Natural History of Post-Allogeneic HSCT EBV-Reactivation: A Single Center Retrospective Survey.
Authors: Schoemans Helene M. , Theunissen Koen , Boogaerts Marc , Maertens Johan 
Published: October 2019

Epstein Barr Virus (EBV) reactivation occurs in about 50% of the allogeneic hematopoietic stem cell transplantation (HSCT) population in the first year post-transplantation. About 1-7% of these patients run the risk of developing a post-transplant lymphoproliferative disorder (PTLD). Several authors have thus advocated systematic screening by EBV real time PCR (RT-PCR) to initiate pre-emptive treatment of reactivations using Rituximab (van Esser 2002). However, the positive predictive value of EBV RT-PCR is only of 40% (van Esser 2001), implying that this algorithm overtreats a number of patients.

Methods: We have retrospectively analyzed 60 consecutive allogeneic HSCT patients transplanted in our center between 1/1/2004 and 31/3/2005. Four patients were excluded because of absence of EBV follow-up (n=2) or autologous reconstitution (n=2). EBV reactivation (EBV (+)) was defined by at least two consecutive episodes of EBV RT-PCR above 1000 copies/ml of whole blood. Any other result was considered as negative (EBV (−)).

Results: 1175 EBV RT-PCR samples were collected over a median follow up of 215 days (range: 21–511). The population observed was essentially adults (median age 42 years, range: 1–65) with leukemia (29 leukemia, 11 lymphomas, 16 other diseases), mixed graft types (26 matched sibling donors, 26 matched unrelated donors, 4 haploidentical donors; 77% peripheral blood stem cells; 20% CD34+ selection) and mixed conditioning (52% non-myeloablative conditioning containing ATG, and 48% full conditioning). The EBV(+) and EBV(−) cohorts were similar for all characteristics analyzed. We observed a median of 18 EBV RT-PCR per patient (range: 4–105), with a median interval between two tests of 7 days (range: 3–45). There were 30 true reactivations, 2 intermittent reactivations (non consecutive EBV titer rises above threshold), 8 isolated reactivations and 16 patients with no reactivation episode. EBV RT-PCR was first performed at a median of 6 days post HSCT (range: 0–245), and reactivation was noted at a median of 44 days post HSCT (range: 6–375). There were no significant difference in PCR follow up (first day of screening, median test interval and length of biological follow up) except for the total number of screening tests per patient, which was higher in the EBV(+) group (p= 0.01). There was only one case of biopsy-proven PTLD in the EBV(+) cohort. No patient was administered Rituximab post- HSCT. Survival curves of the two cohorts were similar regardless of EBV reactivation (log-rank, p= 0.201).

Discussion: The incidence of EBV reactivation (n= 30; 54%) and of PTLD (n=1;1.7%) were standard compared to previous studies, resulting in a standard specificity of 47% for EBV screening. However, within our limited group of patients, we could not show any significant differences in mortality between the EBV(+) and EBV (−) cohorts. Therefore, absence of preventive treatment for EBV reactivation did not result in an increase in mortality in our EBV reactivating cohort. This suggests that systematic prophylactic use of Rituximab may not affect overall mortality, whilst potentially increasing the risk of other opportunistic infections.

Conclusion: Further prospective studies are needed to better define the patients at risk for developing EBV-related PTLD, within the EBV reactivating allogeneic transplant patients group, before prophylactic treatment of reactivation becomes a routine procedure.