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Although there are many viruses of serious concern in the post–hematopoietic stem cell transplant (HSCT) setting, cytomegalovirus (CMV) continues to be the most common, clinically significant viral infection after HSCT.¹ The risk for CMV infection is present in early and late phases after HSCT because of the high community seroprevalence, high risk for reactivation, and high risk for transmission from donor to recipient.¹ Patients who undergo HSCT can be affected by CMV reactivation of the patient’s own latent infection in a seropositive recipient or by a primary CMV infection from a seropositive donor.¹ The major risk factors for CMV infection and disease after allogeneic HSCT as defined by the American Society for Transplantation and Cellular Therapy (ASTCT) are listed in Table 1.² Although the spectrum of infection can range from asymptomatic viremia to end-organ disease, CMV infection after HSCT is associated with increased nonrelapse mortality and lower overall survival.^3,4

The landscape of CMV infection in adults who have had HSCT shifted with the approval of letermovir in 2017, which lowered the rates of clinically significant CMV infection.⁵ Letermovir inhibits CMV replication by targeting CMV DNA terminase complex, which is required for viral DNA processing and packaging.⁶ Letermovir was FDA approved in August 2024 for use in pediatric patients aged ≥6 months who weigh at least 6 kg.^6,7 For patients who weigh <15 kg, letermovir was studied using a new formulation of oral pellets, which has been available since the first quarter of 2025.^6,7 Although the literature describing letermovir prophylaxis in children aged 12 to 18 years is growing, real-world studies that evaluate the appropriate dosing, safety, and efficacy of letermovir in patients aged <12 years remains limited.^8-14 We previously described our institution’s use of letermovir in patients aged 12 to 18 years.⁸ The objective of this study is to expand on our previous findings by evaluating the safety and effectiveness of letermovir prophylaxis in pediatric patients aged <12 years who had HSCT.

Methods

This was a single-center, retrospective cohort study approved by the Colorado Multiple Institutional Review Board. Patients who underwent allogeneic HSCT at Children’s Hospital Colorado between December 2022 and May 2024, were aged <12 years at the time of transplant, and received letermovir for primary prophylaxis against CMV were included. Although letermovir prophylaxis is recommended for patients at high risk for CMV infection (Table 1), it is also used in patients who have a moderate risk for CMV (seronegative recipients receiving grafts from seropositive donors) routinely at our institution. Letermovir was dosed daily and was administered as an intravenous (IV) injection, orally, or via nasogastric or gastrotomy tube.

Historically, we used an IV-to-oral conversion of 1 to 1. However, in September 2023, our institutional dosing recommendations were updated (Table 2) to an IV-to-oral conversion of 1 to 2 (for patients aged <12 years and not receiving concomitant cyclosporine) to align more closely with the dosing proposed at the time in the pediatric pharmacokinetic phase 2b clinical trial (NCT03940586).¹⁵ Patients were included if follow-up data were available through 100 days posttransplant or until death. Eligible patients were identified via the institution’s electronic medical record system. The patients’ demographic data were collected in addition to transplant indication, donor type, CMV serostatus (donor and recipient), preparative regimen, immunosuppression, antifungal agent, and the presence of graft-versus-host disease (GVHD). Information on letermovir dose (mg and mg/kg), route of administration, duration of use, and adverse events (AEs) was also obtained.

The primary end point of this study was clinically significant CMV infection, which was defined as the occurrence of CMV disease or the initiation of anti-CMV preemptive therapy based on prespecified CMV DNAemia thresholds.⁴ The patients’ CMV viral load was monitored weekly starting at approximately 14 days posttransplant through 120 days posttransplant. Patients who continued to be immunosuppressed (ie, receiving ongoing immunosuppressive or GVHD therapy) or who were at increased risk for CMV (ie, received treatment for CMV in first 120 days) received additional monitoring every 2 to 4 weeks beyond 120 days posttransplant. During the study period, CMV viral load was measured by a real-time polymerase chain reaction (PCR) assay that detects a region of the CMV glycoprotein B gene in DNA extracted from whole blood, using 5’-nuclease (TaqMan; Thermo Fisher Scientific) methodology on an Applied Biosystems 7500 instrument. The lower limit of detection for the assay was 100 copies/mL (1 IU/mL=1.72 copies/mL). Positive values of <1000 copies/mL (581 IU/mL) and >108 copies/mL (63 IU/mL) of whole blood were reported as qualitatively positive, but they could not be reliably quantified. Data were collected from electronic medical records, and descriptive statistics were used for data analysis.

