Letermovir at a Prophylactic Dose for Cytomegalovirus Infection in Children Undergoing Allogeneic Hematopoietic Stem Cell Transplantation: A Single-Center Retrospective Study in Japan

Yasuhisa Tatebe; Yohei Manabe; Yuta Tanaka; Takahiro Shiwaku; Motoharu Ochi; Kosuke Tamefusa; Hisashi Ishida; Kaori Fujiwara; Kana Washio; Hirofumi Hamano; Kiminaka Murakawa; Yoshito Zamami

doi:10.1248/bpb.b24-00217

Abstract

Cytomegalovirus (CMV) infection is a major complication of hematopoietic stem cell transplantation (HSCT). Previous studies in adults demonstrated that letermovir prophylaxis for 100 d after HSCT reduces the occurrence of CMV infection; however, studies in children are limited. In this study, we aimed to examine the incidence of CMV infection in children who underwent allogeneic HSCT with prophylactic letermovir therapy. A single-center retrospective study was conducted among patients aged ≤17 who underwent allogeneic HSCT. We compared the cumulative incidence of CMV infection, mainly monitored by pp65-antigenemia, after HSCT between patients with and without letermovir prophylaxis (10–12 or 5–6 mg/kg/d when co-administered with cyclosporine) using Gray’s test. We analyzed 79 patients with a median follow-up period of 126 d. The median age of these patients was 8.3 years (Interquartile range, 3.7–12.4). Prophylactic letermovir was used in 25 patients. Twenty-five patients developed CMV infection, and the cumulative incidence was 38.9% (95% confidence intervals, 25.0–52.5). The cumulative incidence of CMV infection was not significantly different between the letermovir and no-letermovir groups (33.1 vs. 36.6%, p = 0.228). Meanwhile, the cumulative incidence of CMV infection up to 100 d following HSCT was significantly lower in the letermovir group than in the no-letermovir group (8.0 vs. 32.8%, p = 0.026). Most patients experienced no noticeable adverse effects associated with letermovir; however, one patient discontinued letermovir because of nausea and anorexia. In conclusion, the results of this study suggest that letermovir prophylaxis against CMV infection may be effective in children without severe adverse effects.

INTRODUCTION

Cytomegalovirus (CMV) infection is a common complication of allogeneic hematopoietic stem cell transplantation (HSCT) in adults¹⁾ and children.²⁾ Several studies have revealed that the incidence of CMV infection is approximately 30–50% among pediatric patients who receive allogeneic HSCT.^3–5) CMV infection can cause end-organ diseases such as pneumonia or colitis,^6,7) known as CMV disease, leading to treatment-related mortality after allogeneic HSCT.^8,9) Patients diagnosed with CMV infection often undergo preemptive therapy with anti-CMV medicines, such as ganciclovir or foscarnet.¹⁰⁾ These agents are highly effective against CMV infection and have reduced the occurrence of CMV disease.¹¹⁾ However, CMV infection is still associated with non-relapse mortality despite preemptive therapy.^1,4,12,13) Moreover, these drugs are not recommended for the prevention of CMV infection because they are associated with adverse hematological or nephrological effects.^8,10) A previous report demonstrated that prophylactic ganciclovir represented a greater risk for neutropenia, leading to increased bacterial and fungal infections.¹⁴⁾

Letermovir (LMV) is an anti-viral agent that inhibits the CMV terminase complex and has been used to prevent CMV infection for up to 100 d after HSCT and its long-term use of up to 200 d has recently been approved in Japan. A previous study in adults (≥18 years old) demonstrated that prophylactic LMV use significantly decreased the occurrence of CMV infection after HSCT with an acceptable safety profile.¹⁵⁾ Moreover, LMV prophylaxis may reduce all-cause mortality after HSCT among adult patients with CMV disease and those with CMV infection undergoing anti-CMV preemptive therapy.¹⁶⁾ Among pediatric patients, several small retrospective studies have revealed that LMV prophylaxis against CMV infection after HSCT could also be effective^17,18); however, there is limited evidence for the efficacy of LMV in children and little evidence in Japanese.

