occur but often resolves without additional therapy. Extended prophylaxis reduces late CMV infection, and when not feasible, continued viral surveillance or alternative prophylaxis is advised.

Background

The 2025 updated guidelines by the American Society for Transplantation and Cellular Therapy and its Transplant Infectious Diseases Special Interest Group provide comprehensive recommendations for the prevention and management of cytomegalovirus (CMV) infection in hematopoietic cell transplantation (HCT) recipients. The panel states that Letermovir has a significant role in the prophylaxis of CMV infection in high-risk HCT recipients. It is recommended to extend primary prophylaxis up to day 200 post-HCT for patients at high risk of CMV infection, such as those who received allografts from mismatched or haploidentical donors, underwent umbilical cord transplant or T-cell depletion, or received systemic prednisone at high doses within 6 weeks of day 100 post-HCT. This recommendation is based on results from a phase 3 randomized placebo-controlled trial which showed a significantly lower incidence of clinically significant CMV infection (CS-CMVi) by day 200 in patients receiving letermovir compared to placebo. However, by week 48 post-HCT, the incidence of CS-CMVi was similar between the groups. When extending letermovir beyond 100 days is not feasible, continued CMV surveillance and preemptive therapy initiation, or consideration of valganciclovir prophylaxis, are recommended. For secondary prophylaxis following a CMV infection episode, letermovir is considered for HCT recipients at high risk of recurrence, despite limited data mostly from small retrospective studies. The incidence of CS-CMVi during secondary prophylaxis has ranged from 0% to 11%. Recent observations noted breakthrough CS-CMVi at an 11% rate, particularly in patients with ex vivo T-cell depleted HCT. Thus, secondary prophylaxis is advised once the CMV viral load is low or undetectable due to letermovir's low genetic barrier to resistance. CS-CMVi is typically defined by the initiation of antiviral therapy as per specific viral load thresholds or tissue invasive disease occurrence. Low-level CMV DNAemia and CMV DNA blips can occur under letermovir prophylaxis, often representing assay variability or transient viral replication. Most cases revert to undetectable levels, encouraging continued use of letermovir without additional therapy. [1]

References:

[1] Khawaja F, Zamora D, Yong MK, et al. American Society for Transplantation and Cellular Therapy Series #11: Updated Cytomegalovirus Guidelines in Hematopoietic Cell Transplant and Cellular Therapy Recipients. Transplant Cell Ther. 2025;31(10):727-741. doi:10.1016/j.jtct.2025.06.025
Literature Review

A search of the published medical literature revealed 4 studies investigating the researchable question:

What clinical trials and/or guidelines exist regarding the use of letermovir for CMV prophylaxis specifically in allogeneic HCT recipients?

Level of evidence

B - One high-quality study or multiple studies with limitations  Read more→


Please see Tables 1-4 for your response.

Letermovir for Prevention of Recurrent Cytomegalovirus in High-Risk Allogeneic Hematopoietic Cell Transplantation Recipients
Design

Open-label, single-arm study

N= 36
Objective To evaluate the safety and efficacy of letermovir (LTV) as secondary prophylaxis for cytomegalovirus (CMV) in high-risk allogeneic hematopoietic cell transplant recipients
Study Groups All patients (n= 36)
Inclusion Criteria Allogeneic HCT recipients age ≥12 years with preemptive induction therapy for cs-CMVi, undetectable CMV viral load or ≤2 consecutive CMV viral loads <300 IU/mL, and ≥1 high-risk criteria for CMV
Exclusion Criteria Prior LTV primary prophylaxis with suspected or confirmed LTV resistance
Methods Patients received oral LTV 480 mg daily (adjusted to 240 mg with cyclosporine A) for up to 14 weeks. Intravenous LTV was allowed if oral administration was not possible. Adherence was monitored biweekly
Duration Study duration: 24 weeks LTV secondary prophylaxis: up to 14 weeks
Outcome Measures

cs-CMVi at week 14
Baseline Characteristics   All patients (n= 36)
Age, years 59 (17-84)
Female/male 18 (50%)/18 (50%)

Race

White

Asian

Black

Other

 

22 (61.1%)

9 (25.0%)

4 (11.1%)

1 (2.8%)

