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Cancer detection and treatment strategies have improved, leading to prolonged patient survival.^1,2 However, patients are now facing a higher risk for developing cardiovascular complications from cancer therapies than for a recurrence of cancer.^2-4 In breast cancer survivors, the risk for mortality from a cardiovascular complication is higher than the mortality risk from the cancer itself.⁴ Historically, therapeutic agents that can lead to cardiotoxicity have been intravenous therapies, such as anthracyclines, antimetabolites, alkylating agents, and monoclonal antibodies.^2,4,5 Cardiac adverse events (AEs) related to these agents include reduction in left ventricular ejection fraction, cardiomyopathy, hypertension, arrhythmias, and immune-mediated cardiac damage.^3,5 With the number of oral oncolytic agents quickly growing, the list of agents tied to newly identified cardiac AEs continues to increase.⁵

The field of cardio-oncology originated to fulfill the need for prevention, diagnosis, surveillance, and management of cardiovascular disease in patients who were undergoing or completed cancer treatment.^2,6 To deliver high-quality patient-centered care, clinicians must collaborate and implement treatment strategies based on recently published guidelines, expert opinion, and clinical judgment. Implementation of a multidisciplinary approach in the cardio-oncology field allows for shared decision-making, better patient outcomes, and improved knowledge in a field that combines 2 specialties: oncology and cardiology.^2,3,6 Healthcare professionals who may be part of a cardio-oncology program include cardiologists, medical oncologists, mid-level practitioners, pharmacists, nurses, dietitians, and social workers.⁶ Information regarding the role of the oncology pharmacist in the setting of cardiovascular disease secondary to cancer therapy is limited. However, oncology pharmacists can play a unique role in this field by providing in-depth knowledge of intravenous and oral oncolytic therapies (including AE profiles), evaluating the potential for drug interactions, managing AEs, monitoring the efficacy and safety of medications,^2,3 and educating patients and healthcare team members.

This project’s objective was to implement a pharmacist position at the cardio-oncology clinic. Our rationale was that the pharmacist will add additional value to the program as an oncology-trained healthcare professional with cancer medication expertise who can collaborate with the multidisciplinary team to deliver high-quality patient-centered care in our community.

Methods

During the project’s development phase, a literature search was conducted to find evidence of the need and benefits of a pharmacist in the cardio-oncology setting. The proposal for the project and data collection points were reviewed by the institutional review board and found to be exempt. During the planning phase, the project lead and the supervising pharmacists met with 3 pharmacists with cardiology and oncology backgrounds who have established practices in the cardio-oncology setting at their institutions to obtain guidance and examples of their workflow, documentation, resources used, and types of outcomes to evaluate for this project. From this, a draft of the workflow, data collection, and types of interventions to be performed was presented to the cardio-oncology team members (cardiologist and program manager) to assess their needs and gather their input on how a pharmacist could help the team. A second meeting took place 1 month before the pilot started to discuss clinic days, schedule, location, and hours and review proposed smart phrases for the pharmacist to use in the electronic medical records (EMRs).

Patients seen in the cardio-oncology clinic are initially referred by the oncology department for evaluation due to baseline cardiovascular disease, including arrhythmias and significant coronary artery disease, in patients who have planned cancer therapy with an oncolytic agent that could cause or exacerbate cardiac conditions. Furthermore, patients who developed cardiac AEs from chemotherapy, such as a decrease in left ventricular ejection fraction with HER2-targeted therapies, anthracyclines, or tyrosine kinase inhibitors, are also referred. Cardio-oncology referral may also originate after a cardiac event leading to hospitalization in patients receiving active cancer treatment, where the general cardiology team either at discharge or during post-discharge follow-up visit refers the patient to cardio-oncology for further evaluation or ongoing monitoring. In addition, patients undergoing autologous and allogeneic stem cell transplant are referred to the cardio-oncology clinic for cardiovascular evaluation before initiating conditioning chemotherapy.

