The interplay between Epstein-Barr virus and cytomegalovirus reactivation following allogeneic haematopoietic cell transplantation in the era of primary cytomegalovirus prophylaxis.

Objectives: Epstein-Barr virus (EBV) reactivation following allogeneic haematopoietic cell transplantation (allo-HCT) is associated with increased mortality and possible posttransplant lymphoproliferative disorder. With the lack of prophylactic agents, identifying modifiable risk factors to prevent EBV-related mortality is desired. Cytomegalovirus (CMV) DNAemia has been previously associated with EBV DNAemia; the impact of letermovir prophylaxis on this association remains unclear. We aimed to identify risk factors for EBV reactivation; assess the correlation between EBV, CMV reactivation, and letermovir use; and assess the impact of EBV reactivation on mortality.

Methods: We conducted a retrospective cohort study of allo-HCT recipients between March 2016 and December 2019. We excluded patients lacking EBV PCR monitoring or with negative CMV recipient serostatus. A multivariable competing risks analysis was used to identify risk factors for EBV reactivation and mortality at week 48 posttransplantation.

Results: EBV reactivation occurred in 183 of 668 (27.4%) allo-HCT recipients; of those, 57 (31.1%) had significant EBV reactivation, and 10 (5.5%) were diagnosed with posttransplant lymphoproliferative disorder. EBV reactivation was associated with CMV DNAemia, clinically significant CMV infection, and CMV end-organ disease (49.7%, 48.1%, and 19.1% compared with 37.3%, 34.8%, and 9.7% with no EBV reactivation, respectively, all p < 0.05) and was not associated with letermovir primary prophylaxis (24.2% on vs. 29.7% off letermovir, p 0.118). In multivariable analysis, risk factors for EBV reactivation included CMV reactivation (adjusted hazard ratio (aHR) 1.46), Asian (aHR 2.00) or Black race (aHR 2.71), underlying acute myeloid leukaemia (aHR 1.98) or chronic myelomonocytic leukaemia (aHR 3.16), graft-vs.-host disease (aHR 2.35), and antithymocyte globulin exposure (aHR 5.90). A propensity score-adjusted multivariable analysis confirmed no significant association between letermovir prophylaxis and EBV reactivation. EBV reactivation was not independently associated with mortality.

Discussion: EBV reactivation had no apparent correlation with letermovir prophylaxis, was associated with previous CMV reactivation, and had no significant impact on mortality.