Real-life data on the efficacy and safety of letermovir for cytomegalovirus prophylaxis in high-risk pediatric patients: a single-center analysis
Highlight box
Key findings
• We retrospectively analyzed the efficacy and safety of letermovir (LET) in high-risk pediatric patients with cytomegalovirus (CMV) activation, and conducted a preliminary exploration of its duration of use.
What is known and what is new?
• LET can effectively prophylaxis CMV reactivation in patients under 18 years of age and demonstrates good safety. For pediatric patients at high risk of CMV reactivation, extending the duration of prophylaxis beyond 100 days may be beneficial.
• All the patients belong to the high-risk group for CMV recurrence and are all under the age of 18 years old.
What is the implication, and what should change now?
• For high-risk children with CMV reactivation, we should use LET for prophylaxis, extending the treatment beyond 100 days if necessary.
Introduction
Hematopoietic stem cell transplantation (HSCT) is a radical treatment for various malignant and non-malignant disorders. However, its use is limited by various severe transplant-related complications, including cytomegalovirus (CMV) infection. CMV seropositivity and early CMV reactivation after HSCT remain associated with an increased mortality rate (1). Currently, various therapeutic interventions are available to delay the progression of CMV infection, including valganciclovir, ganciclovir, cidofovir, foscarnet, and others. However, due to reasons such as post-transplant bone marrow suppression, the mortality rate associated with CMV reactivation remains high (2,3). And because of the myelosuppression and nephrotoxicity, these drugs cannot be routinely used for CMV prophylaxis. Therefore, it remains crucial to search for safe and effective antiviral drugs to prevent CMV infections (4).
CMV replication relies on a DNA terminase complex composed of multiple subunits (pUL51, pUL56, and pUL89) for processing viral DNA. LET is an antiviral drug that inhibits CMV replication by binding to components of the terminase complex (UL51, UL56, or both) (5,6). Studies have shown that discontinuation of LET within 100 days after transplantation is associated with an increased CMV-related mortality rate (7,8). Letermovir (LET) was approved in the United States for pediatric patients >6 months of age and was also approved for to be continued for at least 200 days post HSCT (9). Studies have shown that LET was used for primary, secondary prophylaxis, or CMV treatment. And there have been no cases of drug discontinuation due to toxicity, with high efficacy as CMV prophylaxis (10,11). However, the use of LET in the pediatric HSCT population lacks extensive real-world research, especially for high-risk pediatric patients with CMV reactivation. We retrospectively analyzed the efficacy and safety of LET in high-risk pediatric patients with CMV activation, and conducted a preliminary exploration of its duration of use. We present this article in accordance with the STROBE reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-241/rc).
Methods
Patients and trial design
We included a total of 123 high-risk pediatric patients with CMV reactivation who underwent transplantation at Beijing Children’s Hospital between January 2022 and December 2023. This study assessed the safety and efficacy of LET in prophylaxis CMV infection in pediatric HSCT. The CMV DNA levels in plasma were undetectable at enrollment. The primary inclusion criteria for high-risk pediatric patients with CMV reactivation were those who met one or more of the following criteria: (I) children undergoing haploidentical HSCT from CMV seropositive donors (12,13); (II) glucocorticoid dose exceeding 1 mg/kg·d (14); (III) concurrently using two or more immunosuppressive agents; (IV) having grade two or higher graft-versus-host disease (GVHD); or a history of previous CMV infection (13,15). The main exclusion criteria included severe impairment of liver and kidney function, as well as current or recent use of antiviral medications with anti-CMV activity. As this is a retrospective study and no patient privacy has been compromised, Beijing Children’s Hospital of Capital Medical University Institutional Review Board waived the need for review.
The dosage of LET was as follows: for pediatric patients receiving a dose of less than 30 mg, it was 240 mg per day; for those weighing 30 kg or more, it was 480 mg per day; for patients younger than 3 years old and weighing less than 15 kg, it was 120 mg per day; and for patients taking concomitant cyclosporine, half the dose of LET should be administered. All patients continued viral prophylaxis after HSCT, including the use of acyclovir and other medications. The need for informed consent was waived due to the retrospective nature of the study and because the data were anonymously analyzed. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.
Endpoints
The primary endpoint was the proportion of patients with clinically significant CMV infection (CsCMVi) at 24 weeks post-transplantation. The secondary endpoints were the proportion of patients with CsCMVi before week 14. All adverse events, including cumulative all-cause mortality, engraftment rates, GVHD, infection rates, and others during the trial period, were collected within 24 weeks post-transplantation for all patients receiving LET.
