FormalPara Key Summary Points

Why carry out this study?

Aplastic anemia (AA) patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) are at high risk for Cytomegalovirus (CMV) infection, which can lead to severe complications and affect the overall success of the transplantation.

Effective prevention strategies for CMV infection post-transplantation are crucial to improve patient outcomes, but the specific efficacy and safety of letermovir in patients with AA have not been extensively studied.

What was learned from the study?

The study demonstrated that letermovir significantly reduced the incidence of CMV infection within the first 100 days after allo-HSCT in patients with AA.

Letermovir showed a high safety profile, with most patients tolerating the treatment well and experiencing a reduction in CMV-DNA load and infection clearance time.

Introduction

Aplastic anemia (AA) is a severe hematopoietic disorder characterized by rapid onset and progression. Currently, the principal intervention for AA is allogeneic hematopoietic stem cell transplantation (allo-HSCT) [1]. Cytomegalovirus (CMV) is among the most common opportunistic infections that occur in patients post-HSCT. Early CMV reactivation can occur in 70% of patients post-HSCT during the immunocompromised phase [2, 1). In the matched group analysis (42 patients), the letermovir group showed a significantly lower incidence of CMV infection (14.3 vs. 90.5% in the control group, P < 0.001; Fig. 3). No cases of CMV disease affecting organ function were observed in the letermovir group. The median maximum peak value of CMV-DNA load was 1900 copies/ml (1070–2270 copies/ml) for letermovir patients and 3060 copies/ml (808–9910 copies/ml) for the control group (P = 0.0165; Fig. 4), indicating a higher viral load in the control group. Additionally, two control-group patients developed CMV retinitis, evidencing the severity of CMV infection in this group.

Fig. 2
figure 2

Cumulative incidence of cytomegalovirus infection after allogeneic hematopoietic stem cell transplantation in the letermovir (n = 34) and control (n = 53) groups before PSM

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Fig. 3
figure 3

Cumulative incidence of cytomegalovirus infection after allogeneic hematopoietic stem cell transplantation in the letermovir (n = 21) and control (n = 21) groups after PSM

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Fig. 4
figure 4

The highest amount of CMV-DNA in both groups after PSM

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Regression of CMV Infection

The mean duration from diagnosis to clearance of CMV infection in the letermovir and control groups was 11.7 and 18.6 days, respectively, which was significantly different (P = 0.0219; Fig. 5). Although three patients in the letermovir group were diagnosed with CMV infection, none experienced organ function impairment or involvement until the end of the follow-up. Conversely, two of 18 patients in the control group with CMV DNAemia developed CMV retinitis.

Fig. 5
figure 5

Days to CMV clearance in both groups after PSM

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Immune Function Reconstitution within 100 days after allo-HSCT

One month after HSCT, no statistical differences were observed 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. Two months after transplantation, there were higher CD3+ and CD8+ T lymphocytes in the control group, with statistical differences between both groups. Three months after transplantation, there were statistical differences in CD19+ B cells, CD16+CD56+ NK cells, and IgG in both groups, which were higher in the control group. Overall, patients in the control group had higher reconstitution of immune function after transplantation than in the letermovir group Fig. 6.

Fig. 6
figure 6

Immune function at 3 months after allo-HSCT in both groups after PSM

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Discussion

CMV belongs to the family of human herpesviruses (HHVs), and it is also known as HHV-5. CMV remains latent in approximately 40–70% of children and 60–90% of adults [15]. CMV activation by the recipient or donor source is observed in patients after allo-HSCT, which causes direct and indirect virulence and increases the risk of bacterial and fungal infections, thereby suppressing the immune system [16].

AA presents a severe and acute condition where allo-HSCT stands as the primary treatment. Prior to transplantation, patients with AA are immunocompromised due to disease characteristics, which increases their risk of develo** various potential infections. Typically, a nonmyeloablative conditioning regimen involving immunosuppressive agents is employed in AA transplantation. A prolonged post-transplantation administration of immunosuppressive drugs is compulsory to prevent rejection and treat GVHD, leading to a slower re-establishment of immune function and a relatively higher rate of CMV infection than in patients with hematologic malignancies after transplantation [6, 7]. In our center, the incidence of CMV infection in patients with AA was 84.8% after 100 days of transplantation before using letermovir as a prophylactic agent. Furthermore, CMV infections are more prone in substitute donor transplants than MSD-HSCT, and the median time onset of CMV infection is 30 days after allo-HSCT. Consequently, our center initiated CMV prophylaxis with letermovir from the day of neutrophil engraftment following transplantation. As CMV activation and CMV disease-related morbidity were found to be associated with transplantation-related mortality, preventing, detecting, and treating CMV infection is crucial, especially during the early stage after transplantation [26]. However, the overall mortality rate of patients in both groups was not significantly different, which may be attributed to the small sample size and short follow-up duration. Using letermovir as a primary prophylaxis in patients with AA after allo-HSCT significantly reduces CMV infection and demonstrates a high safety profile. Therefore, letermovir is currently used as a prophylactic for patients with AA undergoing allo-HSCT in our institution.

At present, primary prophylaxis with letermovir within 100 days after transplantation is the standard protocol for CMV-seropositive allo-HSCT recipients, as endorsed by the latest CMV prophylaxis guidelines of The American Society of Transplant and Cellular Therapy [27]. Letermovir discontinuation significantly increased the cumulative incidences of CMV infection within 200 days post-transplantation. As this study utilized letermovir for a short period, CMV infection occurring only within 100 days after transplantation was analyzed. The incidence of CMV infection in patients beyond the 100-day timeframe is still being monitored. Therefore, the timing of drug discontinuation should be further explored. Ongoing randomized clinical trials have extended the duration of prophylaxis in high-risk patients to 200 days post-transplantation, wherein the effects and benefits should be further explored. In this study, we have not explored the efficacy of letermovir therapy for treating pre-existing CMV infection and resistance to letermovir. A study has shown a low success rate for treating patients with pre-existing CMV activation using letermovir [23]. Studies investigating the use of letermovir for treating CMV infection after transplantation are limited. Here, we treated a few patients with letermovir, but they were excluded from this study due to the small sample size and short follow-up duration.

Although the patients’ overall tolerability to letermovir was good, the possibility of other adverse events exists due to the complex drug interactions [6]. In our center, patients were not prevented from letermovir for a long time, and the follow-up duration was short. Therefore, the long-term effects and cumulative incidences of CMV infection must be monitored continuously. In addition, the viral load of patients in the letermovir group at the time of CMV infection was lower compared to the control group. The treatment duration of patients in the letermovir group with intravenous antiviral drugs was short. Treating CMV infection poses a significant economic burden on patients. Hence, further pharmacoeconomic analyses comparing preventive strategies in transplant populations are essential to determine the role of letermovir in CMV management [24].

Our study has one limitation, which is its small sample size. Therefore, future large sample-sized studies exploring the effect of letermovir in preventing CMV infection after HSCT are warranted.

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.