Background: Epstein-Barr virus (EBV) reactivation and EBV-positive post-transplant lymphoproliferative disorder (EBV+PTLD) are often fatal complications following allogeneic hematopoietic stem cell transplant (HSCT). Risk factors for the development of EBV+PTLD after HSCT include human leukocyte antigen (HLA) mismatches, T cell depletion (TCD) and older age, among others. It has been proposed that specific HLA haplotypes are associated with the development of EBV+PTLD after solid organ transplant (SOT) and that pre-emptive use of Rituximab can reduce the risk of EBV+PTLD. We present a retrospective analysis of patients who underwent HSCT in order to determine the impact of donor source, TCD, age, HLA-A1 haplotypes and use of Rituximab prior to HSCT on the development of EBV reactivation and EBV+PTLD after HSCT.
Methods: We retrospectively reviewed patients who had undergone allogeneic HSCT at our Institution between January 2012 and December 2016. We analyzed the cumulative incidence of EBV reactivation and EBV+PTLD and the impact of known and novel risk factors.
Results: Of 474 patients, 10% developed EBV reactivation and 6% were diagnosed with EBV+PTLD. The cumulative incidence of EBV reactivation and EBV+PTLD was 15% and 11%, respectively, after haplo-cord HSCT, compared to 3% and 2% after MRD HSCT and 8% and 5% after MUD HSCT (p=0.0004 and p=0.02, respectively). EBV reactivation was associated with receipt of ATG compared to Alemtuzumab (p=0.03) and age older than 60 years (p=0.004). The presence of HLA-A1 haplotype in the recipient did not affect the incidence of EBV reactivation and EBV+PTLD (p=0.2 and p=0.9, respectively). The cumulative incidence of EBV reactivation and EBV+PTLD was lower in patients with Rituximab exposure prior to HSCT, although this did not reach statistical significance (p=0.2 and p=0.15, respectively). In a multivariate analysis, donor source (haplo-cord vs HLA-matched) and age older than 60 were found to be independent risk factors for the development of EBV reactivation (HR 1.9; p=0.038 and HR 2.6; p=0.002, respectively) and EBV+PTLD (HR 1.9; p=0.020 and HR 3.5; p=0.004, respectively). PTLD was fatal in 8 of 27 patients (29%) with PTLD and 17% of all patients with EBV reactivation. One patient died of disseminated EBV disease without PTLD.
Conclusions: The cumulative incidence of EBV viremia and PTLD after allogeneic HSCT was 10% and 6%, respectively, and led to death in 2% of the patients. Haplo-cord grafts and age older than 60 years were independent risk factors for EBV reactivation and EBV+PTLD. Rituximab use prior to HSCT may confer protection against EBV reactivation and its use in the conditioning regimen of patients undergoing HSCT, at high risk for EBV reactivation, should be studied prospectively. Further studies are needed to determine the impact of HLA haplotypes on the incidence of EBV reactivation in patients after HSCT.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.