Weekly Low-Dose Rituximab As the Preemptive Management of Epstein-Barr Virus Reactivation after Allogeneic Hematopoietic Stem Cell Transplantation: A Novel Strategy?

Background Reactivation of Epstein-Barr Virus (EBV) frequently occurs after allogeneic stem cell transplantation(allo-SCT) and EBV-induced posttransplant lymphoproliferative  disease(PTLD) is a potentially fatal  complication. Our previous study showed  that  the cumulative incidence of EBV viremia after allo-SCT was 21.3±1.5% ( data based on 892 evaluable patients received allo-SCT from Jun 2011 through Jun 2014 at our institution). As the preemptive treatment for EBV reactivation after allo-SCT , rituximab (anti-CD20) is commonly used, but is associated with the prolonged immune defect. The question of over-treatment of systematic rituximab has been raised and further studies investigating the minimal doses of  rituximab to resolve EBV reactivation and avoid its prolonged B cell impairment are needed. The aim of this single-center study was to evaluate the strategy of weekly low-dose rituximab as the preemptive management of EBV reactivation.

Methods 52 patients received allo-SCT from Mar 2014 through Mar 2015 at our institution were enrolled in a prospective study . 38 males and 14 females, median age 25 years (range, 7–57).  Patients underwent transplantation for acute leukemia (n=33), CML (n=2), NHL (n=4), MDS (n=5), or SAA(n=8). The type of donors included HLA-haploidentical donors (n=41), HLA-matched unrelated donors (n=8) and HLA-identical siblings (n=3). EBV viral loads of patients were monitored by quantitative PCR for EBV DNA performed on whole-blood samples once a week after allo-SCT. EBV reactivation was defined as a single positive EBV PCR result according to institutional thresholds (above 100 copies per millitre). Eligibility included  EBV reactivation and negative hepatitis B surface antigen. Rituximab was administered weekly at the fixed dose of 100mg  after a positive PCR result (>100Cop/mL) and discontinued as soon as  a negative PCR result was available . The numbers of circulating CD20⁺ B cells and serum gammaglobulin levels were assessed weekly during the study .

Results Weekly low-dose rituximab was well tolerated without any serious adverse event. 52 patients receiving preemptive rituximab treatment showed an 100% cumulative complete remission (CR) rate of EBV reactivation, which resulted in cessation of treatment  as per protocol after the 1^st (n=25, 48.1%), 2^nd (n=24, 46.1%), or 3^rd (n=3, 5.8%) dose. To date, none of the patients have developed an EBV-PTLD. There was no significant persistent B cell dysfunction following weekly low-dose rituximab treatment by assessment of the numbers of circulating CD20⁺ B cells and serum gammaglobulin levels.

Conclusions  Our weekly low-dose rituximab-based approach is a high-efficient and safe preemptive therapy for EBV reactivation after allo-SCT. Furthermore, the use of low-dose rituximab for EBV reactivation may avoid  its prolonged B cell impairment due to the over-treatment of 375mg/m² rituxima.