Outcomes with Pre-Emptive Rituximab (pre-R) Treatment for Epstein-Barr Viremia (EBV) after Allogeneic Hematopoietic Stem Cell Transplantation (HCT)

Background: EBV reactivation after HCT increases the risk of post-transplant lymphoproliferative disease (PTLD), a potentially fatal complication of HCT. Although pre-R therapy is recommended for EBV reactivation, the EBV level for which to start therapy and the long term outcome of treatment are not well known. Methods/Results: 488 patients (pts) underwent myeloablative or non-myeloablative HCT between January 2007 and December 2014 at Mayo Clinic in Arizona. Data was obtained by retrospective chart review. EBV DNA more than 500 copies/ml is detectable while >2000 copies/ml is quantifiable. The institutional protocol for initiation of pre-R is when EBV is >2000 copies/ml and continues to rise on a weekly basis (clinically relevant EBV reactivation). Rituximab (R) is given at 375 mg/m2 weekly until EBV levels are undetectable or at provider discretion. 67/488 (14%) pts had clinically relevant EBV reactivation after HCT. Of these, 60 (90%) received pre-R for EBV reactivation which resolved without any additional clinical consequence, 1 (1.5%) received pre-R but later developed PTLD and 6 (9%) developed PTLD prior to initiation of pre-R. Pts treated with pre-R and no progression to PTLD (N = 60): Median age at HCT was 54.5 years (range, 18-75 years) and 26 (43%) were females. Donor source was: related 13 (22%), matched unrelated 25 (42%) and mismatched unrelated 22 (37%). Conditioning regimen was myeloablative in 21 (35%) and reduced intensity in 39 (65%); and included antithymocyte globulin (ATG) in 49 (84%) pts. Doses of ATG (2.5 mg/kg) were 1 in 25 (42%), 2 in 21 (36%) and 3 in 4 (6.8%). All pts were EBV seropositive at the time of HCT. Median time to EBV reactivation was 34 days (range, 13-602) from HCT. Level of EBV copies/ml at the time of initiation of pre-R was 2000-3999 in 14 (23%), 4000-5999 in 11 (18%), 6000-7999 in 3 (5%) and ≥ 8000 in 32 (53%). Median of highest level of EBV load was 10,300 copies/ml (range, 2000-645,000). Doses required to clear viremia were 1 in 31 (53%), 2 in 15 (26%), 3 in 5 (9%) and 4 in 7 (12%) pts. It took a median of 9 days (range, 1-41) from the initiation of pre-R to resolve viremia. No unexpected toxicities were reported from the use of pre-R. On a median follow-up of 22.7 months after HCT, no pts died due to EBV reactivation or rituximab use. Pts who developed PTLD (N = 7): Of the 7 pts who developed EBV related PTLD, one had pre-R treatment prior to developing PTLD. This pt was diagnosed with PTLD 146 days after pre-R treatment. The other 6 had not received pre-R therapy. Known risk factors for PTLD development were compared between the 2 groups and shown in Figure 1. Conclusions: Despite low numbers, this study exhibits compelling evidence that pre-R can be given to prevent PTLD in patients with EBV reactivation post-HCT. Further studies in a prospective fashion are required to further determine the EBV load at which treatment should begin.