Efficiency
Patients’ plasma CMV DNA levels were assessed weekly within the first month post-transplantation, then every 2 weeks until week 14, followed by assessments every month thereafter until week 24. CsCMVi were defined as those with a CMV viral load greater than 500 IU/mL or any case of CMV viremia that necessitates preemptive treatment.
Statistical analysis
The Kaplan-Meier plot is used for event time analysis. Descriptive analysis was conducted to calculate the mean, standard deviation, median, range, and percentage of the variables. Graphs were plotted using GraphPad Prism software. Data analysis was performed using SPSS 22.0 software. P<0.05 indicates a statistically significant difference.
Results
Baseline characteristics
From January 2022 to December 2023, we included a total of 123 high-risk pediatric patients with CMV reactivation post-transplantation. The basic characteristics of the patients are shown in Table 1. The median age was 7 years (range, 4 months to 16 years) and 80 patients were males. The underlying diseases of those patients included acute myeloid leukemia (n=33, 26.83%), acute lymphocytic leukemia (n=28, 22.76%), aplastic anemia (n=19, 15.45%), hemophagocytic syndrome (n=13, 10.57%), and others. The most commonly administered immunosuppressants they received include cyclosporine, mycophenolate mofetil, methotrexate, and glucocorticoids. In the LET group, 61 patients received LET, and the baseline characteristics were generally balanced between the LET group and the control group.
Table 1
| Characteristics | LET group (n=61) | Control group (n=62) | LET-1 (n=28) | LET-2 (n=33) |
|---|---|---|---|---|
| Age (years) | ||||
| Median | 7.3 | 6.5 | 8 | 6 |
| Range | 1.5–16 | 0.4–16 | 1.5–16 | 1.5–16 |
| Sex, n (%) | ||||
| Male | 42 (68.85) | 38 (61.29) | 18 (64.29) | 24 (72.73) |
| Female | 19 (31.15) | 24 (38.71) | 10 (35.71) | 9 (27.27) |
| Diagnose, n (%) | ||||
| AML | 13 (21.31) | 20 (32.26) | 4 (14.29) | 9 (27.27) |
| ALL | 13 (21.31) | 15 (24.19) | 6 (21.43) | 7 (21.21) |
| AA | 12 (19.67) | 7 (11.29) | 6 (21.43) | 6 (18.18) |
| HLH | 10 (16.39) | 3 (9.68) | 7 (25.00) | 3 (9.09) |
| Lymphoma | 5 (8.20) | 5 (8.06) | 1 (3.57) | 4 (12.12) |
| CAEBV | 5 (8.20) | 4 (6.45) | 2 (7.14) | 3 (9.09) |
| Others | 3 (4.92) | 8 (12.90) | 2 (7.14) | 1 (3.03) |
| The type of transplantation, n (%) | ||||
| Haplo-HSCT | 45 (73.77) | 58 (93.55) | 19 (67.86) | 26 (78.79) |
| MSDT | 4 (6.56) | 1 (1.61) | 3 (10.71) | 1 (3.03) |
| MUDT | 12 (19.67) | 3 (4.84) | 6 (21.43) | 6 (18.18) |
| Anti-thymocyte globulin use, n (%) | 61 (100.00) | 62 (100.00) | 28 (100.00) | 33 (100.00) |
| Immunosuppressive therapy use, n (%) | ||||
| Cyclosporine | 61 (100.00) | 62 (100.00) | 28 (100.00) | 33 (100.00) |
| Ruxolitinib | 30 (49.18) | 16 (25.81) | 12 (42.86) | 18 (54.55) |
| Glucocorticoid | 61 (100.00) | 62 (100.00) | 28 (100.00) | 33 (100.00) |
| MMF | 58 (95.08) | 54 (87.10) | 25 (89.29) | 33 (100.00) |
| Methotrexate | 58 (95.08) | 58 (93.55) | 27 (96.43) | 31 (93.94) |
| Anti-CD25 antibodies, n (%) | 3 (4.92) | 4 (6.45) | 0 (0.00) | 3 (9.09) |
| GVHD, n (%) | ||||
| Grade ≥2 | 23 (37.70) | 23 (37.10) | 9 (32.14) | 14 (42.42) |
| Grade <2 | 38 (62.30) | 39 (62.90) | 19 (67.86) | 19 (57.58) |
LET-1: LET use ≤100 days. LET-2: LET use >100 days. AA, aplastic anemia; ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; CAEBV, chronic active Epstein-Barr virus infection; GVHD, graft-versus-host disease; HLH, hemophagocytic lymphohistiocytosis; LET, letermovir; MMF, mycophenolate mofetil; MSDT, HLA-matched sibling donor transplantation; MUDT, HLA-matched unrelated donor transplantation.
