EBV DNAemia after Allogeneic Stem Cell Transplantation (SCT): A Prospective Study in 131 High Risk Patients.
Authors: Volin Liisa , Juvonen Eeva , Nihtinen Anne , Aalto Sanna , Hedman Klaus , Ruutu Tapani 
Published: October 2019

Abstract
We have studied prospectively the incidence of EBV DNAemia and its early treatment in 131 adult allogeneic high risk SCT recipients transplanted during the years 2000 to 2003. Based on our retrospective experience, high risk patients for EBV infection and post-transplant lymphoroliferative disorder (PTLD) were matched unrelated donor (MUD) recipients (of whom a large majority had received anti-thymocyte globulin (ATG) in the conditioning), and patients receiving high dose corticosteroids (HDMP) +/− ATG for the treatment of acute GVHD (aGVHD). 130 patients had a malignant hematological disease, and 1 had aplastic anemia. 23 donors were siblings and 108 unrelated. All donors were A, B, DR matched. 56 grafts were bone marrow and 75 blood stem cells. The grafts were unmanipulated. 101 patients received a standard myeloablative and 30 patients a reduced toxicity conditioning. 101 MUD recipients were given ATG (ThymoglobulineR) as part of conditioning. GVHD prophylaxis consisted of cyclosporine and methotrexate, and 23 patients with a sibling donor received MP in addition. After reduced toxicity conditioning 15 patients received cyclosporine and mycophenolate mophetil. In MUD transplantation EBV was studied weekly for 4 months after SCT and then monthly up to one year after SCT. In sibling SCT EBV was studied from the HDMP treatment of aGVHD on. EBV DNAemia was diagnosed if two consecutive plasma samples had >1000 EBV genome copies/ml detected. The median follow-up of the patients was 12 months, range 2–12. None of the 23 sibling SCT recipients had EBV DNAemia detected during the follow-up despite that 26% of them received also ATG for the treatment of GVHD. Of the 108 MUD recipients 28/108 (26%) had EBV DNAemia detected and 80/108 (74%) remained EBV negative. The activation of EBV was significantly (p<0.001) predicted by the use of high dose (12 mg/kg) ATG during the conditioning treatment but not by the age of the patients, haematological diagnoses, conditioning, the source of the graft, or of the incidence of aGVHD. The median (range) day of the detection of EBV DNAemia was 53 (10–145). The median EBV copy number/ml at detection was 3300 (1200–553700). 20/28 (71%) of the patients had symptoms associated with the DNAemia, 12 fever, 7 enlarged tender lymphnodes, 3 fever and lymphnodes, and 1 had atypical blood lymphocytes. The median day of the first symptoms was 53 (8–102). 21 patients had early EBV treatment started on day 59 (12–139). The decision to initiate treatment was based on the copy number at the onset and its development, and the clinical signs and symptoms. The EBV copy number at treatment was 20150 (1700–2847000). The treatment consisted of Rituximab (R, 375 mg/m2) and decrease of immunosuppression (IS) in 9 patients, R alone in 5, decrease of IS in 7, irradiation of the lymphoma in 4, and donor lymphocyte infusion in 4 patients. The median number of R infusions given per patient was 1.5 (1–4). 12 months after SCT 18/28 (64%) of the patients were alive. Two patients who received EBV-treatment died of PTLD. Other causes of death were 1 rejection, 3 aGVHD, 4 relapses, and 1 epileptic seizure. In conclusion, of the present patients who had received unmanipulated grafts none of the sibling recipients developed EBV DNAemia even after intensive treatment of aGVHD. 26% of the present MUD recipients developed EBV DNAemia but due to the frequent monitoring and early intervention PTLD could in most cases be prevented or cured.