The optimal preemptive therapy for Epstein-Barr virus (EBV)-associated diseases remains under discussion. We developed a stepwise preemptive therapy (antiviral agents and reduction of immunosuppressants [RI] followed by rituximab) for EBV viremia, based on duration of EBV viremia and changes of viral loads. The blood EBV-DNA loads were regularly monitored by quantitative real-time polymerase chain reaction in 251 recipients undergoing allogeneic stem cell transplantation. The 3-year cumulative incidence of EBV viremia and EBV-associated diseases were 31.1% ± 3.1% and 15.6% ± 2.5%, which rose steeply with greater numbers of major risk factors. Of the 64 patients undergoing first-step preemption, 24 achieved complete response (CR) and 40 showed no response, including 25 progressing to EBV-associated diseases. The effective rates of antiviral agents and RI plus antiviral agents were 2/16 and 22/48 (P = 0.017). Fourteen achieved CR and one progressed to lymphoproliferative disease in the 15 patients undergoing rituximab preemption. Of the 26 patients progressing to EBV-associated diseases during preemptive therapy, 20 obtained CR in the 23 cases with rituximab-based treatments. The preemptive efficacy of RI plus antiviral agents was correlated with the numbers of major risk factors (rs = -0.298; P = 0.04). B-cell reconstitution was significantly delayed for at least 6 months in patients with rituximab preemption. The risk of herpesvirus infection was similar in patients who showed effective progress to first-step and rituximab preemption (P = 0.094). RI plus antiviral agents could be given priority to low-risk patients, whereas more frequent monitoring of blood EBV-DNA and earlier preemptive rituximab should be advocated in high-risk patients.
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