In our hospital, we have used LMV at 10–12 mg/kg/d (5–6 mg/kg/d when co-administered with cyclosporine) to prevent CMV infection in children who received allogeneic HSCT since September 2018, although LMV prophylaxis in children is an off-label use. In this study, we aimed to retrospectively investigate the incidence of CMV infection in pediatric patients who received prophylactic LMV compared with those who did not.

PATIENTS AND METHODS

Patients

This was a single-center retrospective study conducted at Okayama University Hospital. We reviewed the medical records of patients who underwent allogeneic HSCT between April 2008 and May 2023. Patients aged ≤17 years at the time of HSCT and being treated by pediatricians were included in the study. If a patient underwent two or more HSCT procedures, we included only data from the first HSCT in our hospital for analysis. We excluded patients who received CMV prophylaxis with anti-CMV drugs other than LMV, such as ganciclovir, and those who were not consistently tested for CMV infection. Furthermore, we collected patient and transplantation information, including age, sex, diagnosis, medications for graft-versus-host disease (GVHD) prophylaxis, donor source of hematopoietic stem cells, human leukocyte antigen (HLA) matching, pre-transplant CMV serostatus of the donor and recipient, conditioning regimen, corticosteroid use, anti-thymocyte globulin use, and pre-transplant estimated glomerular filtration rate based on serum creatinine at the time of starting conditioning regimen. Moreover, pre-transplant hepatic impairment was evaluated based on the results of blood tests at the time of starting conditioning regimen and computed tomography.

Transplantation Procedure

We categorized the conditioning regimens for HSCT into two groups: myeloablative and reduced-intensity conditioning regimens. The myeloablative conditioning regimen was defined as intravenous busulfan (>6.4 mg/kg), high-dose melphalan (≥150 mg/m²), or fractionated total body irradiation of ≥8 Gy,^19,20) and the other was regarded as reduced-intensity conditioning regimen. After HSCT, the patients received antipseudomonal antibiotics and antifungal drugs such as micafungin as bacterial and fungal prophylaxis, respectively. Low-dose acyclovir or valacyclovir was administered to prevent the reactivation of herpes simplex virus and varicella-zoster virus. Calcineurin inhibitors and short-term methotrexate were used to prevent GVHD in most patients. In most patients who underwent haploidentical HSCT, GVHD was prevented by using post-transplant cyclophosphamide combined with tacrolimus and mycophenolate mofetil.

Prophylactic Use of LMV

In clinical practice, we have used prophylactic LMV for CMV infection in most pediatric patients who have received allogeneic HSCT since September 2018 because of the clinical benefits and lower safety concerns of LMV compared with other anti-CMV drugs in adults.²¹⁾ Generally, in Japan, the off-label use of medications in children is not always restricted when a medicine has disease indications in adults, and the eligibility of off-label use is evaluated in individual patients. At Okayama University Hospital, the pediatric off-label use of medicines that have disease indications in adults does not always require ethical committee approval when the risk-benefit balance is assessed by the treatment team and then it is determined that the benefits outweigh the risks. Therefore, the use of LMV prophylaxis in children was determined by discussions relating to the risk-benefit balance of LMV use among physicians in pediatric oncology and pharmacists without the approval of the ethics committee. LMV prophylaxis in children is used only when informed consent is obtained from the patients and/or their parents. Pediatric doses of LMV prophylaxis for CMV infection after allogeneic HSCT have yet to be established. In our hospital, intravenous or oral LMV was administered at approximately 10–12 mg/kg/d (maximum dose, 480 mg/d), reaching the recommended adult dose when the body weight was 40–50 kg. Potential adverse events associated with LMV were assessed by the treating physicians according to general clinical practice. The physician decided on the start date of prophylaxis, generally before neutrophil engraftment. The period of LMV prophylaxis was generally up to approximately 100 d after HSCT, without any reason for discontinuation, such as adverse effects.

