Infusions of Donor Leukocytes to Treat Epstein-Barr Virus-Associated Lymphoproliferative Disorders after Allogeneic Bone Marrow Transplantation

Papadopoulos, Esperanza B.; Ladanyi, Marc; Emanuel, David; Mackinnon, Stephen; Boulad, Farid; Carabasi, Matthew; Castro‐Malaspina, Hugo; Childs, Barrett H.; Gillio, Alfred P.; Small, Trudy N.; Young, James W.; Kernan, Nancy A.; O’Reilly, Richard J.

doi:10.1056/nejm199404283301703

Cited by 1,023 publications

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“…6,7 To the best of our knowledge, this is the first report of DLT for the treatment of EB-LPD in the CNS. It was not clear whether the infused lymphocytes had penetrated into the CNS.…”

Section: Discussionmentioning

confidence: 84%

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Donor lymphocyte transfusion for the treatment of Epstein–Barr virus-associated lymphoproliferative disorder of the brain

Nagafuji

Eto

Hayashi

et al. 1998

Bone Marrow Transplant

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Summary:EBV-associated lymphoproliferative disorder (LPD) is a rare but serious complication in marrow transplant recipients. A 31-year-old Japanese woman in the second chronic phase of CML received an allogeneic BMT from her HLA 2-locus-incompatible 62-year-old father. Around day +200, she developed EBV-LPD of the right parieto-temporal lobe which caused slowly progressive left hemiparesis. Two courses of donor lymphocyte transfusions (DLT) of 10 6 CD3 + T cells/kg of body weight failed to suppress her central nervous system (CNS) EBV-LPD. The patient died of recurrent blastic crisis of CML. This case suggests that DLT may be ineffective for the treatment of CNS EBV-LPD. Keywords: Epstein-Barr virus-associated lymphoproliferative disorder; donor lymphocyte transfusion; central nervous system EBV-associated lymphoproliferative disorder (LPD) is a rare but serious complication in marrow transplant recipients. 1,2 Although there are reports of successful treatment of polyclonal or oligoclonal proliferations with agents such as interferon-␣ and intravenous ␥-globulin, high-dose acyclovir, and anti-B-cell MoAb, 3-5 monoclonal disease has remained refractory to treatment in marrow transplant recipients.Recently, donor lymphocyte transfusions (DLT) have been shown to be an effective treatment for EBV-LPD. 6,7 We report the case of a Japanese woman, who developed EBV-LPD of the right cerebrum following allogeneic BMT and who was then treated with DLT. Case reportA 31 year-old Japanese woman was admitted to our hospital for the treatment of myeloid blastic crisis (BC) of CML Correspondence: Dr K Nagafuji, Department of Hematology, Hara Sanshin General Hospital, 1-8 Taihaku-machi, Hakata-ku, Fukuoka 812, Japan Received 4 August 1997; accepted 22 December 1997 in July 1996. She entered the second chronic phase after treatment with vincristine and prednisolone. The patient had no HLA-identical siblings, nor were there any HLAidentical unrelated donors in the Japan Marrow Donor Program. Because of the poor prognosis in BC, we decided to perform a BMT using her HLA 2-locus-incompatible 62-year-old father as donor. The donor was seropositive for human T cell leukemia virus type 1 (HTLV-1), while the recepient was seronegative. 8 Both the recipient and the donor were seropositive for EBV (VCA IgG ×40 VCA IgM Ͻ×10 EBNA ×10, VBCA IgG ×640 VCA IgM Ͻ×10 EBNA ×10, respectively).The pre-transplant conditioning consisted of BU 4 mg/kg orally in divided doses daily on days −8 to −5, and CY 50 mg/kg i.v. daily on days −4 to −2. Because of ABO major incompatibility, bone marrow mononuclear cells isolated by density-gradient centrifugation (1.8 × 10 8 /kg of body weight) were given. Tacrolimus (FK506; Fujisawa, Osaka, Japan) in combination with MTX was used for GVHD prophylaxis. Grade II GVHD of the skin developed on day +11 but this responded well to high-dose methylprednisolone therapy. Granulocytes exceeded 0.5 × 10 9 /l on day +16, and platelets exceeded 50 × 10 9 /l on day +26. Prolonged administration of immunosuppressive agents wa...

