Four Cases of Chronic Active Epstein-Barr Virus Infection That Performed Reduced-Intensity Conditioning Bone Marrow Transplantation.

Abstract 4734

Epstein-Barr virus (EBV) is B cell tropic virus. However, the EBV-infected T and NK cells play a critical role on the pathogenesis of chronic active EBV infection (CAEBV). The diagnostic criteria are fever, lymphadenopathy and hepatosplenomegaly with abnormal antibody titer to EBV and increased amount of the EBV genome in the blood. But the mechanism on how EBV infects T and NK cells is not fully known yet. Once leukemic transformation occur the prognosis of the disease becomes very poor. The evidence that hematopoietic stem cell transplantation (SCT) is effective on CAEBV has accumulated, however, controversy still remains on the necessity of pre-transplant chemotherapy, and what kind of conditioning regimen is suitable during SCT.

In this article, we reported 2 cases of T cell type CAEBV and 2 cases of NK cell type CAEBV that have been treated by bone marrow transplantation (BMT) with reduced intensity regimen (RIC) without pre-transplant chemotherapy. RIC consists of Cyclophosphamide (CY, 100-120 mg/Kg), Fludarabine (Flu, 120-150 mg/m²) and low dose TBI (3-4 Gy).

Case 1 is an 8-year-old boy with EBV infected CD4 positive T cells. He showed elevated serum enzyme, coronary artery aneurysm, generalized rash, and positive EBV DNA in cerebrospinal fluid. The EBV genome in peripheral mononuclear cells was 1.3+10⁵ copies /μgDNA. Southern blot analysis with EBV terminal repeat probe revealed clonal proliferation of virus. Tetramer analysis did not detect EBV specific CTL. He received modified HLH 2004 protocol (Henter et al, 2006). Immediately after normalization of liver dysfunction, BMT were performed from unrelated donor. Now he is in complete remission.

Case 2 is an 8-year-old boy with EBV infected CD4 positive T cells. He also showed liver dysfunction, lymphadenopathy and positive EBV DNA in cerebrospinal fluid. The EBV genome in peripheral mononuclear cells is 2.6+10⁵ copies /μgDNA. EBV clonality was detected by Southern bolt analysis. Tetramer analysis of BRLF1, EBNA3A and EBNA3B peptides showed EBV specific CTL. BMT from HLA-matched sibling donor achieved complete chimeras. But the EBV genomes in his peripheral blood increased to 4.7 +10³ copies /μgDNA after BMT. EBV positive CD4 T cells were present. At the moment, it is not clear whether the origin of EBV positive T cells is from donor or not.

Case 3 is a 21-year-old female with mosquito allergy with EBV infected NK cells. Liver dysfunction and lymphadenopathy were occasionally complained. The EBV genome in her peripheral blood is 1.2+10⁵ copies /μgDNA. EBV showed monoclonal amplification. BRLF1 specific CTL were detected by tetramer analysis. HLA one antigen mismatched BMT from unrelated donor induced complete remission after grade 3 skin GVHD.

Case 4 is a 19-year-old boy with CAEBV secondary to EBV-hemophagocytic lymphohistiocytosis. EBV positive NK cells were present. EBV genome in his peripheral blood was 1.2+10⁴ copies /μgDNA. EBV showed monoclonal amplification. EBV specific CTL were not detected. After BMT from HLA-matched unrelated donor, EBV DNA was rapidly eliminated from his blood. But he suffered from pure red cell aplasia caused by major Blood type incompatibility and now treated with Rituximab.

Four cases of CAEBV were described. RIC was demonstrated to be effective for engraftment of donor bone marrow cells without any serious adverse effects except pure red cell aplasia. Addition of pre-transplant chemotherapy seemed to be non-essential for engraftment or remission induction. In case 2 EBV infected peripheral CD4 positive cells were demonstrated after BMT. Determining the origin of the EBV infected CD4 positive T cells may provide hints for understanding on how EBV infects T cells or how EBV infected Tcells survive after BMT.