Modification of LMV Dose Combined with Cyclosporine

LMV is a substrate of the organic anionic transporting polypeptides 1B1/1B3,²²⁾ which can be inhibited by cyclosporine. A previous study showed that the combined use of cyclosporine and LMV increased the LMV area under the plasma concentration-time curve by 2.1-fold.²³⁾ Furthermore, a previous study reported that the dose of LMV was reduced by 50% when cyclosporine was used in combination with LMV.¹⁵⁾ Meanwhile, CYP only plays a minor role in the metabolism of LMV.²²⁾ Moreover, there are no rules relating to modifying the dose of LMV when medications other than cyclosporine are used in combination with LMV according to the drug label of LMV.²²⁾ In the current study, we reduced the dose of LMV by 50% (5–6 mg/kg/d) only when oral or intravenous cyclosporine was used for GVHD prophylaxis, regardless of whether the concentration of cyclosporine remained in a steady state or not.

Definition and Treatment of CMV Infection

The CMV viral load was monitored weekly using the pp65-CMV antigenemia assay (C10/11 method) until discharge or 100 d after HSCT. Polymerase chain reaction kits to detect CMV DNA were not commercially available in Japan until August 2020. Therefore, patients tested positive for CMV infection when 1) three or more CMV antigen-positive cells were detected by the pp65-CMV antigenemia assay, 2) one or more CMV antigen-positive cells were detected by the pp65-CMV antigenemia assay, and concomitant preemptive therapy against CMV was administered, and 3) CMV DNA was detected by PCR in peripheral blood. Patients were diagnosed with CMV disease when CMV was detected in tissues associated with clinical symptoms by virus isolation, histopathology, or immunohistochemistry.⁷⁾ When a patient was diagnosed with CMV infection, preemptive therapy was generally performed using ganciclovir or foscarnet. Furthermore, the administration of LMV was discontinued at that time if the patient received prophylactic LMV.

Data Analysis

Here, we describe the dose, duration, and prophylactic LMV therapy start date after HSCT. When LMV was used concomitantly with cyclosporine, the described LMV dose was corrected to double because of using the one-half dose. We investigated the cumulative incidence of CMV infection after HSCT as described above. Eligible patients were followed up until the last test for CMV infection. Furthermore, we ended the follow-up period during the cumulative incidence analysis when a patient was diagnosed with a CMV infection or received a second HSCT. To evaluate the safety of LMV, we examined neutrophil engraftment (defined as >500 cells/µL in three consecutive tests) or platelet engraftment (>20000 cells/µL in three consecutive tests without platelet transfusion within seven days in each group. Furthermore, we investigated the adverse effects of LMV that led to the discontinuation of LMV prophylaxis.

Statistical Analyses

Death was regarded as a competing risk factor. Thus, the cumulative incidence of CMV infection was analyzed using the Gray’s method. To examine the effectiveness of prophylactic LMV, we divided the patients into a LMV prophylaxis group (LMV group) and a no-prophylaxis group (no-LMV group). Although LMV was not initiated on the date of HSCT in some patients, we regarded these patients as the LMV group and analyzed the cumulative incidence of CMV infection from the date of HSCT. Differences in the incidence of CMV infection between the groups were analyzed using Gray’s test. Moreover, we also evaluated the difference in the occurrence of CMV infection until 100 d after HSCT using Gray’s test because prophylactic LMV is generally discontinued 100 d after HSCT. For this analysis, the patients were censored at the time of discontinuation of LMV administration to accurately evaluate the effectiveness of LMV prophylaxis. Patients diagnosed with CMV infection within seven days after starting LMV were excluded from the analysis because it was difficult to determine whether the event was attributable to a lack of LMV effectiveness or preexisting CMV infection before LMV administration. Moreover, in the subgroup analysis, we compared the incidence of CMV infection between patients who started LMV within seven days after HSCT and those who did not receive LMV using Gray’s test to reduce the bias of selecting patients with no early CMV infection for the LMV group. In the multivariate analysis, we evaluated the cumulative incidence of CMV infection using the Fine–Gray model, although we could only evaluate a few factors owing to the small number of patients and events in the current study. The factors utilized in multivariate analysis were pre-transplant CMV serostatus, whether transplantation was from an HLA-matching related donor or not, and LMV use, as reported previously.⁸⁾ Binary variables were evaluated using Fisher’s exact test, and other categorical variables were investigated with the chi-squared test. Moreover, we evaluated continuous variables using the Mann–Whitney U test. Statistical analyses were performed using EZR (Saitama Medical Center, Jichi Medical University),²⁴⁾ a graphical user interface for R (R Foundation for Statistical Computing version 4.3.1; Vienna, Austria). Statistical significance was set at two-sided p-values <0.05 for all analyses.