During the project implementation phase, the pharmacist completed chart reviews before seeing patients in the clinic. A proposed workflow was created and is outlined in Figure 1. If the patient was new to the clinic, an intervention was identified, or if there were medication-related questions, the pharmacist joined the cardiologist during the patient visit and completed pharmacist-specific documentation. Documentation included the completion of progress notes under a documentation-only encounter and was facilitated with EMR smart phrases that captured assessments, interventions, and recommendations for each patient evaluated by the pharmacist. The pharmacist then tracked the workload, including number of patients seen, documentation and types of interventions completed, patient demographics, patients’ ability to continue cancer treatment, education completed by the pharmacist, and time spent, via an Excel sheet. Drug–drug interactions between cardioprotective agents and chemotherapy were assessed based on the Lexicomp drug-interaction tool or on the American Heart Association Scientific Statement that provides guidance outlining cardio-oncology drug–drug interactions.⁷ Depending on the level of interaction and if the interacting agent was a cardioprotective medication, the medication was changed after discussion with the cardiologist. If the interacting agent was a home medication, a message was sent notifying the prescribing clinician of the interaction. Cardiovascular disease monitoring recommendations were based on the 2022 European Society of Cardiology (ESC) Guidelines on cardio-oncology,8 as well as patient-specific symptoms and risk factors. The follow-up time frame was determined by the cardiologist, who considered the severity of the cardiovascular disease and risk factors for chemotherapy-induced cardiac disease.^7,8

Results

A total of 118 patients were seen in the cardio-oncology clinic during 10 clinic days from February 5, 2024, to March 8, 2024. Documentation was completed on 57 patients due to time constraints in chart review, and 2 patients were evaluated by the pharmacists outside of the clinic and were excluded from the final analysis. Clinic patients’ demographic information is found in Table 1. The most common cancer diagnosis was breast cancer, followed by diffuse large B-cell lymphoma and prostate cancer (Table 2).

Interventions were performed in 47 (82.5%) patients (Figure 2). The most common interventions completed were individualizing monitoring plans based on the patient’s baseline risk factors and chemotherapy regimen (n=30), followed by initiation of cardioprotective therapy for the management of chemotherapy-induced cardiac AEs (n=14), and assessment of drug–drug interactions (n=8). Monitoring recommendations included baseline and follow-up echocardiograms in patients who were actively receiving chemotherapy treatment or after treatment completion (including hematopoietic stem cell transplant), follow-up lipid panels in patients on hormonal therapy, and baseline cardiac biomarkers (cardiac troponin and natriuretic peptides) for high-risk patients undergoing treatment with immune checkpoint inhibitors. All patients reviewed were evaluated for drug–drug interactions, but in certain cases, the cardiologist asked the pharmacist to specifically assess which medications could be safely prescribed with the patient’s current chemotherapy regimen if therapy for blood pressure control or hyperlipidemia became necessary in the future.

Of the 47 patients who received interventions, 39 (83%) patients had 1 intervention, and 8 (17%) patients had 2 interventions completed by the pharmacist per visit. All interventions done by the pharmacist were accepted by the team. In addition, 10 (17.5%) patients of the cohort of 57 patients had no interventions, but baseline assessments and documentation were still completed in the EMR for future reference. The average chart-review time spent before clinic visits was 40 minutes, with a total of approximately 60 minutes when taking into account the clinic visits and final changes in the recommendations based on visit findings and discussion with the cardiologist. Given this time limitation, chart review was prioritized to patients on active treatment, hematopoietic stem cell transplant recipients, and patients who are childhood and adolescent cancer survivors. No cancer therapy was discontinued secondary to cardiovascular disease during the pilot project.

Discussion

During the first 2 weeks of the pilot project, the EMR documentation performed by the oncology pharmacist was modified based on the cardiologist and the supervising oncology pharmacist’s feedback. The assessment portion was changed to reflect the cardiovascular baseline risk for patients based on the 2022 ESC cardio-oncology guidelines⁸ and drug-specific cardiovascular AEs based on the drugs’ prescribing information. Assessments for venous thromboembolism risk based on the Khorana scoring system⁹ and cardiovascular events based on the 10-year atherosclerotic cardiovascular disease risk tool¹⁰ were performed in the clinic for those patients not already on anticoagulation or hyperlipidemia therapy.

Patients who did not have specific interventions completed by the pharmacist were either affected by early adjustments in the pilot project process, where optimal opportunities for interventions were still being investigated, or were on active surveillance, where no specific monitoring or change in therapy was needed. Areas of improvement that can be evaluated with further refinement of the workflow include opportunities for educating patients regarding their chemotherapy regimen and the risk for cardiac AEs and drug–drug interactions. A second area of improvement includes educating the healthcare team regarding newly released cancer therapies. Other areas of growth include implementing prospective and retrospective studies on the use of cardioprotective agents in patients undergoing cancer treatment, gathering data to optimize the utilization of cardioprotective agents in this setting, establishing a collaborative practice agreement, and developing a cardio-oncology rotation for our institution’s PGY2 oncology pharmacy residency program.

