Molecular Monitoring and Stepwise Preemptive Therapy to Prevent Epstein-Barr Virus-Associated Diseases After Allogeneic Hematopoietic Stem Cell Transplantation.

Epstein-Barr virus (EBV)-associated diseases progress rapidly and are severe complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Despite various therapeutic options being developed, the mortality of EBV-associated disease is still high. As the EBV-DNA loads of blood are associated with the occurrence of EBV-associated disease, we developed a stepwise preemptive therapy (administration of antiviral agents and reduction of immunosuppression [IS] followed by rituximab treatment) based on quantitative real-time polymerase chain reaction (RQ-PCR) monitoring EBV-DNA levels.

The blood EBV-DNA levels were regularly monitored by RQ-PCR in 192 recipients of allo-HSCT. The stepwise preemptive therapy was administered in patients experiencing blood EBV-DNA positive (more than 500 copies/ml) twice consecutively. Administration of antiviral agents and reduction of IS were first taken. If EBV-DNA was continuously positive four times with a rising trend, rituximab was administered weekly until EBV-DNA was negative or for a total of 4 times. The patients who were diagnosed as EBV-associated diseases or appeared the signs and symptoms of EBV-associated diseases within three days after preemptive therapy were withdrawn from the study of preemptive therapy.

Sixty patients developed EBV viremia and 31 developed EBV-associated diseases, including 19 EBV-associated post-transplant lymphoproliferative diseases (PTLD) and 12 EBV-associated other diseases (7 EBV-associated fever, 1 encephalitis, 1 myelitis, 1 encephalitis with lung involvement, 1 encephalitis with lung and liver involvement and 1 pneumonia). The median time to onset of EBV viremia and EBV-associated diseases was 51 days (range, 22–368 days) and 65 days (range, 22–289 days) post-transplantation, respectively. The 3-year cumulative incidence of EBV-viremia and EBV-associated diseases was 34.0% ± 3.7% and 18.1% ± 3.0%. The 3-year cumulative incidence of EBV-associated diseases rose steeply with increasing number of risk factors: 2.7% ± 1.9%, 16.9% ± 11.0%, 36.7% ± 7.8% and 37.6% ± 9.0% for patients with 0, 1, 2, and 3 major risk factors (antithymocyte globulin, unrelated donor and HLA-mismatched, as none of the grafts were T-cell-depleted), respectively. The EBV-DNA levels of blood exceeded the threshold for 0 to 17 (median 7) days before the clinical manifestations of EBV-associated diseases emerged. Fifty-five patients received the first-step preemptive therapy and 12 cases followed by rituximab preemptive treatment. Nineteen (34.5%) cases became EBV-DNA negative, and 36 showed no response including 24 progressing to EBV-associated diseases during the first-step preemptive therapy. The effective rates of antiviral agents and antiviral agents plus reduction of IS were 11.1% and 45.9%, respectively (P=0.011). Of the 12 patients undergoing rituximab preemptive therapy, 11 (91.7%) cases achieved complete responses (CR) and one progressed to PTLD. The effective rates of preemptive therapy were 100%, 75%, 48% and 50% for patients with 0, 1, 2, or 3 major risk factors, respectively. Twenty-three (88.5%) of the 26 cases obtained CR after rituximab-based treatments; one case without use of rituximab and four who gave up treatment all died of EBV-associated diseases. Of the 23 cases with CR, 17 survived and 6 died with a median follow up of 320 days (range, 62 to 1070 days) after the onset of EBV-associated diseases.

The stepwise preemptive therapy has some effect on prevention of EBV-associated diseases, but more frequent monitoring of blood EBV-DNA levels and earlier preemptive rituximab should be advocated in patients at high risk of EBV-associated diseases.

No relevant conflicts of interest to declare.