Introduction
(Article introduction authored by Conquest Editorial Team)
Aplastic anemia (AA) is a severe hematopoietic disorder often treated with allogeneic hematopoietic stem cell transplantation (allo-HSCT). Cytomegalovirus (CMV) reactivation is a common complication post-HSCT, associated with increased mortality, particularly within the first 100 days post-transplant.
The spectrum of HSCT donors for AA has expanded, but CMV infection remains a significant concern, with high incidences reported across different donor types. Preventing CMV reactivation is crucial for patient prognosis, but current treatments have limitations due to adverse effects and drug resistance.
Letermovir, approved by the US FDA in 2017, has shown promise in preventing and treating CMV infection in allo-HSCT recipients. Phase III trials demonstrated low infection rates and mortality with letermovir prophylaxis post-transplant.
In this retrospective cohort study, the efficacy of letermovir in preventing CMV infection among AA patients post-allo-HSCT is investigated and compared with standard treatments.
Methods
Patients with aplastic anemia (AA) undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) at Guangzhou First People’s Hospital from January to December 2022 were included in this study.
The inclusion criterion was patients testing positive for CMV antibodies before HSCT (R +), with exclusion criteria including patients who died within 30 days post-HSCT or had active CMV DNAemia at letermovir initiation.
CMV infection was monitored based on CMV-DNA load using quantitative polymerase chain reaction on plasma samples, with a threshold of 500 copies/ml. CMV prophylaxis with letermovir was administered post-HSCT until day + 100, while the control group received conventional preemptive treatment.
Statistical analyses included propensity score matching (PSM), Mann–Whitney tests, χ2 tests, Kaplan–Meier method, log-rank tests, Gray’s test, and univariate and multivariate COX regression analyses. Factors with P < 0.1 in univariate analysis were evaluated in multivariate analysis, with P < 0.05 considered statistically significant.
Results
A total of 87 CMV-seropositive patients with aplastic anemia (AA) undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) were included in the study.
Among them, 31 patients underwent MSD-HSCT, 19 underwent MUD-HSCT, and 37 underwent HID-HSCT. Propensity score matching (PSM) analysis was performed to balance potential confounding factors between patients treated with letermovir or acyclovir tablets for CMV infection prevention. After matching, 21 pairs of cases were included, with all variables balanced between the groups.
During the observation period, only one patient receiving letermovir discontinued medication due to gastrointestinal side effects, while two patients died from severe pneumonia and sepsis. The overall survival (OS) rate was 97.7%, with no significant difference between the letermovir and control groups (P = 0.34), (Fig 1)
CMV Infection and Risk Factors
Within the first 100 days after allogeneic hematopoietic stem cell transplantation (allo-HSCT), 34 patients receiving letermovir showed a significantly lower incidence of CMV infection compared to the control group, with 26.5% versus 77.4% of patients developing CMV infection, respectively. The cumulative incidence of CMV infection within 100 days post-transplant was significantly different between the two groups (P < 0.0001), (Fig 2)
Cox regression analysis identified letermovir and younger age at HSCT (< 30 years) as statistically significant protective factors against CMV infection within 100 days after transplantation. In the matched group analysis, the letermovir group demonstrated a significantly lower incidence of CMV infection compared to the control group (14.3% vs. 90.5%, P < 0.001), (Fig 3)
No cases of CMV disease affecting organ function were observed in the letermovir group, and the median maximum peak value of CMV-DNA load was significantly lower in the letermovir group compared to the control group (1900 copies/ml vs. 3060 copies/ml, P = 0.0165).
In the letermovir group, the mean duration from diagnosis to clearance of CMV infection was 11.7 days, compared to 18.6 days in the control group, showing a significant difference (P = 0.0219).
While three patients in the letermovir group were diagnosed with CMV infection, none experienced organ function impairment or involvement throughout the follow-up period. Conversely, two out of 18 patients in the control group with CMV DNAemia developed CMV retinitis.
Immune Function Reconstitution within 100 days after allo-HSCT
One month after HSCT, there were no significant differences in the absolute number of T cell subsets (CD3+, CD4+, CD8+), CD19+ B cells, CD16+CD56+ NK cells, and serum immunoglobulin concentrations (IgM, IgG, IgA) levels between the letermovir and control groups. However, two months post-transplantation, the control group exhibited higher CD3+ and CD8+ T lymphocytes compared to the letermovir group, showing statistical significance.
By the third month after transplantation, significant differences were observed in CD19+ B cells, CD16+CD56+ NK cells, and IgG levels, all of which were higher in the control group. Overall, patients in the control group demonstrated superior immune function reconstitution following transplantation compared to those in the letermovir group.
Discussion
Cytomegalovirus (CMV), a member of the human herpesviruses (HHVs) family also known as HHV-5, remains latent in a significant portion of the population. However, activation of CMV, particularly following allogeneic hematopoietic stem cell transplantation (allo-HSCT), poses serious risks due to increased susceptibility to other infections and immune suppression. Aplastic anemia (AA) patients undergoing allo-HSCT are particularly vulnerable, given their immunocompromised state.
The incidence of CMV infection is notably high in these patients, necessitating effective preventive strategies. Letermovir has emerged as a promising prophylactic agent against CMV infection post-transplantation. It inhibits the CMV DNA terminase complex without causing common adverse effects like myelosuppression and nephrotoxicity.
Studies have shown its efficacy and safety profile, even in pediatric patients. In clinical practice, letermovir prophylaxis has significantly reduced the incidence of CMV infection after allo-HSCT, particularly within the crucial first 100 days post-transplantation.
Immune function reconstitution is slower in AA patients undergoing transplantation, making them more susceptible to infections like CMV. Letermovir prophylaxis has been associated with a lower incidence of CMV infection in this population, despite potential concerns about reduced CMV-specific immune reconstitution.
However, while letermovir shows promise, its long-term effects, especially on cumulative CMV infection incidences, warrant continuous monitoring. Additionally, further research is needed to explore its efficacy in treating pre-existing CMV infection and resistance. Large-scale studies are also necessary to validate its effectiveness in preventing CMV infection after HSCT comprehensively.
Although this study underscores the potential of letermovir as a primary prophylaxis against CMV infection in AA patients post-allo-HSCT, the small sample size highlights the need for future research with larger cohorts to confirm these findings and address existing limitations.
Conclusions
CMV infection is a dangerous complication in patients with AA undergoing allo-HSCT. Researchers have attempted to balance the risk of CMV infection and the toxicity of therapeutic agents, considering the adverse effects and resistance to previous nucleoside analogs. Letermovir offers a new option for managing CMV infection in patients post-HSCT due to its unique mechanism of action.
In addition, it has demonstrated a high safety profile and effectiveness in preventing and treating CMV infection in patients with AA post-transplantation, especially in patients with slow reestablishment of immune function.
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