Primary endpoints and key secondary endpoints
In our study, 61 patients received LET. All pediatric patients were concurrently using cyclosporine, resulting in a dose reduction of LET by half for all patients (Table 2). The median duration was 100 days (ranging from 52 to 298 days). Thirty-six patients were under primary prophylaxis, 23 were secondary prophylaxis. And two patients were additionally treated with LET in combination therapy due to a slow decline in CMV DNA titer while receiving other antiviral medications. After the CMV DNA became negative, they continued to receive LET for prophylaxis (Table 2). As shown in Figure 1, the proportion of CMV reactivation at 24 weeks post-transplantation in the LET group was significantly lower than the control group (8.20% vs. 43.55%, P<0.001). The secondary endpoint was that the proportion of CMV reactivation in the LET group was also significantly lower than the control group at week 14 (6.56% vs. 41.94%, P<0.001). Among the 123 pediatric patients, there was no statistically significant difference in 1-year overall survival (OS) between the LET group and the control group (P=0.40).
Table 2
| Characteristic | Value |
|---|---|
| LET dosage (mg/d) | |
| Weight ≥30 kg | 240 |
| Weight <30 kg | 120 |
| Age <3 years and weight <15 kg | 60 |
| Purpose of treatment, n (%) | |
| Primary prophylaxis | 36 (59.02) |
| Secondary prophylaxis | 23 (37.70) |
| Salvage therapy | 2 (3.28) |
| Duration of LET (days), median [range] | 100 [52–298] |
LET, letermovir.
Safety
Among the 61 patients treated with LET, none discontinued the drug due to intolerance. The median engraftment times for both white blood cells and platelets were 12 days. In 19.67% of the pediatric patients, aspartate aminotransferase (AST) levels exceeded three times the normal range, and in 36.06% of the patients, alanine aminotransferase (ALT) levels exceeded three times the normal range. However, there was no statistically difference compared to the control group, as shown in Table 3. Other common side effects included rash (22.95%), fever (21.31%), nausea (11.48%), hypertension (11.48%), etc. These adverse reactions were also present in the control group, with a higher frequency of fever and rash.
Table 3
| Event | LET group (n=61) | Control group (n=62) | P |
|---|---|---|---|
| GVHD | 39 (63.93) | 52 (83.87) | 0.01 |
| AST | 12 (19.67) | 15 (24.19) | 0.55 |
| ALT | 22 (36.06) | 20 (32.26) | 0.66 |
| Diarrhea | 6 (9.84) | 9 (14.52) | 0.43 |
| Nausea | 7 (11.48) | 5 (8.06) | 0.52 |
| Fever | 13 (21.31) | 23 (37.10) | 0.054 |
| Rash | 14 (22.95) | 28 (45.16) | 0.009 |
| Vomiting | 4 (6.56) | 15 (24.19) | 0.007 |
| Cough | 2 (3.28) | 4 (6.45) | 0.41 |
| Headache | 1 (1.64) | 4 (6.45) | 0.18 |
| Abdominal pain | 5 (8.20) | 2 (3.23) | 0.23 |
| Hypertension | 7 (11.48) | 8 (12.90) | 0.81 |
Data are presented as n (%). ALT, alanine aminotransferase; AST, aspartate transaminase; GVHD, graft-versus-host disease; LET, letermovir.
Extending the duration of LET use reduces CMV reactivation
Among the 61 pediatric patients, 33 patients had LET use exceeding 100 days (LET-2 group), with a median duration of 120 days. As shown in Table 1, the baseline characteristics were generally balanced between the two groups when compared to the LET-1 group (LET use ≤100 days). However, the proportion of CMV reactivation at 24 weeks post-transplantation in the LET-2 group (LET use >100 days) was significantly lower than that in the LET-1 group (5.89% vs. 11.10%, P=0.009). And there are statistically significant differences in CMV reactivation rates among the LET-1, LET-2, and control groups (P<0.001).