Indication for HCT

Leukemia/myelodysplastic syndrome

Lymphoma

Aplastic anemia

 

30 (83.3%)

5 (13.9%)

1 (2.7%)
Recipient CMV seropositive/seronegative, 33 (91.7%)/ 3 (8.3%)

Donor type

Matched related/unrelated

Mismatched unrelated

Related haploidentical

Cord blood

 

24 (66.7%)

4 (11.1%)

3 (8.3%)

5 (13.9%)

Conditioning intensity

Myeloablative

Reduced intensity

Nonmyeloablative

 

16 (44.4%)

17 (47.2%)

3 (8.3%)
T cell depletion 25 (69.4%)

Number of high risk-criteria

1

≥2

 

19 (52.8%)

17 (47.2%)
Prior LTV primary prophylaxis 27 (75%)

CMV viral load at start of LTV secondary prophylaxis

Not detected

Detected

 

22 (61.1%)

14 (38.8%)
Results   All patients (n= 36)
cs-CMVi by week 14 5 (14%)
Cumulative incidence of cs-CMVi at week 14 14.9%
Breakthrough cs-CMVi 4 patients
Rebound cs-CMVi 1 patient
Adverse Events No cases of CMV EOD, CMV-related death, or LTV-related adverse events by week 14 or by week 24.
Study Author Conclusions LTV secondary prophylaxis is safe and effective in high-risk HCT recipients, with a low incidence of cs-CMVi and no CMV EOD or CMV-related deaths.
Critique The study provides valuable data on LTV as secondary prophylaxis, but the single-arm design and lack of immune reconstitution data are limitations. The fixed duration of 14 weeks may not be optimal for all patients, and the sample size limits subgroup analyses. 
References:

Han G, Stern A, Lee YJ, et al. Letermovir for Prevention of Recurrent Cytomegalovirus in High-Risk Allogeneic Hematopoietic Cell Transplantation Recipients. Transplant Cell Ther. 2025;31(2):105.e1-105.e9. doi:10.1016/j.jtct.2024.12.010

Efficacy and safety of extended duration letermovir prophylaxis in recipients of haematopoietic stem-cell transplantation at risk of cytomegalovirus infection: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial
Design

Multicentre, randomised, double-blind, placebo-controlled, phase 3 trial

N= 220
Objective To evaluate the efficacy and safety of extending the duration of letermovir prophylaxis for clinically significant cytomegalovirus infection from 100 days to 200 days following haematopoietic stem-cell transplantation (HSCT)
Study Groups

Letermovir group (n= 145)

Placebo group (n= 75)
Inclusion Criteria Cytomegalovirus-seropositive HSCT recipients (aged ≥18 years) who had received letermovir prophylaxis for up to 100 days following HSCT and remained at high risk of late clinically significant cytomegalovirus infection
Exclusion Criteria Severe liver impairment, end-stage renal impairment, recent treatment with antiviral agents with anti-cytomegalovirus activity, history of cytomegalovirus end-organ disease, receiving PET for cytomegalovirus before randomisation
Methods Participants were randomly assigned to receive either an additional 100 days of letermovir (480 mg once daily, adjusted to 240 mg for participants on cyclosporin A) or 100 days of placebo following HSCT. Randomisation was stratified by study centre and haploidentical donor. Cytomegalovirus DNA viral load was measured every 2 weeks from week 14 to week 40 and every 4 weeks thereafter until week 48
Duration June 21, 2019, to March 16, 2022
Outcome Measures Proportion of participants with clinically significant cytomegalovirus infection from randomisation to week 28 
Baseline Characteristics   Letermovir group (n=144) Placebo group (n=74)
Female 52 (36%) 31 (42%)
Age, years 55 (22–74) 55 (20–74)

Race

White

Asian

 

113 (79%)

16 (11%)

 

60 (81%)

8 (11%)

Region

Europe

 

98 (68%)

 

52 (70%)

Primary reason for HSCT

Acute myeloid leukaemia

 

61 (42%)

 

30 (41%)
Cytomegalovirus-seropositive donor 86 (60%) 56 (76%)

GVHD at study entry

None

 

114 (79%)

 

