The Interplay between EBV and CMV Reactivations Following Allogeneic Hematopoietic Cell Transplantation in the Era of Primary CMV Prophylaxis

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Background Epstein-Barr virus (EBV) reactivation can occur following allogeneic hematopoietic cell transplantation (allo-HCT) and can potentially progress to post-transplant lymphoproliferative disorder (PTLD). While cytomegalovirus (CMV) reactivation is associated with increased mortality risk, the correlation between EBV reactivation and mortality is not well described; in addition, the correlation between CMV and EBV reactivation is unknown. Recent data from China have suggested a possible association between CMV prophylaxis with letermovir and an increased risk for EBV reactivation and PTLD (1, 2). Therefore, we aimed to examine the association between EBV reactivation, CMV reactivation, and letermovir prophylaxis post allo-HCT and evaluate the impact of EBV on mortality in the broader population. Methods We conducted a retrospective single-center cohort study of patients who underwent an allo-HCT between 2016 and 2019. We excluded patients with negative CMV recipient serostatus (R-) and those without EBV PCR monitoring. Multivariate Cox regression analysis with time-dependent variables was used to identify the independent risk factors for the primary outcomes, including EBV reactivation, non-relapse, and all-cause mortality at week 48 after allo-HCT. Results EBV reactivation occurred in 183 out of 668 (27.4%) allo-HCT recipients; 23 of them (12.6%) required rituximab therapy and 10 (5.5%) were subsequently diagnosed with PTLD (Table 1). CMV reactivation with detectable viral load was diagnosed in 281 patients (42.1%) and was associated with increased risk for EBV reactivation (33.8% compared to 22.7%, P<0.001). Moreover, a CMV peak viral load of at least 500 IU/mL was more likely associated with EBV reactivation than a peak viral load of less than 500 IU/mL (35.3% vs. 23.9%, p=0.002). Letermovir primary prophylaxis was not significantly associated with EBV reactivation (24.2% in the letermovir group, compared to 29.7% in the non-letermovir group, p=0.118). In multivariable analysis, independent risk factors for EBV reactivation were previous CMV reactivation, Asian or Black ethnicity, acute myeloid leukemia or chronic myelomonocytic leukemia as an indication for HCT, graft versus host disease , and anti-thymocyte globulin exposure (Table 2, Figure 1), whereas cord blood as a cell source (vs. peripheral/bone marrow) was associated with a decreased risk. EBV reactivation was not independently associated with non-relapse or all-cause mortality. Conclusions EBV reactivation occurred in a quarter of allo-HCT recipients within 48 weeks post-transplant and was not significantly associated with letermovir prophylaxis. EBV reactivation was independently associated with previous CMV reactivation but had no significant impact on mortality.

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