A 43-year-old Japanese woman underwent unrelated cord blood transplantation (CBT) during remission for acute lymphoblastic leukemia with t(4;11)(q21;q23). Tacrolimus was given for prophylaxis of graft-versus-host disease. The posttransplantation clinical course was mostly uneventful, and the leukemia remained in remission. Fourteen months after CBT, the patient developed pancytopenia and hepatic dysfunction with persistent high-grade fever. The bone marrow was hypocellular with increased numbers of macrophages and hemophagocytes. The numbers of Epstein-Barr virus (EBV) copies in peripheral blood samples were remarkably high. Although the patient showed complete donor-type hematopoiesis, the titer of viral capsid antigen immunoglobulin G was low, and the results of a test for EBV nuclear antigen were negative. There was no clinical response to the reduction of immunosuppressive therapy or to the administration of high-dose methylprednisolone, human immunoglobulin, or acyclovir.The patient died 466 days after CBT of massive gastrointestinal hemorrhage due to bone marrow and hepatic failures. This case demonstrates that fatal EBV-associated hemophagocytic syndrome (HPS) can occur more than 1 year after CBT. This report is the first of a case of late-onset EBV-associated HPS following CBT.
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Zutter MM, Martin PJ, Sale GE, et al. Epstein-Barr virus lympho-proliferation after blood marrow transplantation. Blood. 1988;72:520–529.
Lucas KG, Pollok KE, Emanuel DI. Post-transplant Epstein-Barr virus induced lymphoproliferative disorders. Leuk Lymphoma. 1997;25:1–8.
O’Relly R, Small T, Papadopoulos E, Lucas K, Lacerda J, Koulova L. Biology and adoptive cell therapy of Epstein-Barr virus associated lymphoproliferative disorders in recipients of marrow allografts. Immunol Rev. 1997;157:195–216.
Knowles DM. Immunodeficiency-associated lymphoproliferative disorders. Mod Pathol. 1999;12:325–342.
Walker RC, Marshall WF, Strickler J, et al. Pretransplantation assessment of the risk of lymphoproliferative disorder. Clin Infect Dis. 1995;20:1346–1353.
Nalesnik MA. The diverse pathology of post-transplant assessment of the risk of lymphoproliferative disorders: the importance of a standardized approach. Transpl Infect Dis. 2001;3:88–96.
Leblond V, Davi F, Charlotte F, et al. Post-transplant lymphoproliferative disorders not associated with Epstein-Barr virus: a distinct entity? J Clin Oncol. 1998;16:2052–2059.
Curtis RE, Travis LB, Rowlings PA, et al. Risk of lymphoproliferative disorders after bone marrow transplantation: multi-institutional study. Blood. 1999;94:2208–2216.
Gratama JW. Epstein-Barr virus infections in bone marrow transplantation recipients. In: Forman SJ, Blume KG, Thomas ED, eds. Bone Marrow Transplantation. Boston, Mass: Blackwell Scientific Publications; 1994:429–442.
Imashuku S. Clinical features and treatment strategies of Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis. Crit Rev Oncol Hematol. 2002;44:259–272.
Sirvent N, Reviron D, de Lamballerie X, Michel G. First report of Epstein-Barr virus lymphoproliferative disease after cord blood transplantation. Bone Marrow Transplant. 2000;25:120–121.
Ohga S, Kanaya Y, Maki H, et al. Epstein-Barr virus-associated lymphoproliferative disease after a cord blood transplantation for Diamond-Blackfan anemia. Bone Marrow Transplant. 2000;25: 209–212.
Haut PR, Kovarik P, Shaw PH, Walterhouse D, Jenson HB, Kletzel M. Detection of EBV in the cord blood donor for a patient developing Epstein-Barr virus-associated lymphoproliferative disorder following mismatched unrelated umbilical cord blood transplantation. Bone Marrow Transplant. 2001;27:761–765.
Barker JN, Martin PL, Coad JE, et al. Low incidence of Epstein-Barr virus-associated posttransplantation lymphoproliferative disorders in 272 unrelated donor umbilical cord blood transplant recipients. Biol Blood Marrow Transplant. 2001;7:395–399.
Meyer-Bahlburg A, Winkler J, Meerbach A, et al. Fatal late-onset EBV-associated post transplant lymphoproliferative disease after umbilical cord blood transplantation due to persistent mixed chimerism and severe delay in T-cell recovery in a patient with Omenn’s syndrome. Bone Marrow Transplant. 2004;34:283–284.
Knowles DM, Cesarman E, Chadburn A, et al. Correlative morphologic and molecular genetic analysis demonstrates three distinct categories of posttransplantation lymphoproliferative disorders. Blood. 1995;85:552–565.
