Impaired CMV-specific CD4⁺ T-cell reconstitution is associated with CMV infection after letermovir cessation

Cytomegalovirus (CMV) is a prevalent virus that causes substantial morbidity and mortality in allogeneic hematopoietic stem cell transplantation (allo-HSCT). Although letermovir (LTV) prophylaxis has revolutionized CMV management, clinically significant CMV infection (cs-CMVi) after letermovir cessation presents a new challenge. Effective CMV control is heavily dependent on the reconstitution of CMV-specific cell-mediated immunity (CMI); however, there is a lack of reliable immunologic biomarkers for identifying cs-CMVi after LTV withdrawal. The aim of the present study was to determine how different CMV preventive regimens and cs-CMVi impacted CMV-CMI reconstitution and the risk factors for late-onset cs-CMVi after LTV cessation. The patients were divided into the preemptive therapy (PET, n = 55) and LTV (n = 23) groups. LTV was significantly more effective at decreasing the cumulative incidence of cs-CMVi than PET (4.3% vs. 65.4%, p < 0.01) within 100 days post-allo-HSCT. Meanwhile, after day 100, the cumulative incidence of late-onset cs-CMVi was higher in the LTV than in the PET group (26.1% vs. 7.3%, p = 0.02). We found that LTV delayed the reconstitution of CMV-specific CD8⁺ T cells. Patients who experienced cs-CMVi had lower CMV-specific interferon (IFN)-γ⁺CD4⁺ T-cell counts than those who did not develop cs-CMVi. Patients with CMV disease had the lowest numbers of CMV-specific polyfunctional CD4⁺ T cells. Polyfunctional CMV-specific CD4⁺ T-cell count < 2.01 cells/µL might predict late-onset cs-CMVi after LTV cessation (50.0% vs. 7.69%, p = 0.04). Our findings establish an association between CMV prophylaxis, cs-CMVi, and CMV-specific T-cell response reconstitution post-allo-HSCT.