Epstein–Barr virus-associated lymphoproliferative disease (EBV-LPD) has emerged as a commonly fatal complication of allogeneic bone marrow transplantation (BMT).1 Cord blood (CB) is an alternative source of hematopoietic stem cells for transplantation to treat hematologic disorders.2 We report the first case of EBV-LPD following CB transplantation (CBT). A 3-year-old girl in second complete remission of pre-B acute lymphoblastic leukemia (ALL) underwent CBT using an unmanipulated unrelated 5/6 HLA matched CB. HLA-DPB1 genotyping was DPB1*0401, DPB1*1101 for recipient and DPB1*0401, DPB1*0501 for donor. The pretransplant conditioning regimen consisted of fractionated total body irradiation (12 Gy) with cyclophosphamide (60 mg/kg i.v. daily on days -5 and -4) and antithymocyte globulin (20 mg/kg daily on days -3 to -1). Cyclosporine in combination with high-dose corticosteroids (methylprednisolone: 5 mg/kg on days 5 to 9, 3 mg/kg on days 10 and 11, then tapered 10% per week and stopped at day 110) was used for graft-versus-host disease (GVHD) prophylaxis. The recipient was EBV seropositive before CBT; the EBV genome was absent from the CB. No GVHD occurred. Engraftment was delayed, with hematologic recovery occurring at around day 100, but complete chimerism was proven by HLA-DPB1* genotyping: DPB1*0401, DPB1*0501. Around day +180, when cyclosporine was being tapered, the patient developed fever and neurologic disturbances. Contrast-enhanced T2-weighted magnetic resonance imaging of the brain revealed diffuse lesions of the two parieto-temporal and occipital lobes, and of the brain stem. EBV-DNA was detected by polymerase chain reaction within the CSF. The patient died from neurologic complications on day 216. An autopsy was performed and histologic study of the brain revealed immunoblastic large-cell B lymphoma (CD20+); most cells expressed EBV-encoded latent membrane protein 1. These CNS lymphomatous cells were investigated using HLA-DPB1* genotyping and polymerase chain reaction amplification of a polymorphic DNA marker (D17S5); samples were analyzed by Southern blotting and showed a different pattern with the recipient CNS cells. These results indicated that the lymphoma was of donor origin: DPB1*0401, DPB1*0501, excluding an ALL relapse. Rare immunoblastic cells were also found in the spleen. Risk factors for EBV-LPD have been reported to be HLA disparity between donor and recipient, T cell depletion of the marrow graft, severity of acute GVHD, and use of intensive T cell-targeted immunosuppressive regimens. Cord blood cells which are immunologically immature may decrease the severity of acute GVHD, and use of T cell-targeted immunosuppressive regimens.3 Furthermore, Moretta et al4 recently demonstrated that CB lymphocytes are able to develop a strong innate immunity, directed against EBV-infected cells, mediated by both natural killer cells and IL-2 producing CD4+ T cells. Nevertheless, Lucas et al5 clearly showed that profound deficiencies of EBV- specific cytotoxic T cells in the post-transplantation setting are associated with an increasing risk of EBV-LPD. The absence of these EBV-specific cytotoxic T cells in naive CB cells could be one of the mechanisms responsible for the emergence of LPD in our patient.
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