Ethics Statement

The present study was conducted in accordance with the Declaration of Helsinki. Patient data were anonymized to avoid identifying private information. As this was a retrospective study, informed consent was obtained using an opt-out approach. The study protocol, including the fact that we have already used prophylactic LMV for CMV infection in children, was reviewed and approved by the Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences and Okayama University Hospital Ethics Committee (K2306-030).

RESULTS

Patients

There were 85 eligible patients, of whom six were excluded from the analysis because three patients were not routinely tested for CMV antigenemia, one received prophylactic ganciclovir due to transplantation from a CMV immunoglobulin M (IgM)-positive donor, and two were diagnosed with CMV infection on the LMV start day or two days after starting LMV administration, respectively. Therefore, 79 patients were included in this study. The median age of these patients was 8.3 years (interquartile range (IQR), 3.7–12.4), and the cohort included 46 boys and 33 girls. This population consisted of the patients with acute lymphoblastic leukemia (n = 23, 29.1%), acute myeloid leukemia (n = 22, 27.8%), aplastic anemia (n = 10, 12.7%), non-Hodgkin lymphoma (n = 9, 11.4%), myelodysplastic syndrome (n = 7, 8.9%), juvenile myelomonocytic leukemia (n = 3, 3.8%), langerhans cell histiocytosis (n = 2, 2.5%), hemophagocytic lymphohistiocytosis (n = 1, 1.3%), chronic active Epstein-Barr virus infection (n = 1, 1.3%), and neuroblastoma (n = 1, 1.3%). The median follow-up period was 126 d (IQR, 53–231 d). Twenty-five patients received prophylactic LMV, and the median dose was 11.3 mg/kg/d (IQR, 9.9–12.7). The median LMV start day after HSCT was day 1 (IQR, 0–13.5), and the median duration of LMV prophylaxis was 92 d (IQR, 79.5–100). Patient characteristics of the LMV and no-LMV groups are shown in Table 1. The number of patients with low-risk pre-transplant CMV serostatus (recipient- and donor-negative) was similar between the groups, although the pre-transplant CMV serostatus differed significantly between the LMV and no-LMV groups (Table 1). There were three patients with fatty liver at the time of HSCT. Moreover, transiently elevated alanine or aspartate transaminase at the time of HSCT was observed in six (24.0%) and seven patients (13.0%) in the LMV and no-LMV groups, respectively. The Child–Pugh score was class A in these patients.

Table 1. Patient Characteristics in the LMV Prophylaxis Group (LMV Group) and No Prophylaxis Group (No-LMV Group)