64 (87%)
Results   Letermovir group (n=144) Placebo group (n=74) p-value
Clinically significant cytomegalovirus infection from week 14 to week 28 4 (3%) 14 (19%) 0.0005
Initiation of PET based on documented cytomegalovirus viraemia from week 14 to week 28 3 (2%) 12 (16%) 0.0012
All-cause mortality from week 14 to week 28 3 (2%) 1 (1%) 0.62
Adverse Events The most common adverse events were graft-versus-host disease (30% vs 31%), diarrhoea (12% vs 12%), nausea (11% vs 18%), pyrexia (9% vs 12%), and decreased appetite (4% vs 12%). The most frequently reported serious adverse events were recurrent acute myeloid leukaemia (4% vs none) and pneumonia (2% vs 3%).
Study Author Conclusions Extending the duration of letermovir prophylaxis to 200 days following HSCT is efficacious and safe in reducing the incidence of late clinically significant cytomegalovirus infection in patients at risk.
Critique The study demonstrated the efficacy and safety of extending letermovir prophylaxis, but the generalisability may be limited due to the specific inclusion criteria and the exclusion of patients with severe comorbidities. The study's design did not allow for accounting of deaths or cases of clinically significant cytomegalovirus infection that occurred before study entry, which may impact the assessment of mortality benefit.
References:

Russo D, Schmitt M, Pilorge S, et al. Efficacy and safety of extended duration letermovir prophylaxis in recipients of haematopoietic stem-cell transplantation at risk of cytomegalovirus infection: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Haematol. 2024;11(2):e127-e135. doi:10.1016/S2352-3026(23)00344-7

Impact of Letermovir Use for Cytomegalovirus Prophylaxis on Re-Hospitalization Following Allogeneic Hematopoietic Stem Cell Transplantation: An Analysis of a Phase III Randomized Clinical Trial
Design

Phase III, multicenter, double-blind, placebo-controlled, randomized trial

N= 570
Objective To assess the impact of letermovir use as cytomegalovirus (CMV) prophylaxis on rates and duration of re-hospitalization in adult CMV-seropositive allogeneic hematopoietic stem cell transplantation (HSCT) recipients from the letermovir phase III clinical trial
Study Groups

Letermovir (n= 325)

Placebo (n= 170)
Inclusion Criteria Adult CMV-seropositive allogeneic HSCT recipients who received at least one dose of study medication and had no detectable CMV DNA on day 1
Exclusion Criteria Not specified in the provided text
Methods Participants were randomized 2:1 to receive letermovir (480 mg/day, adjusted to 240 mg/day with concomitant cyclosporine) or placebo within 28 days post-HSCT through week 14 post-HSCT with follow-up through week 48 post-HSCT. Re-hospitalization was prospectively recorded via case report form at each site following discharge from the initial hospitalization for HSCT. 
Duration Follow-up through week 48 post-HSCT
Outcome Measures Rates and duration of re-hospitalization post-transplant 
Baseline Characteristics Baseline demographics and disease characteristics were similar across the two groups. 
Results   Letermovir Placebo 95% CI
All-cause re-hospitalization at week 14 36.6% 47.6% 31.4–42.1 vs 39.9–55.4
All-cause re-hospitalization at week 24  49.2% 55.9% 43.7–54.8 vs 48.1–63.5
All-cause re-hospitalization at week 48 (%) 55.7 60.6 50.1–61.2 vs 52.8–68.0
Mean total duration of re-hospitalization at week 14, days 7.6 11.3 5.9–9.8 vs 8.6–14.8
Mean total duration of re-hospitalization at week 24, days 13.9 15.5 11.2–17.2 vs 11.9–20.1
Mean total duration of re-hospitalization at week 48, days) 18.0 20.7 14.8–21.9 vs 15.8–27.1
Adverse Events Not specified 
Study Author Conclusions Letermovir prophylaxis reduced rates of re-hospitalization and shortened lengths of stay compared with placebo treatment in CMV-seropositive HSCT recipients. Further research could examine the broader healthcare and societal impact of letermovir prophylaxis in different healthcare systems in a real-world setting. 
Critique The study provides valuable insights into the potential benefits of letermovir in reducing re-hospitalization rates and duration post-HSCT. However, as re-hospitalization was an exploratory endpoint, the study was not powered to detect statistical differences. The complexity of the patient population and lack of detailed clinical conditions recorded in the re-hospitalization case report form limit the ability to assess reasons for re-hospitalizations. Additionally, healthcare costs were not collected, which may vary across different health systems, necessitating further health economic modeling and cost-effectiveness analysis. 
References:

