Both high and low levels of cellular Epstein-Barr virus DNA in blood identify failure after hematologic stem cell transplantation in conjunction with acute GVHD and type of conditioning

Abstract

// Qin Li 1 , Lalit Rane 1 , Thomas Poiret 2 , Jiezhi Zou 1 , Isabelle Magalhaes 3 , Raija Ahmed 4 , Ziming Du 5 , Nalini Vudattu 6 , Qingda Meng 2 , Åsa Gustafsson-Jernberg 7 , Jacek Winiarski 7,9 , Olle Ringdén 2,8 , Markus Maeurer 2,8 , Mats Remberger 2,8 and Ingemar Ernberg 1 1 Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden 2 Division of Therapeutic Immunology, Labmed, Karolinska University Hospital, Huddinge, Stockholm, Sweden 3 Department of Oncology-Pathology (OnkPat), Karolinska University Hospital, Stockholm, Sweden 4 Public Health Agency, Solna, Sweden 5 Division of Neuropathology, Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA 6 Department of Immunobiology and Internal Medicine, Yale University, New Haven, CT, USA 7 Department of Clinical Science, Intervention an Technology (CLINTECH), Karolinska University Hospital, Huddinge, Stockholm, Sweden 8 Center for Allogeneic Stem Cell Transplantation, Karolinska University Hospital, Huddinge, Stockholm, Sweden 9 Department of Pediatrics, Karolinska University Hospital, Huddinge, Stockholm, Sweden Correspondence to: Ingemar Ernberg, email: // Keywords : stem cell transplantation, EBV DNA-load, T-cell phenotype, total body irradiation, aGVHD, Immunology and Microbiology Section, Immune response, Immunity Received : March 04, 2016 Accepted : April 11, 2016 Published : April 19, 2016 Abstract The level of Epstein-Barr virus DNA in blood has proven to be a biomarker with some predictive value in allogeneic hematopoietic stem cell transplantation patients (HSCT). We evaluated the impact of EBV load on survival of 51 patients (32M/19F, median age: 32 years, from < 1 to 68 years old), who had received HSCT for different types of malignancies (49 cases) or non-malignancies (2 cases). The overall survival [ 1 ]was compared between patients with extreme and moderate cell bound EBV DNA levels. Different sources of stem-cells (peripheral blood stem, n = 39; bone marrow, n = 9; or umbilical cord blood, n = 3) were used. Twenty patients received reduced-intensity conditioning regimen while the other 31 received myeloablative conditioning. Patients with high or very low level of cell bound EBV-DNA levels had a shorter OS than those with moderate EBV load: OS at 5 years was 67% vs 90% ( p < 0.03). There was a conspicuous relationship between EBV load and the reconstitution dynamics of total and EBV-specific T cells, CD4+ and CD4- CD8- (double negative) T cells in the few patients where it was analyzed. This was not statistically significant. Two other factors were associated to early mortality in addition to high or low EBV load: acute GVHD II-IV ( p < 0.02) and pre-transplant conditioning with total body irradiation (TBI) ≥6 Gy, ( p < 0.03). All the patients meeting all three criteria died within two years after transplantation. This points to a subgroup of HSCT patients which deserve special attention with improvement of future, personalized treatment.