Characteristics	LMV group	No-LMV group	p-Value
Characteristics	n = 25	n = 54	p-Value
Median age (IQR)	7.25 (4.2–13.2)	8.7 (2.8–12.0)	0.632
Sex (male/female)	17/8	29/25	0.327
Median body weight, kg (IQR)	27.3 (14.7–37.6)	24.3 (13.6–37.6)	0.666
Follow-up days, median (IQR)	235 (125–399.5)	87.5 (38–168)	<0.001^∗
Pre-transplant CMV serostatus (%)			0.593
R−/D−	1 (4.0)	3 (5.6)
R+/D−	9 (36.0)	13 (24.1)
R−/D+	0 (0)	4 (7.4)
R+/D+	13 (52.0)	30 (55.6)
R+/D^NA	2 (8.0)	4 (7.4)
Disease (%)			0.707
Acute lymphoblastic leukemia	9 (36.0)	14 (25.9)
Acute myeloid leukemia	7 (28.0)	15 (27.8)
Aplastic anemia	4 (16.0)	6 (11.1)
Non-Hodgkin lymphoma	2 (8.0)	7 (13.0)
Myelodysplastic syndrome	2 (8.0)	5 (9.3)
Others	1 (4.0)	7 (13.0)
HLA-matching and donor type (%)			0.004
Matched related donor	1 (4.0)	12 (22.2)
Matched unrelated donor	5 (20.0)	19 (35.2)
Mismatched related donor^a⁾	0 (0)	6 (11.1)
Mismatched unrelated donor	13 (52.0)	13 (24.1)
Haploidentical related donor	6 (24.0)	4 (7.4)
Hematopoietic stem cell source (%)			<0.001
Bone marrow	12 (48.0)	46 (85.2)
Peripheral blood	7 (28.0)	0 (0)
Cord blood	6 (24.0)	8 (14.8)
GVHD prophylaxis (%)			0.094
Tac-based	19 (79.2)	36 (66.7)
CyA-based	1 (4.2)	14 (25.9)
Tac/MMF/PT-Cy	5 (16.7)	4 (7.4)
Conditioning regimen (%)			0.609
Myeloablative conditioning regimen	16 (64.0)	38 (70.4)
Reduced-intensity conditioning regimen	9 (36.0)	16 (29.6)
Corticosteroid use (%)	20 (80.0)	35 (64.8)	0.199
Anti-thymocyte globulin use (%)	8 (32.0)	14 (25.9)	0.598
Acute GVHD (%)	17 (68.0)	30 (55.6)	0.334
Median eGFR, mL/min/1.73m² (IQR)	144.3 (122.0–164.9)	142.4 (118.8–162.2)	0.983

LMV, letermovir; IQR, interquartile range; CMV, cytomegalovirus; R, recipient; D, donor; NA, not available; HLA, human leukocyte antigen; GVHD, graft-versus-host disease; CyA, cyclosporine; Tac, tacrolimus; MMF, mycophenolate mofetil; PT-Cy, post-transplant cyclophosphamide; eGFR, estimated glomerular filtration rate. a) “Mismatched related” do not include patients who received stem cell transplant from haploidentical related donors. ^∗ A two-sided p-value <0.05 was considered statistically significant.

Incidence of CMV Infection

In the whole population, CMV infection occurred in 25 patients (31.6%). The cumulative incidence for CMV infection was 38.9% (95% confidence intervals, 25.0–52.5, Fig. 1A). CMV infection was most frequent among patients with donor- and recipient-positive serostatuses (D+/R+) (Fig. 1B). The influence of other clinical factors on the occurrence of CMV infection is shown in Table 2. Myeloablative conditioning regimens were associated with a higher risk of CMV infection, and HLA-matched related donors tended to be associated with a lower risk. The cumulative incidence of CMV infection did not significantly differ between the LMV and no-LMV groups during the observation period (33.1 and 36.6%, respectively, p = 0.228; Fig. 2). The time to CMV infection was significantly longer in the LMV group than in the no-LMV group (median time, 126 d [IQR, 31–207 d] vs. 37 d [IQR, 26–55.5; p = 0.034). Multivariate analysis revealed that the incidence of CMV infection tended to be lower in the LMV group but did not differ significantly (hazard ratio, 0.50; 95% confidence intervals, 0.23–1.09, p = 0.081). We investigated the incidence of CMV infection for up to 100 d following HSCT. In the LMV group, the cumulative incidence of CMV infection up to 100 d after HSCT was significantly lower compared with in the no-LMV group (8.0 vs. 32.8%, p = 0.026; Fig. 3). Multivariate analysis revealed that the cumulative incidence of CMV infection up to 100 d after HSCT was significantly lower than in the no-LMV group (hazard ratio, 0.19; 95% confidence intervals, 0.04–0.88, p = 0.034). Considering that LMV use began in September 2018, the difference in treatment period between the groups may have contributed to the low incidence of CMV infection until 100 d after HSCT. However, the cumulative incidence of CMV infection 100 d after HSCT among patients without LMV prophylaxis was similar between those who underwent HSCT in 2008–2014 and 2015–2023 (34.5 vs. 30.4%, p = 0.834; Supplementary Fig. 1). In the subgroup analysis, 15 patients started LMV prophylaxis within seven days after HSCT, and the incidence of CMV infection until 100 d following HSCT was also lower in the LMV group compared with in the no-LMV group (0 vs. 32.8%, p = 0.013; Supplementary Fig. 2).

