Epstein Barr Virus (EBV) Reactivation After Reduced Intensity Conditioning (RIC) Unrelated Umbilical Cord Blood Transplantation (UCBT)
Authors: Peric Zinaida , Cahu Xavier , Chevallier Patrice , Brissot Eolia , Malard Florent , Guillaume Thierry , Delaunay Jacques , Ayari Sameh , Dubruille Viviane , Gouill Steven Le , Mahe Beatrice , Gastinne Thomas , Blin Nicolas , Saulquin Beatrice , Harousseau Jean-Luc , Moreau Philippe , Milpied Noel , Coste-Burel Marianne , Imbert-Marcille Berthe-Marie , Mohty Mohamad 
Published: October 2019

Abstract
Abstract 2334
Umbilical cord blood has been increasingly used as an alternative stem cell source for allogeneic hematopoietic stem cell transplantation (allo-HSCT). RIC regimens have been increasingly used prior to allo-HSCT with the aim to decrease transplant-related mortality (TRM) in patients ineligible for standard conditioning. Because of the slow kinetics of immune reconstitution after UCBT, previous studies showed that EBV reactivation and EBV induced lymphoprolipherative disease (LPD) may be of matter of concern, particularly in the reduced intensity setting. The aim of this analysis was to investigate the features of EBV reactivation in 33 patients who underwent RIC UCBT between January 2005 and June 2009.
In our series, 30 patients (91%) received a double UCBT and 3 patients (9%) received a single UCBT, with a median of 4.0×107/Kg (range, 2.2–5.8) total nucleated cells. Donors and recipients were mismatched with one mismatch in 14 (43%) of cases and 2 mismatches in 19 (57%) of cases. A RIC including fludarabine, cyclophosphamide and low dose TBI was used in 29 cases (88%), while 8 patients (24%), who were not heavily pretreated before UCBT, received ATG. EBV reactivation was defined as any EBV PCR load above 1000 copies of EBV DNA /105 cells. EBV LPD was defined as biopsy or autopsy proven post-transplantation lymphoma, or reactivation along with computerized tomography nodal or soft-tissue abnormalities consistent with LPD. Patients with EBV viral load >1000 copies/105 cells on at least two consecutive occasions were treated with rituximab at a dose of 375 mg/m2 weekly until clearance of EBV viremia.
Engraftment occurred in 25 patients (76%) at a median time of 12 days after UCBT (range, 8–60). Clinically significant grade II to IV acute GVHD occurred in 5 of cases (15%). The cumulative incidence of EBV reactivation at 6 months and three years after allo-HSCT was 13% and 17%. EBV reactivation was observed at a median of 132 (range 85–438) days after allo-HSCT, with 3 (60%) reactivations occurring during the first 6 months. In 28 patients (85%), the EBV load remained less than 1000 EBV copies/105 cells at all time, and none of these patients experienced any sign or symptom of LPD. The remaining 5 patients (15%) experienced at least one EBV reactivation episode. Among the 5 patients experiencing EBV reactivation, 2 patients received ATG as part of their RIC. Among these 5 patients, 1 patient experienced an EBV load superior to 1000/105 cells at a single time point after allo-HSCT. In this patient, there were no concomitant clinical symptoms and the EBV load normalized spontaneously. Only this patient had a normal T-lymphocyte count at the time of reactivation. Four patients who had EBV DNA levels exceeding 1000 copies/105 cells on 2 or more occasions were treated with a median of 3 (range, 1–8) rituximab infusions. Two patients responded to rituximab, but 2 patients developed LPD (cumulative incidence of 6 % at three years). Both of our patients were severely immunosupressed with high dose corticosteroid therapy at the time of the occurrence of EBV LPD. One of these 2 patients died before receiving any other anti-EBV therapy. In the other patient, LPD could be controlled after additional chemotherapy, radiotherapy and 2 infusions of EBV specific Cytotoxic T-cell Lines (CTLs). Three of five patients (60%) who experienced EBV reactivation had Human Herpes Virus 6 (HHV 6) detected in the same blood sample by PCR. With a median follow-up of 468 (range, 92–1277) days post allo-HSCT among surviving patients, 21 patients (64%) were still alive and the overall survival (OS) was 62% at 3 years. 5 patients died of disease progression and 7 patients died of transplant-related complications. One patient died of LPD. There was no statistically significant difference in terms of OS or TRM between those patients who experienced an EBV reactivation after UCBT and those who did not (OS: log rank test, p=0.33, TRM: Gray test, p= 0.82). Univariate analysis did not find any risk factors significantly different between subgroups with and without EBV reactivation.
Overall, this study shows the rate of EBV reactivation after RIC UCBT to be comparable to the incidence expected with RIC mismatched unrelated bone marrow or peripheral blood HSCT. Despite small numbers, our observations support close EBV monitoring and the use of pre-emptive rituximab treatment since some cases may progress to LPD requiring additional interventions such as EBV-specific CTLs.

Disclosures:
No relevant conflicts of interest to declare.