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“…6,7 To the best of our knowledge, this is the first report of DLT for the treatment of EB-LPD in the CNS. It was not clear whether the infused lymphocytes had penetrated into the CNS.…”

Section: Discussionmentioning

confidence: 84%

“…6,7 We report the case of a Japanese woman, who developed EBV-LPD of the right cerebrum following allogeneic BMT and who was then treated with DLT.…”

Section: Discussionmentioning

confidence: 99%

Donor lymphocyte transfusion for the treatment of Epstein–Barr virus-associated lymphoproliferative disorder of the brain

Nagafuji

Eto

Hayashi

et al. 1998

Bone Marrow Transplant

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“…Papadopolous et al [28] found that infusion of donor leucocytes was effective in patients with EBV-associated lymphoproliferative disease who had undergone allogeneic bone marrow transplantation. Precursors of anti-EBV CTL in the infused leucocytes appeared to be expanded in vivo to control EBV-infected cells.…”

Section: Discussionmentioning

confidence: 99%

Establishment of anti-Epstein–Barr virus (EBV) cellular immunity by adoptive transfer of virus-specific cytotoxic T lymphocytes from an HLA-matched sibling to a patient with severe chronic active EBV infection

Kuzushima

Yamamoto

Kimura

et al. 1996

Clinical and Experimental Immunology

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SUMMARYWe describe an experience of a specific immune transfer treatment in a patient with chronic active EBV infection. The patient had low anti-EBV T cell-mediated cytotoxic activity in his peripheral blood mononuclear cells (PBMC), which may have been the primary cause of the disease. An EBV-specific cytotoxic T lymphocyte (CTL) line was established from PBMC obtained from the patient's sister whose human leucocyte antigens (HLA) are identical to patient's. The patient received three courses of intravenously administered CTL at 3-week intervals. The number of the cells was increased with each course of treatment. After infusion of the T cell line, anti-EBV CTL activity was detected in the patient's PBMC. CTL activity increased markedly after the second course of immune transfer therapy. The amount of EBV DNA in the patient's plasma showed transient but repeated decreases. Serum levels of tumour necrosis factor-alpha (TNF-), which had elevated before treatment, began to decrease after initiation of treatment. No adverse effects were directly associated with CTL infusions. Despite having previously received a pneumococcal vaccine and prophylactic antibodies, the patient died of infection caused by Streptococcus pneumoniae bacteraemia 27 days after the third infusion. Although the longterm efficacy and safety of this therapy remains to be established, our findings suggest that adoptive transfer of CTL specific for EBV obtained from an HLA-matched donor might be a promising treatment for patients with chronic active EBV infection.

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“…18,19 For this reason, the EBV-directed CTL response has been carefully investigated after allogeneic BMT, where up to 30% of the recipients of allografts from mismatched or matched unrelated donors may develop EBV lymphoma. 20,21 The aims of our study were: (1) to determine whether a specific EBV-directed cytolytic activity exists after PBSCT; (2) to characterize this CTL response; and (3) to analyze qualitatively this CTL response in some patients with lymphoid malignancies early vs late after PBSCT. By these means we wished to determine whether the assessment of the EBV-specific CTL response can be used as a surrogate marker for the reconstitution of the antigen-specific T cell response after PBSCT.…”

mentioning

confidence: 99%

Assessment and characterization of the cytolytic T lymphocyte response against Epstein–Barr virus in patients with non-Hodgkin’s lymphoma after autologous peripheral blood stem cell transplantation