Fig. 1. Cumulative Incidence of CMV Infection after Allogeneic HSCT in Pediatric Patients

(A) Cumulative incidence of CMV infection following allogeneic HSCT in the whole population. (B) Cumulative incidence for CMV infection after allogeneic HSCT stratified by pre-transplant donor- and recipient-CMV serostatus (D/R) among patients with confirmed CMV serostatus. CMV, cytomegalovirus; HSCT, hematopoietic stem cell transplantation.

Table 2. Association between Clinical Factors and the Incidence of CMV Infection

Clinical factors	CMV infection	No CMV infection	p-Value
Clinical factors	n = 25	n = 54	p-Value
Median age (IQR)	8.93 (4.2–12.7)	7.56 (3.4–12.0)	0.451
Male/female (%)	15/10 (60.0)	31/23 (57.4)	1.000
LMV usage (%)	7 (28.0)	18 (33.3)	0.796
Pre-transplant CMV serostatus (%)			0.009
R−/D−	1 (4.0)	3 (5.6)
R+/D−	3 (12.0)	19 (35.2)
R−/D+	0 (0.0)	4 (7.4)
R+/D+	16 (64.0)	27 (50.0)
R+/D^NA	5 (20.0)	1 (1.9)
HLA-matched related donor (%)	1 (4.0)	12 (22.2)	0.052
HLA-matched related and unrelated donor (%)	12 (48.0)	25 (46.3)	1.000
Myeloablative conditioning regimen (%)	22 (88.0)	33 (61.1)	0.018^∗
Corticosteroid use (%)	20 (80.0)	35 (64.8)	0.199
Anti-thymocyte globulin use (%)	5 (20.0)	17 (31.5)	0.419
Acute GVHD (%)	15 (60.0)	32 (59.3)	1.000

CMV, cytomegalovirus; IQR, interquartile range; R, recipient; D, donor; NA, not available; HLA, human leukocyte antigen; GVHD, graft-versus-host disease. ^∗ A two-sided p-value <0.05 was considered statistically significant.

Fig. 2. Cumulative Incidence of CMV Infection after Allogeneic HSCT in the LMV Prophylaxis Group and No Prophylaxis Group

The dotted line shows the LMV group (LMV group), and the solid line represents the no prophylaxis group (no-LMV group). CMV, cytomegalovirus; HSCT, hematopoietic stem cell transplantation; LMV, letermovir.

Fig. 3. Cumulative Incidence of CMV Infection until 100 d after Allogeneic HSCT in the LMV Prophylaxis Group and No Prophylaxis Group

The dotted line shows the LMV group (LMV group), and the solid line represents the no prophylaxis group (no-LMV group) CMV, cytomegalovirus; HSCT, hematopoietic stem cell transplantation; LMV, letermovir.

LMV Safety and CMV-Related Outcome

Most patients continued LMV treatment without any noticeable adverse effects. One patient experienced nausea and anorexia while receiving oral but not intravenous LMV and discontinued LMV prophylaxis 54 d after HSCT. The neutrophil engraftment rates were 100 and 98.1%, and the median days to engraftment were 20 (IQR, 15.5–28) and 18 (IQR, 16–21) in the LMV and no-LMV groups, respectively. The differences in neutrophil engraftment rate and time to neutrophil engraftment between the groups were not statistically significant (p = 1.000 and p = 0.171, respectively). Meanwhile, the platelet engraftment rate was 92.0 and 88.9%), and the median days to the engraftment were 34 (IQR, 27–36) and 31 (IQR, 26.5–34.75) in the LMV and no-LMV groups, respectively. The engraftment rate and time to platelet engraftment did not differ significantly between the groups (p = 1.000 and p = 0.712, respectively). In the LMV group, the CMV viral load was decreased using ganciclovir or valganciclovir, and no CMV disease or CMV-related deaths occurred. However, one patient in the no-LMV group was insufficiently treated with anti-CMV medication due to ganciclovir-induced neutropenia and foscarnet-induced acute kidney injury, thus leading to the development of CMV colitis. Furthermore, one patient died of pneumonia with positive CMV antigenemia in the peripheral blood on day 54 after HSCT in the no-LMV group, while the CMV viral load in the lung tissue was not tested.