Discussion
We administered LET off-label to high-risk pediatric patients with CMV reactivation after HSCT, and some patients received the drug for more than 100 days. Compared with the control group, LET significantly reduced the incidence of CsCMVi after HSCT, which is generally consistent with previously reported data in adults and children (9,16). Therefore, we believe that high-risk pediatric patients with CMV reactivation can benefit from LET prophylaxis. This is consistent with the recent European Conference on Infections in Leukaemia (ECIL) guidelines (17).
In our study, we found that LET was effective as both primary prophylaxis, secondary prophylaxis, and salvage therapy (16,18,19). Only six pediatric patients developed CsCMVi after using LET, and all of them achieved negative conversion after aggressive treatment. However, further studies are needed to assess whether earlier use of LET is able to reduce CMV reactivation.
Currently, drugs used for CMV treatment, such as ganciclovir and foscarnet, cannot be routinely used for CMV prophylaxis due to their bone marrow suppression and renal toxicity. We observed no bone marrow suppression events after LET prophylaxis. And the use of LET prior to engraftment did not affect neutrophil and platelet engraftment. This suggests that LET is suitable for patients <18 years old (20). Moreover, the adverse events observed in the LET group were generally similar to those in the control group. It is noteworthy that the proportions of fever and rash were even higher in the control group, which may be related to the use of other antiviral drugs such as ganciclovir, foscarnet, and valganciclovir.
Studies have shown that discontinuing LET within 100 days after HSCT is associated with an increased risk of CMV-related mortality in adults (7). And extending the duration of LET use can reduce the incidence of late-onset CMV infection (21). In our study extending the use of LET in high-risk pediatric patients with CMV reactivation was also beneficial, significantly reducing the incidence of CMV reactivation. And there was no increase in side effects. However, we did not observe a difference in all-cause mortality between the LET-1 group and the LET-2 group, which may be related to the short follow-up duration and the small number of enrolled patients.
This study is a single-center, retrospective study with a relatively short follow-up period, and therefore no difference in all-cause mortality was found between the LET group and the control group. However, the strength of our analysis lies in the fact that, compared with other retrospective cohort studies, we provide real-world data on a relatively large population of high-risk pediatric patients with CMV reactivation after HSCT, including data on younger and lower-weight patients. Further data are still needed to confirm our findings.
Conclusions
LET can effectively prophylaxis CMV reactivation in patients under 18 years of age and demonstrates good safety. For pediatric patients at high risk of CMV reactivation, extending the duration of prophylaxis beyond 100 days may be beneficial.
Acknowledgments
We are grateful to the patients and their families who participated in this study. We also thank all the physicians, nurses and other patient caregivers who participated in the study.
Footnote
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-241/rc
Data Sharing Statement: https://tp.amegroups.com/article/view/10.21037/tp-2025-241/dss
Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-241/prf
Funding: This work was supported by
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-241/coif). The authors have no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. As this is a retrospective study and no patient privacy has been compromised, Beijing Children’s Hospital of Capital Medical University Institutional Review Board waived the need for review. The need for informed consent was waived due to the retrospective nature of the study and because the data were anonymously analyzed. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
References
- Rowe RG, Guo D, Lee M, et al. Cytomegalovirus Infection in Pediatric Hematopoietic Stem Cell Transplantation: Risk Factors for Primary Infection and Cases of Recurrent and Late Infection at a Single Center. Biol Blood Marrow Transplant 2016;22:1275-83. [Crossref] [PubMed]
