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On the basis of the results of this study we conclude that patients undergoing RIC allo-HSCT using ATG as part of the preparative regimen are at higher risk for EBV reactivation. However, this did not translate into a significant impact on outcome since monitoring of EBV viral load using quantitative PCR and early systematic preemptive rituximab therapy allowed for significantly reducing the risk of EBV-related LPD.

Following allogeneic hematopoietic stem cell transplantation (allo-HSCT), EBV reactivation and EBV lymphoprolipherative disease (LPD) are well recognized complications. To date, few data has been reported regarding the features of EBV LPD following RIC allo-HSCT. The aim of this study was to define the incidence and risk factors of EBV reactivation in 175 consecutive adult patients undergoing RIC allo-HSCT between January 2005 and June 2009 in our institution and to assess its impact on clinical outcome. In this series, the median age of recipients was 56 (range 18–71) years. In all, 85 patients (49%) had a myeloid malignancy, whereas 86 (49%) patients were diagnosed with lymphoid malignancies. The remaining 4 patients (2%) were treated for severe aplastic anemia. In total, 165 patients (94%) received peripheral blood stem cells (PBSC) whereas 10 patients (6%) received a bone marrow (BM) graft. 84 grafts (48%) were obtained from HLA identical sibling donors, 80 (46%) from HLA matched unrelated donors and 11 (6%) from 1 Ag HLA mismatched unrelated donors. The conditioning regimen associated fludarabine, busulfan, and ATG in 107 cases (61%), while 37 patients (21%) received fludarabine and low-dose TBI. The remaining 31 patient (18%) received different chemotherapy-based RIC regimens. 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 viremia. In our series, the median time to neutrophil recovery (absolute neutrophil count >0.5x109/L) was 17 (range, 6–48) days. Clinically significant grade II to IV acute GVHD occurred in 61 of cases (35%) and severe grade III to IV acute GVHD occurred in 37 of cases (21%). The cumulative incidence of EBV reactivation at 6 months after allo-HSCT was 15% (95% CI, 10–21%). EBV reactivation was observed at a median of 58 (range 0–930) days after allo-HSCT, with 27 (79%) of reactivations occurring during the first 6 months. In 141 patients (81%), the EBV load remained less than 1000 EBV copies/105 cells at all time. The remaining 34 patients (19%) experienced at least one EBV reactivation episode. Among these 34 patients, 17 patients had an EBV load superior to 1000/105 cells at a single time point after allo-HSCT. In these 17 cases, there were no concomitant clinical symptoms and the EBV load normalized spontaneously. The 17 patients who had EBV DNA levels exceeding 1000 copies/105 cells on 2 or more occasions were pre-emptively treated with a median number of 3 (range, 1–4) rituximab infusions which resulted in complete clearance of EBV viremia in all, but one patient (97%). This patient was severely immunosupressed, receiving three different immunosupressive agents and experienced both EBV and adenovirus (ADV) infection. This patient had symptoms mainly related to ADV infection, and died of multiorgan failure. Most importantly, none of the patients from this series developed EBV induced LPD. With a median follow-up of 655 (range, 92–1542) days post allo-HSCT among surviving patients, 104 patients (59%) were still alive and the overall survival (OS) was 47% at 4 years. There was no statistically significant difference in terms of OS or transplant related mortality (TRM) between patients who experienced an EBV reactivation and patients who did not (OS: log rank test, p=0.62 ; TRM: Gray test, p=0.99). In univariate analysis for risk factors associated with EBV reactivation only the use of ATG as part of the RIC regimen prior to allo-HSCT was significantly different between subgroups with and without EBV reactivation (Fisher's exact test, p=0.006). In the multivariate analysis, the use of ATG remained the only independent risk factor associated with EBV reactivation (Fine and Gray test ; RR=4.9 ; 95%CI, 1.1–21.0 ; p=0.03). In all, we conclude that patients undergoing RIC allo-HSCT using ATG as part of the preparative regimen are at higher risk for EBV reactivation. However, this did not translate into a significant impact on outcome since monitoring of EBV viral load with quantitative PCR and early systematic pre-emptive rituximab therapy allowed for significantly reducing the risk of EBV-related LPD.

Overall, this study shows the rate of EBV reactivation after RIC UCBT to be relatively low (15%) and this is comparable to the incidence expected with PBSC or BM unrelated mismatched transplants. However, close EBV monitoring and the use of pre-emptive rituximab treatment appears to be mandatory since some cases may progress to LPD requiring additional interventions such as EBV-specific CTLs.