Golan Y, Tang Y, Mt-Isa S, et al. Impact of Letermovir Use for Cytomegalovirus Prophylaxis on Re-Hospitalization Following Allogeneic Hematopoietic Stem Cell Transplantation: An Analysis of a Phase III Randomized Clinical Trial. Pharmacoecon Open. 2021;5(3):469-473. doi:10.1007/s41669-021-00264-9

Letermovir Prophylaxis for Cytomegalovirus in Hematopoietic-Cell Transplantation
Design

Phase 3, double-blind, randomized, placebo-controlled trial

N= 565
Objective To evaluate the efficacy and safety of letermovir prophylaxis in preventing clinically significant CMV infection in CMV-seropositive hematopoietic-cell transplant recipients
Study Groups

Letermovir (n= 373)

Placebo (n= 192)
Inclusion Criteria CMV-seropositive patients, 18 years or older, undergoing allogeneic hematopoietic-cell transplantation, with undetectable CMV DNA in plasma within 5 days before randomization, able to start trial regimen by day 28 after transplantation
Exclusion Criteria Severe liver impairment, estimated creatinine clearance <10 ml/min, current or recent receipt of antiviral agents with anti-CMV activity
Methods Patients were randomized to receive letermovir (480 mg/day or 240 mg/day with cyclosporine) or placebo, orally or intravenously, through week 14 post-transplantation.
Duration June 2014 to March 2016
Outcome Measures Proportion of patients with clinically significant CMV infection through week 24, proportion of patients with clinically significant CMV infection through week 14
Baseline Characteristics   Letermovir Group (N= 373) Placebo Group (N= 192)
Age, years 53 54
Male sex 211 (56.6%) 116 (60.4%)
White 301 (80.7%) 162 (84.4%)
Asian 40 (10.7%) 18 (9.4%)
CMV-seropositive donor 230 (61.7%) 114 (59.4%)
Acute myeloid leukemia 142 (38.1%) 72 (37.5%)
Myelodysplastic syndrome 63 (16.9%) 22 (11.5%)
Non-Hodgkin’s lymphoma 47 (12.6%) 28 (14.6%)
Acute lymphocytic leukemia 35 (9.4%) 17 (8.9%)
Matched unrelated donor 138 (37.0%) 78 (40.6%)
Matched related donor 121 (32.4%) 63 (32.8%)
Peripheral blood stem-cell source 279 (74.8%) 134 (69.8%)
Myeloablative conditioning regimen 186 (49.9%) 97 (50.5%)
Antithymocyte globulin use 140 (37.5%) 58 (30.2%)
Results   Letermovir Group (N= 325) Placebo Group (N= 170) p-value
Clinically significant CMV infection by week 24 122 (37.5%) 103 (60.6%) <0.001
Clinically significant CMV infection by week 14 62 (19.1%) 85 (50.0%) <0.001
Adverse Events Vomiting (18.5% vs. 13.5%); edema (14.5% vs. 9.4%); atrial fibrillation or flutter (4.6% vs. 1.0%)
Study Author Conclusions Letermovir prophylaxis significantly reduces the risk of clinically significant CMV infection compared to placebo, with mainly low-grade adverse events. It is effective in preventing CMV infection in high-risk patients and is associated with lower all-cause mortality. 
Critique The study's strengths include its large sample size and rigorous design, confirming the efficacy and safety of letermovir. However, the exclusion of patients with detectable CMV DNA at baseline may limit the generalizability of the findings to all transplant recipients. Additionally, the study did not explore the long-term effects of letermovir beyond the trial period
References:

Marty FM, Ljungman P, Chemaly RF, et al. Letermovir Prophylaxis for Cytomegalovirus in Hematopoietic-Cell Transplantation. N Engl J Med. 2017;377(25):2433-2444. doi:10.1056/NEJMoa1706640