- Gagelmann N, Ljungman P, Styczynski J, et al. Comparative Efficacy and Safety of Different Antiviral Agents for Cytomegalovirus Prophylaxis in Allogeneic Hematopoietic Cell Transplantation: A Systematic Review and Meta-Analysis. Biol Blood Marrow Transplant 2018;24:2101-9. [Crossref] [PubMed]
- Chen K, Cheng MP, Hammond SP, et al. Antiviral prophylaxis for cytomegalovirus infection in allogeneic hematopoietic cell transplantation. Blood Adv 2018;2:2159-75. [Crossref] [PubMed]
- Chan ST, Logan AC. The clinical impact of cytomegalovirus infection following allogeneic hematopoietic cell transplantation: Why the quest for meaningful prophylaxis still matters. Blood Rev 2017;31:173-83. [Crossref] [PubMed]
- Neuber S, Wagner K, Messerle M, et al. The C-terminal part of the human cytomegalovirus terminase subunit pUL51 is central for terminase complex assembly. J Gen Virol 2018;99:119-34. [Crossref] [PubMed]
- Neuber S, Wagner K, Goldner T, et al. Mutual Interplay between the Human Cytomegalovirus Terminase Subunits pUL51, pUL56, and pUL89 Promotes Terminase Complex Formation. J Virol 2017;91:e02384-16. [Crossref] [PubMed]
- Liu LW, Yn A, Gao F, et al. Letermovir Discontinuation at Day 100 After Allogeneic Stem Cell Transplant Is Associated With Increased CMV-Related Mortality. Transplant Cell Ther 2022;28:510.e1-9. [Crossref] [PubMed]
- Mendoza MA, Bhaimia E, Alkhateeb HB, et al. Which allogeneic hematopoietic cell transplant recipients have an increased risk for delayed-onset clinically significant cytomegalovirus infection after letermovir prophylaxis? Transpl Infect Dis 2024;26:e14377. [Crossref] [PubMed]
- Marty FM, Ljungman P, Chemaly RF, et al. Letermovir Prophylaxis for Cytomegalovirus in Hematopoietic-Cell Transplantation. N Engl J Med 2017;377:2433-44. [Crossref] [PubMed]
- Galaverna F, Baccelli F, Zama D, et al. Letermovir for Cytomegalovirus infection in pediatric patients undergoing allogenic hematopoietic stem cell transplantation: a real-life study by the Infectious Diseases Working Group of Italian Association of Pediatric Hematology-Oncology (AIEOP). Bone Marrow Transplant 2024;59:505-12. [Crossref] [PubMed]
- Wang Q, Liu M, Zhang S, et al. Letermovir prophylaxis for cytomegalovirus in pediatric patients undergoing allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 2025;60:422-4. [Crossref] [PubMed]
- Lin CH, Su YJ, Hsu CY, et al. Haploidentical allogeneic hematopoietic stem cell transplantation increases the risk of cytomegalovirus infection in adult patients with acute leukemia. Transpl Infect Dis 2019;21:e13096. [Crossref] [PubMed]
- Jaing TH, Chang TY, Chen SH, et al. Factors associated with cytomegalovirus infection in children undergoing allogeneic hematopoietic stem-cell transplantation. Medicine (Baltimore) 2019;98:e14172. [Crossref] [PubMed]
- Al-Hajjar S, Al Seraihi A, Al Muhsen S, et al. Cytomegalovirus infections in unrelated cord blood transplantation in pediatric patients: incidence, risk factors, and outcomes. Hematol Oncol Stem Cell Ther 2011;4:67-72. [Crossref] [PubMed]
- Yi ES, Lee JW, Kim YJ, et al. Risk factors and outcomes of cytomegalovirus infection in children post cord blood transplantation with focus on impact of graft-versus-host disease and immunosuppressants. Ann Hematol 2022;101:409-19. [Crossref] [PubMed]
- Kuhn A, Puttkammer J, Madigan T, et al. Letermovir as Cytomegalovirus Prophylaxis in a Pediatric Cohort: A Retrospective Analysis. Transplant Cell Ther 2023;29:62.e1-4. [Crossref] [PubMed]
- Ljungman P, Alain S, Chemaly RF, et al. Recommendations from the 10th European Conference on Infections in Leukaemia for the management of cytomegalovirus in patients after allogeneic haematopoietic cell transplantation and other T-cell-engaging therapies. Lancet Infect Dis 2025;25:e451-62. [Crossref] [PubMed]
- Kilgore JT, Becken B, Varga MG, et al. Use of Letermovir for Salvage Therapy for Resistant Cytomegalovirus in a Pediatric Hematopoietic Stem Cell Transplant Recipient. J Pediatric Infect Dis Soc 2020;9:486-9. [Crossref] [PubMed]
- César T, Le MP, Klifa R, et al. Letermovir for CMV Prophylaxis in Very High-Risk Pediatric Hematopoietic Stem Cell Transplantation Recipients for Inborn Errors of Immunity. J Clin Immunol 2023;44:6. [Crossref] [PubMed]
- Li WW, Zhang YM, Shen MZ, et al. Efficacy and safety of letermovir prophylaxis for cytomegalovirus infection after hematopoietic stem cell transplantation. Blood Sci 2024;6:e00178. [Crossref] [PubMed]
- 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:e127-35. [Crossref] [PubMed]
