Cytomegalovirus reactivation under pre-emptive therapy during allogeneic hematopoietic stem cell transplant: The pattern, survival, and risk factors in South Korea

초록

Background: South Korea is an endemic area of cytomegalovirus (CMV), and the CMV seropositivity of Koreans is estimated to be over 90%. Recently, letermovir has been considered as primary prophylaxis for CMV in CMV-seropositive recipients of allogeneic hematopoietic stem cell transplant (HSCT). Consequently, most HSCT recipients in South Korea are indicated for the use of letermovir. However, its high costs make this strategy nonfeasible. In this study, we analyzed the pattern and survival of CMV reactivation in patients undergoing pre-emptive therapy for CMV infection during HSCT, and assessed high-risk patients who can benefit from CMV prophylaxis. Methods: We retrospectively analyzed the patients undergoing pre-emptive therapy for CMV infection during HSCT in the Korea University Transplant Registry from November 2003 to July 2020. CMV monitoring was performed in all enrolled patients using CMV antigen (from 2003 to 2013) or CMV polymerase chain reaction (PCR) (from 2013 to 2020), and pre-emptive therapy for CMV was done using ganciclovir (5 mg/kg, intravenous injection every 12 hours) in the patients who presented CMV antigenemia or PCR titer more than 1,000 copies/ml. Results: A total of 295 patients with HSCT were analyzed. The median age was 47 years (range: 16‒68), and the reasons for HSCT were aplastic anemia (26 patients, 8.8%), acute myeloid leukemia/myelodysplastic syndrome (182 patients, 61.7%), acute lymphoblastic leukemia (64 patients, 21.7%), multiple myeloma (11 patients, 3.7%), and lymphoma (12 patients, 4.1%). CMVseropositivity was confirmed in 87.2% (donor + or recipient + ). Antithymocyte globulin (ATG) was used in 68.8% of patients. Pre-emptive therapy for CMV was performed in 142 patients (48.1%), and the median time from day 0 of HSCT to the start of therapy was 33 days (range: 3‒192). The overall survival of the patients who were treated with pre-emptive therapy for CMV was not different compared to those who were not treated. Of these 142 patients, 75 patients (52.8%) underwent more than two preemptive therapies for CMV during HSCT. The median duration of pre-emptive therapy for CMV was 14 days (range: 1‒74). In the multivariate analysis, the risk of the use of pre-emptive therapy for CMV was high in patients with multiple myeloma (OR: 14.979, 95% CI: 1.436‒156.282, p = 0.024), acute graft-versus-host disease of grade more than 3 (OR: 2.262, 95% CI: 1.175‒4.356, p = 0.015), and ATG. In case of patients with ATG use, the risk escalated with an increase in the total dose of ATG ( < 5 mg/kg, OR: 2.601, 95% CI: 1.227‒5.515, p = 0.013; ≥5 mg/kg and <9 mg/kg, OR: 4.846, 95% CI: 2.235‒10.507, p < 0.001; and ≥9 mg/kg, OR: 17.905, 95% CI: 5.255‒61.012, p < 0.001) compared to that in those with no use. Conclusions: In this study, half of the patients with HSCT were treated with pre-emptive therapy for CMV, without any effect on their survival, reflecting that pre-emptive therapy has enough advantage even in CMV endemic area. However, 50% of the patients experienced CMV reactivation repeatedly with a median duration of 14 days more than twice; therefore, it is necessary to re-evaluate the cost-effectiveness of CMV prophylaxis in high-risk patients.