Nolte

Buhmann

Straka

et al. 1998

Bone Marrow Transplant

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Summary:The cytolytic T lymphocyte (CTL) response has often been used to assess the reconstitution of T cell function after allogeneic or autologous bone marrow transplantation (BMT). Less is known, however, about the reconstitution of the CTL response after peripheral blood stem cell transplantation (PBSCT). Therefore, we investigated the CTL response against Epstein-Barr virus (EBV) of patients undergoing autologous PBSCT. CTLs of six patients with relapsed non-Hodgkin's lymphoma and multiple myeloma were established before and at different times after PBSCT by in vitro stimulation of peripheral blood lymphocytes with autologous EBVtransformed lymphoblastoid cell lines (LCLs). The efficiency of T cell priming by LCLs was assessed at the time of initiation of CTL lines; the proliferative response was strongly reduced during the first 4 months and increased 5 months or more following PBSCT. Cytolytic activity was measured after three or four restimulations of CTLs. All patients investigated had a detectable EBV-specific CTL response which was poor during the first weeks after transplantation, accompanied by a strong non-MHC-restricted cytotoxic activity and a high proportion of CD56-positive T cells. Five or more months after PBSCT, a specific CTL response against EBV was seen which was similar to the situation prior to PBSCT, while the unspecific cytotoxic response decreased. Blocking experiments with monoclonal anti-CD3, anti-CD8 or anti-MHC I antibodies resulted in substantial inhibition of autologous LCL lysis, whereas anti-CD4 or anti-MHC II antibodies had no effect. Finally, autologous PHA blasts of a patient with the HLA haplotype A1/9+, B5/8+, Cw4/7+, were loaded with various EBNA-derived nonapeptides known to be presented by HLA B8 or A11, and exposed to autologous, EBV-directed In the last few years, autologous peripheral blood stem cell transplantation (PBSCT) has been established as a standard treatment for relapsed aggressive non-Hodgkin's lymphoma and has proven advantageous when compared with autologous or allogeneic bone marrow transplantation (BMT). 1-5 However, in contrast to autologous or allogeneic BMT, little information is available concerning the reconstitution of the immune system following autologous peripheral blood stem cell transplantation (PBSCT). As after BMT, the CD4/CD8 ratio seems to be inversed after PBSCT, but lymphocyte subpopulations and functions recover more rapidly, including the proliferative response to mitogens and the cytotoxic activity of lymphocytes after stimulation with high-dose IL-2 (lymphocyte-activated killer cells, LAK). [6][7][8][9][10] Previous investigations mainly examined non-specific lymphocyte functions in patients undergoing autologous PBSCT and the reconstitution of the antigen-specific cytolytic T lymphocyte (CTL) response has not been evaluated so far. Therefore, we examined the CTL response of these patients to Epstein-Barr virus (EBV), a widespread lymphotropic herpes virus. Most people are infected with EBV by adulthood, and the life-long persist...

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Infusions of Donor Leukocytes to Treat Epstein-Barr Virus-Associated Lymphoproliferative Disorders after Allogeneic Bone Marrow Transplantation

Abstract: In a small number of patients, infusions of unirradiated donor leukocytes were an effective treatment for EBV-associated lymphoproliferative disease that arose after allogeneic bone marrow transplantation.

Cited by 1,023 publications

References 30 publications

Donor lymphocyte transfusion for the treatment of Epstein–Barr virus-associated lymphoproliferative disorder of the brain

Donor lymphocyte transfusion for the treatment of Epstein–Barr virus-associated lymphoproliferative disorder of the brain

Establishment of anti-Epstein–Barr virus (EBV) cellular immunity by adoptive transfer of virus-specific cytotoxic T lymphocytes from an HLA-matched sibling to a patient with severe chronic active EBV infection

Assessment and characterization of the cytolytic T lymphocyte response against Epstein–Barr virus in patients with non-Hodgkin’s lymphoma after autologous peripheral blood stem cell transplantation

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