DISCUSSION

The present study showed that LMV prophylaxis at 10–12 mg/kg/d in children did not decrease the incidence of CMV infection after HSCT during the follow-up period compared to no prophylaxis. However, the incidence of CMV infection up to 100 d after HSCT was significantly lower in the LMV group compared with in the no-LMV group. These results suggest that this dose of LMV in children could effectively prevent CMV infection after HSCT, although CMV infection increased after discontinuation. This retrospective study is the largest research to evaluate the effectiveness of LMV prophylaxis for CMV infection after allogeneic HSCT in Japanese pediatric patients, and had a relatively larger scale than previous studies that evaluated LMV dosage and effectiveness among pediatric patients.^18,25–27) Additionally, the present study included many younger pediatric patients than a recent study.²⁸⁾ Therefore, the current study provides valuable information for children undergoing allogeneic HSCT in Japan.

In the present study, the cumulative incidence of CMV infection was 38.9% across the entire study population during the follow-up period. This incidence rate was similar to that reported in previous studies,^3,29) and most CMV infections developed within 100 d after HSCT in the no-LMV group (Fig. 2). However, the incidence of CMV infection within 100 d following HSCT was significantly lower in the LMV group compared with in the no-LMV group (Fig. 3), although the incidence increased after the discontinuation of LMV prophylaxis. Considering that the present study and previous reports^2,3,5) have shown that CMV infection often occurs within 100 d after HSCT, our results showed a low incidence of CMV infection up to 100 d in the LMV group, thus supporting the prediction that LMV at a dose of 10–12 mg/kg/d could be effective in preventing CMV infection. Additionally, we believe that LMV prophylaxis against early CMV infection is clinically important because the patient’s condition is likely to worsen within 100 d after HSCT owing to treatment-related complications. Moreover, previous studies have demonstrated that early CMV infection is associated with higher non-relapse mortality after allogeneic HSCT.^1,5,12)

Several studies in adults who received prophylactic LMV demonstrated that late CMV infection developed after LMV discontinuation, and the cumulative incidence increased to 20–50%,^30–32) consistent with our results. A previous study in adults showed that HLA-mismatched donors or CMV-IgG-negative donors were at a high risk of late CMV infection.³³⁾ Moreover, LMV use is associated with a delay in CMV-specific T-cell reconstitution.^34,35) These results imply that long-term prophylactic LMV may be needed beyond 100 d after HSCT to prevent CMV infection in high-risk patients. We cannot sufficiently analyze the risk factors of late CMV infection because of the small sample size in the present study; however, in previous reports, risk factors associated with early and late CMV infection were positive recipient CMV serostatus, HLA-mismatch transplant, cord blood or haploidentical transplants, T-cell depleted transplants, use of 0.5–1 mg/kg corticosteroid, or GVHD.^8,36,37) Therefore, we believe CMV antigenemia or CMV DNA monitoring should continue after LMV discontinuation among these high-risk patients.

Recently, phase 2b study of LMV among pediatric patients had been performed (NCT03940586), but the study results in young children (<12 years old) have not yet been published.³⁸⁾ In a retrospective study, prophylactic LMV was used in 9 patients at a median dose of 10 mg/kg/d, and CMV infection was preventable without adverse effects.¹⁸⁾ These results correspond to our data that LMV, with a median dose of 11.3 mg/kg/d (IQR, 9.9–12.7), decreased CMV infection until 100 d after HSCT. Other pediatric studies have also shown that reduced-dose LMV based on age and body weight may be effective as prophylaxis against CMV infection,^6,25,26) although weight-based dose calculations were not performed in these studies. Previous studies showed that pediatric patients weighing 30 kg or more received an adult dose of LMV (480 mg/d); this implies that the dose of LMV was 15–16 mg/kg/d if the patient weighed approximately 30 kg.^17,27) Therefore, we speculate that a dose of 10–12 mg/kg/d is not too high for children. In contrast, our results showed that the use of prophylactic LMV at a dose of 10–12 mg/kg/d was associated with a lower incidence of CMV infection up to 100 d after HSCT (Fig. 3), thus indicating that this dose was not too low. Regarding safety, one patient discontinued LMV prophylaxis in the present study because of nausea and anorexia, whereas the other patient had no LMV-related adverse effects. Moreover, the rate of engraftment and days to engraftment did not differ between groups. Therefore, LMV prophylaxis in children could be tolerated, which is consistent with previous studies.^18,26,28)

