Real-World Safety and Effectiveness of Letermovir in Pediatric Patients Undergoing Allogenic Hematopoietic Stem Cell Transplantation
Authors: Wang Qingwei , LI Zhiheng , Hu Yixin , Gao Li , Cheng Shengqin , Ji Qi , Zhang Senlin , Lu Jun , Li Jie , Xiao Peifang , Hu Shaoyan 
Published: December 2024

Background: Cytomegalovirus (CMV) infection remains a common complication after allogeneic hematopoietic-cell transplantation (allo-HSCT). Letermovir，an antiviral drug that inhibits the CMV-terminase complex, has been proven in adult patients but there is a lack of clinical data in pediatric patients.

Methods: We retrospectively analyzed individuals &lt; 18 years who underwent allo-HSCT at the Children's Hospital of Soochow University. All patients had survived nd had survived at least 3 months after allo-HSCT. The patients were divided into two groups based on whether they received prophylactic letermovir therapy (120 or 240 mg per day according to the body weight and 120 or 240 mg every other day in those patients taking cyclosporine) after allo-HSCT. Patients who received letermovir until 100 days after allo-HSCT (experimental group) were compared with those similar patients who did not receive letermovir (control group). The treatment was discontinued if patients who developed clinically significant CMV infection. The time to CMV reactivation in peripheral blood, the peak CMV copy number, and serious adverse events according to CTCAE 5.0 were recorded.

Results：A total of 178 pediatric patients were included in the study, including 101 boys and 77 girls, with a median age of 6 years and 8 months (range, 9 months to 18 years). Primay disease included acute myeloid leukemia (57), cute lymphoblastic leukemia (33), aplastic anemea (64), other diseases (24).There was no statistically significant difference between CMV reactivation and primary disease type (P=0.283). Thepatients' donors included matched unrelated (37), mismatched unrelated (14), matched sibling (20), haploidentical related donor (107). The reactivation of CMV showed no significant difference with the donor types (P=0.293). Eighty patients received letermovir and 98 patients did not. The median follow-up time was 12 months (range, 3 months to 23 months) after allo-HSCT. The median administration time of letermovir was the second day after allo-HSCT (0-23 days). The reactivation rate of CMV in experimental group and control group was 25.0% vs 61.5% (P &lt; 0.001, HR 0.220, 95% CI 0.115-0.421). The median time of CMV reactivation was 139 (88-301) days and 34 (7-153) days respectively. The proportion of patients with the peak CMV copy number in the range of ≥400-10^2-10^3 copies/ml was 8.8% vs 11.2%, that in the range of 10^3-10^4 copies/ml was 12.5% vs 35.7% and that in the range of 10^4-10^5 copies/ml was 0 vs 2.0% with statistical significance between the two (P＜0.001). There were 16 patients who received cord blood allo-HSCT，CMV reactivation occurred in 3 out of 10 patients in the test group and 4 out of 6 patients in the control group, with no statistical significance (P=0.302), however, the peak value of CMV reactivation in the test group was 10^2 copies/ml in 2 patients and 10^3 copies/ml in 1 patient while 10^3 copies/ml in 3 patients and 10^4 copies/ml in 1 patient in the control group. Mostly CMV antibody combination before allo-HSCT was R+/D+ (R, receptor; D, donor) and CMV reactivation existed statistically difference with whether or not to receive letermovir in this combination (P＜0.001). 10 patients belonged to R+/D-, 6 patients in the test group did not have CMV reactivation, and 2 of 4 patients in the control group did. 4 patients in the control group belonged to R-/D+ and 3 patients had CMV reactivation. The hematopoietic stem cells of all patients were implanted successfully. The average engraftment of neutrophil between the two was 13.0 days vs 12.2 days (P=0.046), the average engraftment of platelet was 13.8 days vs 12.5 days (P=0.120), and all the patients received letermovir were with no serious adverse events.

Conclusions：Letermovir as prophylactic treatment after allo-HSCT reduce the CMV reactivation, delay the time to CMV reactivation, and reduce the peak CMV copy number in pediatric patients, which may affect the engraftment time of neutrophil but does not cause the failure of engraftment or serious adverse events. Letermovir may also reduce CMV reactivation and peak value after cord blood transplantation, but larger sample data are needed to support it.This study confirms the effectiveness and safety of letermovir for CMV prophylaxis in pediatric patients undergoing allo-HSCT in real-world settings.