Knowles D. Immunodeficiency-associated lymphoproliferative disorders Mod Pathol. 1999;12:200–217.
Wagner HJ, Rooney CM, Heslop HE. Diagnosis and treatment of posttransplantation lymphoproliferative disease after hemato-poietic stem cell transplantation. Biol Blood Marrow Transplant. 2002;8:1–8.
Paya CV, Fung JJ, Nalesnik, et al, for the ASTS/ASTP EBV-PTLD Task Force and the Mayo Clinic organized International Consensus Development Meeting on Epstein-Barr Virus-Induced Post-transplant Lymphoproliferative Disorders (PTLD). Epstein-Barr virus-induced posttransplant lymphoproliferative disorders. Transplantation. 1999;68:1517–1525.
Porcu P, Eisenbeis CF, Pelletier RP, et al. Successful treatment of posttransplantation lymphoproliferative disorder (PTLD) following renal allografting is associated with sustained CD8+ T-cell restoration. Blood. 2002;100:2341–2348.
Imashuku S Kuriyama K, Teramura T, et al. Requirement for etoposide in the treatment of Epstein-Barr virus-associated hemo-phagocytic lymphohistiocytosis. J Clin Oncol. 2001;19:2665–2673.
Papadopoulos EB, Ladanyi M, Emanuel D, et al. Infusion of donor leukocytes to treat Epstein-Barr virus-associated lymphoproliferative disorders after allogeneic bone marrow transplantation. New Engl J Med. 1994;330:1185–1191. 23. Rooney CM, Smith CA, Ng CY, et al. Use of gene modified virus-specific T lymphocytes to control Epstein-Barr virus-related lymphoproliferation. Lancet. 1995;345:9-13. 24. Hoshino Y, Kimura H, Tanaka N, et al. Prospective monitoring of the Epstein-Barr virus DNA by a real-time quantitative poly-merase chain reaction after allogeneic stem cell transplantation. Br J Haematol. 2001;115:105-111.
Stevens SJ, Verschuuren EA, Pronk I, et al. Frequent monitoring of Epstein-Barr virus DNA load in unfractionated whole blood is essential for early detection of posttransplant lymphoproliferative disease in high-risk patients. Blood. 2001;97:1165–1171.
Ohga S, Kubo E, Nomura, et al. Quantitative monitoring of circulating Epstein-Barr virus DNA for predicting the development of posttransplantation lymphoproliferative disease. Int J Hematol. 2000;73:323–326.
Kuehnle I, Huls MH, Liu Z, et al. CD20 monoclonal antibody (rituximab) for therapy of Epstein-Barr virus lymphoma after hemopoietic stem-cell transplantation. Blood. 2000;95:1502–1505.
Faye A, Quartier P, Reguerre Y, et al. Chimaeric anti-CD20 monoclonal antibody (rituximab) in post-transplant B-lymphoproliferative disorder following stem cell transplantation in children. Br J Haematol. 2001;115:112–118.
Imashuku S, Hibi S, Ohara T, et al, for the Histiocyte Society. Effective control of Epstein-Barr virus-related hemophagocytic lymphohistiocytosis with immunochemotherapy. Blood. 1999;93: 1869–1874.
Imashuku S. Advances in the management of hemophagocytic lymphohistiocytosis. Int J Hematol. 2000;72:1–11.
Moretta A, Comoli P, Montagna D, et al. High frequency of Epstein-Barr virus (EBV) lymphoblastoid cell line-reactive lymphocytes in cord blood: evaluation of cytolytic activity and IL-2 production. Clin Exp Immunol. 1997;107:312–320.
Sun Q, Burton RI, Pollok KE, Emanuel DJ, Lucas KG. CD4+ Epstein-Barr virus-specific cytotoxic T-lymphocytes from human umbilical cord blood. Cell Immunol. 1999;195:81–88.
Yazaki M, Takahashi T, Ito Y, Ito T, Mori C, Wada Y. Generation of HLA-A2 subtype specific cytotoxic T lymphocytes from cord blood used for cord blood stem cell transplantation. Bone Marrow Transplant. 2000;26:451–453.
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Kawabata, Y., Hirokawa, M., Saitoh, Y. et al. Late-Onset Fatal Epstein-Barr Virus—Associated Hemophagocytic Syndrome Following Cord Blood Cell Transplantation for Adult Acute Lymphoblastic Leukemia. Int J Hematol 84, 445–448 (2006). https://doi.org/10.1532/IJH97.06101
- Late onset