The present study has several limitations. First, it was a retrospective study with a small sample size. Several confounding factors, such as the above-mentioned CMV risk factors, may have affected the results, although we were able to use multivariate analysis to evaluate the effects of a few factors on CMV infection, including LMV use, pre-transplant CMV serostatus, and transplantation from an HLA-matching related donor. However, patient characteristics, including myeloablative conditioning regimen and corticosteroid use, were similar between the LMV and no-LMV groups. In addition, there was a lower incidence of CMV infection until 100 d after HSCT in the LMV group than that previously reported,^2,5) and CMV infection increased after discontinuation of LMV, indicating that the population in the LMV group was at risk but did not develop CMV infection during prophylaxis. Second, we did not analyze the survival benefit of LMV prophylaxis because this cohort included patients with heterogeneous diseases, such as leukemia, malignant lymphoma, aplastic anemia, or myelodysplastic syndrome. Thus, the survival benefit of LMV prophylaxis in children remains unclear, although no cases of CMV disease or CMV-related death occurred in the LMV group. Third, we did not analyze the pharmacokinetics of LMV. Given that it is unclear whether an LMV of 10–12 mg/kg/d reaches an effective concentration in the peripheral blood, we cannot conclude that the optimal dose of LMV is 10–12 mg/kg/d. Fourth, we did not investigate the CMV genes associated with LMV resistance, such as UL56 or UL89.³⁹⁾ However, we speculate that no examinations of these genes do not affect our results that CMV infection until 100 d after allogeneic HSCT was lower in patients who received LMV prophylaxis than in patient without LMV prophylaxis. Mutations in these genes may be associated with the poor efficacy of LMV, thus leading to the inappropriate assumption that LMV prophylaxis is ineffective. Moreover, it is important to consider that the occurrence of CMV infection during LMV prophylaxis may be associated with mutations in certain genes.³⁹⁾ Finally, although we consider the short-term adverse effects acceptable, the long-term safety of LMV in children is unknown. Moreover, LMV inhibits or induces several types of CYP; a previous study reported that LMV can influence the pharmacokinetics of tacrolimus²³⁾ or voriconazole.²⁸⁾ However, it is uncertain how LMV prophylaxis at a dose of 10–12 mg/kg/d can influence the effects of other medications because we did not evaluate the concentration of tacrolimus, cyclosporine, or voriconazole in this study. Considering that LMV can affect the pharmacokinetics of other drugs, such as tacrolimus and voriconazole, its use may be associated with an increased incidence of adverse events associated with other drugs. Therefore, we believe that therapeutic drug monitoring of immunosuppressants such as tacrolimus or voriconazole should be performed when LMV administration is initiated or discontinued. Nevertheless, we believe that LMV prophylaxis is a more attractive therapeutic option than other CMV medicines because previous studies indicated that LMV prophylaxis for CMV infection could improve overall survival in patients who underwent allogeneic HSCT¹⁶⁾ and have lower adverse effects than ganciclovir.²¹⁾ Taken together, a larger study is warranted to examine the benefits and safety of prophylactic LMV therapy in children with CMV infection after HSCT. In conclusion, this retrospective study suggests that LMV prophylaxis at 10–12 mg/kg/d (5–6 mg/kg/d when co-administered with cyclosporine) against CMV infection may be effective in children. However, a larger-scale prospective study is required to confirm its efficacy and safety.

Conflict of Interest

The authors declare no conflict of interest.

Supplementary Materials

This article contains supplementary materials.

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