Results

From December 1, 2022, to May 31, 2024, there were 40 allogeneic HSCT recipients who received letermovir for prophylaxis. Of those patients, 22 were excluded from this study because they were aged ≥12 years at the time of transplant, and 3 were excluded for not meeting the follow-up duration criteria. In all, 15 patients met the inclusion criteria for the cohort analysis (median age, 5.5 years; age range, 12 months-11.6 years). The patients’ baseline characteristics are shown in Table 3. None of the patients received a T-cell–depleted graft, and none had documented CMV end-organ disease or viremia before HSCT.

Letermovir prophylaxis most often began on the day of the transplant (range, 1 day before HSCT to 6 days after HSCT; Table 4). Of the 15 patients, 7 (47%) received the recommended dose of letermovir, as outlined in Table 2. A total of 11 (73.3%) patients received both IV and oral formulations of letermovir, whereas 4 (26.7%) patients received only the oral formulation of letermovir. Of the 15 patients, 13 (86.7%) required the letermovir tablets to be crushed and dissolved for administration via a nasogastric or gastrotomy tube. Patient-specific information on letermovir use is shown in Table 4.

The duration of letermovir treatment ranged from 12 days to 274 days (median, 93 days), with 2 patients continuing to receive letermovir prophylaxis at the end of the study period. The follow-up period ranged from 65 days to 541 days after transplant (median, 260 days). None of the AEs were attributed to letermovir treatment. Of the 15 patients, 13 (86.7%) were considered high risk per the ASTCT definition as defined by Table 1, and all 7 (46.7%) patients who had acute GVHD during the follow-up period received systemic steroids.

Of the 15 patients, 2 (13.3%; patients 7 and 12) had CMV infection requiring preemptive therapy. The trend in CMV viral load for these 2 patients is shown in the Figure. The first quantifiable CMV PCR after HSCT was detected on day 11 after HSCT for patient 7 and on day 26 after HSCT for patient 12. On routine viral monitoring, patient 7 had detectable CMV DNA in the serum, with 165,952 copies/mL. Her CMV viral load decreased to 11,172 copies/mL on day 25 post-HSCT after receiving 2 weeks of foscarnet induction therapy. She was discharged with valganciclovir maintenance therapy on day 33 after HSCT, and initially the viral load fluctuated but ultimately decreased to a level as low as 10,072 copies/mL on day 58.

Patient 7 remained asymptomatic until she was readmitted with polymicrobial bacteremia on day 59. At that time, she was transitioned back to foscarnet treatment because of concern for marrow suppression with valganciclovir. Despite treatment with foscarnet, she presented with CMV pneumonitis at approximately day 70, as evidenced by a positive qualitative CMV PCR on bronchoalveolar lavage. CMV resistance genotyping was negative for patient 7, but she continued to have refractory CMV infection that ultimately became quiescent after a 3-week course of dual therapy with valganciclovir plus foscarnet. Of note, she received letermovir at a dose of 60 mg (4 mg/kg; IV and oral) because of age, weight, and concomitant use of cyclosporine.

Patient 12 also presented with refractory CMV infection (resistance testing was negative). For patient 12, the first quantifiable CMV PCR post-HSCT was detected on day 26, at 38,674 copies/mL. However, this patient had 3 earlier detectable CMV PCRs that were not quantitative, on days 12, 15, and 19. Preemptive therapy with foscarnet was initiated on day 28. After 4 weeks of foscarnet treatment, she received virus-specific cytotoxic T-lymphocytes and then transitioned to valganciclovir treatment. Patient 12 received only oral letermovir prophylaxis at a dose of 480 mg (15.2 mg/kg; Table 2). Letermovir was held during CMV treatment, but both patients (7 and 12) who had CMV viremia resumed letermovir for secondary prophylaxis after the viral load became undetectable. There was no recurrence of clinically significant CMV infection on secondary prophylaxis.