Having a pharmacist on the team may also provide beneficial recommendations beyond patient appointments. Our primary analysis excluded 2 patients because they were not seen by the pharmacist in the clinic. Of these, 1 patient was admitted to the hospital due to possible immune checkpoint inhibitor–induced myocarditis and the second patient was excluded because of a new onset of heart failure caused by lenvatinib, a vascular endothelial growth factor tyrosine kinase inhibitor. The pharmacist provided recommendations to the cardiologist on the management of myocarditis and dose reduction for lenvatinib. Other types of discussions that occurred between the pharmacist and cardiologist involved specific drug information questions on chemotherapy regimens, a literature search on rare AEs of agents and their management, and an estimation of anthracycline lifetime cumulative dose in patients who are childhood or adolescent cancer survivors.

Limitations

This pilot project has limitations, including its short duration. The 4-week time frame limited our ability to assess the long-term impact of the cardio-oncology pharmacist and overall clinical benefit in this patient population. Data collection over an extended trial period is necessary to more accurately reflect actual patient volumes, the expanded role of the pharmacist during follow-up visits under a collaborative practice agreement (including blood pressure management and guideline-directed medical therapy titrations), and outcomes of clinical interventions. Although the project’s short duration was acknowledged, the support for and anticipated benefit of adding a pharmacist to the clinic led to the approval of a 0.5 full-time equivalent (FTE) employee at our institution, and ongoing data collection will continue to demonstrate the clinical significance of this role and support the addition or increase of FTE employees as the practice of cardio-oncology and role of the pharmacist continue to expand.

Another limitation was patient volume and completion of chart review. During the pilot project, the pharmacist dedicated significant time to chart review. Depending on the FTE level, it might not be feasible to obtain dedicated days for this task. To optimize efficiency, it would be beneficial to develop a patient acuity tool within the EMR that considers baseline cardiovascular disease risk, visit status (new vs established patient), and current treatment status (active vs surveillance). This limitation may be mitigated with time and experience as the role of the cardio-oncology pharmacist is solidified in the clinic’s workflow.

The third limitation was the inability to accurately calculate the percentage of oncology patients who would qualify for a cardio-oncology referral. This was hindered by overlap during the transition period, in which the cardiology provider was seeing cardio-oncology and general cardiology patients, as well as by the time needed for oncology providers to become familiar with the referral process. The implementation and analysis of specific cardio-oncology quality measures and long-term referral data would be beneficial in helping other institutions implement similar services.

As the field of cardio-oncology continues to grow and the involvement of oncology pharmacists becomes an integral component of patient care, it is important to identify patients who may benefit from cardiovascular assessment before, during, and after cancer treatment. These oncology patient populations include patients with risk factors for cardiovascular disease who are undergoing cancer treatment with anthracyclines, HER2-targeted therapies, vascular endothelial growth factor inhibitors, BCR-ABL tyrosine kinase inhibitors, multiple myeloma therapies, therapies targeting the BRAF gene, MEK inhibitors, and other high-risk medications for which baseline cardiovascular risk stratification is recommended.⁸

Conclusion

The results of our pilot project show that the addition of an oncology-trained pharmacist to the cardio-oncology clinic facilitated interdisciplinary discussions on chemotherapy-induced cardiac AEs and proper management. The oncology pharmacist at the cardio-oncology clinic was able to aid in implementing individualized guideline-recommended monitoring plans based on the type of cancer treatment and patient’s baseline risk factors, which facilitated safer medication management, and assessing drug–drug interactions between home medications and cancer treatments. This project was limited by its short duration, which hindered the ability to assess long-term clinical impact and feasibility of pharmacist involvement. Future assessments of expansion of pharmacist roles during follow-up visits and extended data collection of pharmacist interventions are needed to better reflect actual patient volume, optimize pharmacist workflow, and continue to justify the addition of an FTE oncology pharmacist in this setting. Oncology pharmacists play a vital role in identifying patients at increased risk for chemotherapy-induced cardiovascular AEs, particularly those with preexisting cardiovascular risk factors.

Author Disclosure Statement

Dr Mancini is a consultant to GSK, and on the speakers bureau of Janssen and Genmab/AbbVie; Dr Ayres has received honoraria from BTG Pharmaceuticals (now SERB Pharmaceuticals) and Curio Science; Dr Heiss has received honoraria from Sumitomo Pharma.

