Epstein-Barr virus reactivation and post-transplant lymphoproliferative disorder following letermovir prophylaxis in allogeneic hematopoietic stem cell transplant recipients: A systematic review and meta-analysis.

Abstract

e18569 Background: Letermovir is a cytomegalovirus (CMV) terminase complex inhibitor that significantly reduces clinically significant CMV infection following allogeneic hematopoietic stem cell transplant (allo-HSCT). Recently, several studies have suggested that letermovir prophylaxis may delay immune reconstitution, potentially increasing the risk of Epstein-Barr virus (EBV) viremia and post-transplant lymphoproliferative disorder (PTLD), although consistency of this association remain unclear. We conducted a systematic review and meta-analysis to evaluate the incidence of EBV viremia, EBV-associated diseases, and PTLD in allo-HSCT recipients receiving letermovir prophylaxis. Methods: We systematically searched PubMed, Embase, and Cochrane Central Register of Controlled Trials from inception to December 2025 with the following eligibility criteria: (1) randomized or non-randomized trials; (2) adult patients with hematological malignancies treated with allo-HSCT; (3) comparing letermovir use versus no letermovir use; and (4) reporting at least one of the clinical outcomes of interest. The primary outcomes included: (1) incidence of EBV viremia; (2) EBV disease; and (3) PTLD. A random-effects model using restricted maximum likelihood estimation was applied, with effect sizes calculated using the Mantel-Haenszel method. This review adheres to the recommendations from the Cochrane Collaboration and the Preferred Reporting Items for Systematic Reviews and Meta-Analysis statement guidelines. Results: One randomized controlled trial and 12 retrospective cohort studies were included, comprising a total of 4,230 patients (1,903 receiving letermovir and 2,327 not receiving letermovir). In those receiving prophylactic letermovir, compared to those who did not, we found a significant association with higher incidence of PTLD (6.14% vs 2.31%; risk ratio [RR] 2.34; 95% CI 1.62 to 3.38; p <0.001). No statistically significant differences were observed in the incidence of EBV viremia (27.7% vs 24.3%; RR 1.29; 95% CI 0.98 to 1.70; p = 0.071) or EBV-associated diseases (8.6% vs 7.9%; RR 1.08; 95% CI 0.63 to 1.83; p = 0.783). Meta-regression analyses demonstrated a significant positive association between the proportion of umbilical cord blood transplantation and the risk of EBV viremia, whereas no significant associations were observed for the proportions of haploidentical donors or unrelated donors. Conclusions: Letermovir prophylaxis in allo-HSCT recipients is associated with higher incidence of PTLD, while no significant differences were observed in EBV viremia and EBV-associated diseases. Continued clinical vigilance is warranted in patients receiving letermovir prophylaxis, and prospective studies are needed to further clarify this association.