Discussion

Our study shows that letermovir is well tolerated in patients aged <12 years, with no identified AEs. In previous studies without letermovir prophylaxis, the incidence rates of CMV infection were 17% to 29% of high-risk pediatric patients after HSCT.^8,13 Our findings indicate that letermovir prophylaxis in patients aged <12 years was associated with a decreased incidence of clinically significant CMV infection post-HSCT (13.3%) compared with historical rates as described in prior literature in high-risk pediatric patients without letermovir prophylaxis.^8,13 The incidence of clinically significant CMV infection among patients receiving crushed letermovir tablets (15.4%) was similar to that observed in the overall cohort, suggesting that crushing letermovir tablets for administration via nasogastric or gastrostomy tube retains the drug’s efficacy. Although letermovir was approved by the FDA for use in pediatric patients in August 2024, our findings are still relevant while the new dosage form of letermovir in oral pellets is still not widely used.^6,7 In addition, the prescribing information does not recommend prescribing letermovir tablets in patients aged <12 years who also weigh <15 kg (without cyclosporine) or <30 kg (with the coadministration of cyclosporine).^6,16 The results of this study demonstrate the feasibility of prescribing letermovir tablets in that patient population if the oral pellet formulation is not available.⁷

In evaluating letermovir dosing, patient 7 received a dose of 60 mg (oral and IV), which was the lowest weight-based dosing (4 mg/kg) of the study. When excluding patient 7 in the dose analysis, the average oral dose of letermovir was 12.6 mg/kg. Across all weight groups, oral dosing of letermovir was reduced by 50% when used concomitantly with cyclosporine (Table 2). It could be extrapolated that a dose closer to 6.3 mg/kg (50% of the average oral letermovir dose without cyclosporine) may have been more appropriate for patient 7. This would have been a 60% dose increase from the 4-mg/kg oral dose, which we believe is clinically significant. The most recent FDA-approved dosing recommendations for this patient are 120 mg for oral and IV letermovir.^6,16 It is possible that the lower dosing of letermovir contributed to the presence of CMV infection in this patient. Further pharmacokinetic studies are necessary to determine appropriate weight-based dosing and to assess serum concentrations of letermovir across all weight- and age-groups when received with or without cyclosporine.

In addition, per the clinical trial’s dosing protocol (NCT03940586), IV letermovir dosing was not reduced when received concomitantly with cyclosporine.¹⁵ Cyclosporine decreases letermovir hepatic uptake via cyclosporine-mediated inhibition of organic anion-transporting polypeptide 1B1/3 transporters, which subsequently can increase letermovir serum concentrations.⁶ For patients aged >12 years, IV and oral letermovir doses are decreased by 50% when given with cyclosporine.6,16 Most of our patients received dosing using an IV-to-oral conversion of 1 to 1 regardless of calcineurin inhibitor used, based on studies with adults.^6,15 The dosing proposed in the clinical trial (NCT03940586) that suggested the IV-to-oral conversion should be 1 to 2 in patients aged <12 years who were not receiving concomitant cyclosporine was confirmed, based on the study’s interim analyses of pharmacokinetics, safety, and tolerability, which led to our dosing practice change.^6,15 Although our historical institutional practice did not underdose patients, it may have led to unnecessary overexposure of patients to letermovir. Based on the preliminary pharmacokinetic results of the phase 2b clinical trial,¹⁵ effective and safe serum drug exposure can be achieved using the FDA-approved pediatric dosing of letermovir with a more specific dose-banded weight strategy for patients who weigh <15 kg (body weight of 7.5 to <15 kg and 6 to <7.5 kg).^6,16