References

1. Howlader N, Noone A, Krapcho M, et al. National Cancer Institute; 2012. Apr, SEER Cancer Statistics Review, 1975–2009 (Vintage 2009 Populations) based on November 2011 SEER data submission.
2. Merali A, Anwar M, Boyd JM, et al. Exploration of current pharmacy practice in cardio-oncology: experiences & perspectives. J Oncol Pharm Pract. 2023;29:1844-1852.
3. Einsfeld L, do Canto Olegário I, Fagundes ML. Intersecting care through specialized pharmacists: a case report of residency rotation focused on the new horizon of cardio-oncology. Curr Pharm Teach Learn. 2023;15:508-513.
4. Liang Z, He Y, Hu X. Cardio-oncology: mechanisms, drug combinations, and reverse cardio-oncology. Int J Mol Sci. 2022;23:10617.
5. White RT, Sirek ME, Marrs JC. Oral oncolytics and cardiovascular risk management and monitoring. J Cardiovasc Pharmacol. 2023;82:266-280.
6. Parent S, Pituskin E, Paterson DI. The cardio-oncology program: a multidisciplinary approach to the care of cancer patients with cardiovascular disease. Can J Cardiol. 2016;32:847-851.
7. Beavers CJ, Rodgers JE, Bagnola AJ, et al. Cardio-oncology drug interactions: a scientific statement from the American Heart Association. Circulation. 2022;145:e811-e838.
8. Lyon AR, López-Fernández T, Couch LS, et al. 2022 ESC Guidelines on cardio-oncology developed in collaboration with the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO) and the International Cardio-Oncology Society (IC-OS). Eur Heart J. 2022;43:4229-4361. Erratum in: Eur Heart J. 2023;44:1621.
9. Mulder FI, Candeloro M, Kamphuisen PW, et al. The Khorana score for prediction of venous thromboembolism in cancer patients: a systematic review and meta-analysis. Haematologica. 2019;104:1277-1287.
10. Goff DC Jr, Lloyd-Jones DM, Bennett G, et al. 2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129(25 Suppl 2):S49-S73. Erratum in: Circulation. 2014;129(25 Suppl 2):S74-S75.

Mayor Ravi S. Bhalla and the City of Hoboken today announced that Jolt Charge, Inc. (Jolt) will become the new operator of 14 of the City’s on-street electric vehicle (EV) charging stations beginning Jan. 5, providing additional revenue and services to the City and community.  

The transition follows approval by the Hoboken City Council and a competitive procurement process to ensure continued operation and maintenance of the City’s on-street EV charging infrastructure at no cost to taxpayers. 

Under a contract, originally authorized by the Hoboken City Council in July 2022, the City’s previous partner, Volta, installed 14 on-street EV charging stations throughout Hoboken at no cost to the City. Since October 2023, these stations have supported more than 10,000 charging sessions and delivered over 700,000 electric vehicle miles,  

Under the new agreement, Jolt will operate and maintain the 14 on-street EV charging stations at no cost to the City and pay the City 54 percent more in monthly rent than the previous operator. This increased revenue will be reinvested into essential municipal services, infrastructure improvements, and sustainability initiatives, to help advance the City’s Climate Action goals of achieving net-zero energy by 2030 and carbon neutrality by 2050.

The initial contract term is two years, with three one-year renewal options. Additionally, Jolt will offer monthly maintenance, charging station wait time predictions through the Jolt app, and more. 

“The continued expansion and reliability of electric vehicle charging infrastructure is essential to Hoboken’s sustainability and climate goals,” said Mayor Bhalla. “Through our new partnership with Jolt Charge, we are ensuring that residents have access to dependable EV charging while responsibly generating a recurring revenue stream for the City through monthly rental fees. It is a win-win for the City that will benefit the community and our climate.”

“We’re proud to partner with the City of Hoboken to strengthen its on-street EV charging program,” said William Watts, General Manager US Network & Operations at Jolt Charge. “Our goal is to ensure both Level 2 and DC fast charging stations remain reliable, accessible, and easy to use for residents and visitors, while also delivering increased value back to the City. Jolt is proud to support Hoboken’s commitment to sustainable transportation and to help communities adapt as electric vehicle adoption continues to grow.”  

Fees will be set at a reduced rate of $.35 per kWh for L2 charging, and $0.50 per kWh for DCFC fast charging, both with a $1 connection fee.  

The 14 Jolt charging stations are an important component of Hoboken’s municipally-owned and publicly accessible electric vehicle charging network, which includes a total of 28 level 2 ports and eight DC fast charging ports. 

Users can download the Jolt app via the Apple and Google app stores and learn more about Jolt by visiting www.joltcharge.com/us.  

For more information about the City’s EV-charging options, go to www.hobokennj.gov/resources/electric-vehicle-charging-hoboken.  

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.

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