Both cases of CMV infection in our study were significant, requiring >1 line of therapy. Patient 12 was seropositive for CMV before undergoing HSCT, so her post-HSCT infection likely represented CMV reactivation, whereas patient 7 was seronegative before the transplant, which is likely reflective of a primary infection. Patient 12 also had a known history of noncompliance with medications, including letermovir, which was discovered by persistently low tacrolimus levels. Both patient 7 and patient 12 received T-cell depletion with alemtuzumab in their conditioning regimens, which may have contributed to the refractory nature of their CMV infections. Mutations in UL56 have been responsible for letermovir resistance,1 but this was not observed in our 2 patients.

Limited evidence suggests that the presence of low levels of CMV DNA may not indicate the presence of CMV infection, but may be related to letermovir’s mechanism of action, which inhibits virion maturation by targeting the CMV DNA terminase complex.^3,17 This article suggests that these single detection “blips” in CMV DNAemia post-HSCT could potentially be caused by the release of noninfectious material from abortively infected cells rather than from active viral replication.¹⁷ However, this is likely not the case in our patients with DNAemia because they both demonstrated persistent CMV detection as well as clinically significant infections.

To date, there have been limited published studies that evaluate letermovir prophylaxis in patients aged <12 years.^8-12 Our findings add to the existing literature and include patients aged as young as 1 year. A recent study retrospectively analyzed letermovir primary prophylaxis in 39 children (aged 2 months-17.1 years) in which none had clinically significant CMV reactivation during letermovir primary prophylaxis.⁹ We previously reported on the use of letermovir prophylaxis at our institution from 2015 to 2022.⁸ In that study, the youngest patient was aged 11.5 years, and it was concluded that letermovir prophylaxis was associated with reduced clinically significant CMV DNAemia through day 180.⁸ Three additional studies of letermovir prophylaxis have included patients aged <12 years.^10-12 One study included 9 patients aged 4 to 19 years who received doses of 240 mg or 480 mg daily at a mean and median dose of 10 mg/kg daily.¹² Of the 9 patients, 1 had low-level viremia while receiving letermovir, and none of the other patients had CMV reactivation.¹²

Our study confirms previous findings that letermovir is well tolerated in the pediatric population, including in patients aged as young as 1 year. In addition, our study supports the effectiveness of letermovir prophylaxis in reducing the incidence of CMV infection after HSCT, specifically in patients aged <12 years. We were unable to confirm if crushing letermovir tablets altered the pharmacologic properties of the drug, but we did not observe the loss of clinical effect or an increase in AEs when letermovir tablets were crushed for administration, similar to the results by Kuhn and colleagues.¹²

Limitations

The limitations of this study include its retrospective design, small sample size, and the lack of a comparator group. Although no AEs were attributed to letermovir, the retrospective design of the study may have contributed to the under-identification of AEs. Also, the wide range for letermovir use and patient follow-up period could have affected the incidence of CMV infection observed. The variance in IV-to-oral conversion of letermovir is another weakness of our study because we used a 1 to 1 conversion for many of our patients, but the updated dosing proposed in Table 2 (based on clinical trial NCT03940586) uses a conversion ratio of 1 to 2. Although our study was descriptive in nature, it would have been valuable to evaluate serum letermovir concentrations in relation to dose, age, and route of administration.

Conclusion

Letermovir prophylaxis in pediatric patients aged <12 years who received HSCT was well tolerated and was associated with a reduced incidence of CMV infection compared with previous incidences in the high-risk pediatric patient population that did not receive letermovir prophylaxis. There was no difference in CMV reactivation when letermovir tablets were crushed and administered through a nasogastric or gastrotomy tube versus when tablets were administered whole orally. This single-center cohort analysis was limited by its small sample size and descriptive nature. Larger, real-world studies are needed to further establish the safety, efficacy, and appropriate dosing of letermovir in patients aged <12 years.

Author Disclosure Statement

Dr Chen, Dr David, Dr Strommen, Dr Barthelmess, and Dr McLaughlin have no conflicts of interest to report.

References

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