Abstract
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective measure for the treatment of hematological disease. With the progress and widespread use of allo-HSCT, Epstein–Barr virus (EBV) related central nervous system (CNS) diseases have gotten more and more attention because of its poor prognosis and overall survival. Since currently there is no standard treatment for patients with EBV-associated CNS diseases and reported therapies are heterogeneous with mixed results, we attempted to develop a novel therapeutic method. We applied a regimen of intrathecal donor lymphocyte infusion (IDLI) in three patients with EBV-associated CNS diseases after allo-HSCT in addition to immunosuppressants reduction and combined antiviral therapy. All of three patients were responsive to this therapy: all clinical symptoms and EBV load in CSF were resolved 10, 17, and 12 days after initial IDLI, respectively, and magnetic resonance imaging (MRI) showed that lesions of case 1 and 2 disappeared 15 and 19 days after initial IDLI, respectively. Even more appealing, there were no acute or chronic adverse reactions during the infusion and up to 23 months of follow-up. In conclusion, IDLI seems to be an effective and safe method for EBV-associated CNS diseases in allo-HSCT recipients. We recommend this treatment modality for further investigation.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Lv M, Huang XJ. Allogeneic hematopoietic stem cell transplantation in China: where we are and where to go. J Hematol & Oncol. 2012;5:10.
Ahmed SO, Ghavamzadeh A, Zaidi SZ, Baldomero H, Pasquini MC, Hussain F, et al. Trends of hematopoietic stem cell transplantation in the Eastern Mediterranean region, 1984–2007. Biol Blood Marrow Transplant. 2011;17:1352–61.
Juric MK, Ghimire S, Ogonek J, Weissinger EM, Holler E, van Rood JJ, et al. Milestones of hematopoietic stem cell transplantation—from first human studies to current developments. Front Immunol. 2016;7:470.
Kutok JL, Wang F. Spectrum of Epstein-Barr virus-associated diseases. Annu Rev Pathol. 2006;1:375–404.
Rasche L, Kapp M, Einsele H, Mielke S. EBV-induced post transplant lymphoproliferative disorders: a persisting challenge in allogeneic hematopoetic SCT. Bone Marrow Transplant. 2014;49:163–7.
Schmidt-Hieber M, Schwender J, Heinz WJ, Zabelina T, Kuhl JS, Mousset S, et al. Viral encephalitis after allogeneic stem cell transplantation: a rare complication with distinct characteristics of different causative agents. Haematologica. 2011;96:142–9.
Evens AM, Roy R, Sterrenberg D, Moll MZ, Chadburn A, Gordon LI. Post-transplantation lymphoproliferative disorders: diagnosis, prognosis, and current approaches to therapy. Curr Oncol Rep. 2010;12:383–94.
Rouce RH, Louis CU, Heslop HE. Epstein-Barr virus lymphoproliferative disease after hematopoietic stem cell transplant. Curr Opin Hematol. 2014;21:476–81.
Landgren O, Gilbert ES, Rizzo JD, Socie G, Banks PM, Sobocinski KA, et al. Risk factors for lymphoproliferative disorders after allogeneic hematopoietic cell transplantation. Blood. 2009;113:4992–5001.
Styczynski J, van der Velden W, Fox CP, Engelhard D, de la Camara R, Cordonnier C, et al. Management of Epstein-Barr Virus infections and post-transplant lymphoproliferative disorders in patients after allogeneic hematopoietic stem cell transplantation: Sixth European Conference on Infections in Leukemia (ECIL-6) guidelines. Haematologica. 2016;101:803–11.
Jagadeesh D, Woda BA, Draper J, Evens AM. Post transplant lymphoproliferative disorders: risk, classification, and therapeutic recommendations. Curr Treat Options Oncol. 2012;13:122–36.
Buell JF, Gross TG, Hanaway MJ, Trofe J, Roy-Chaudhury P, First MR, et al. Posttransplant lymphoproliferative disorder: significance of central nervous system involvement. Transplant Proc. 2005;37:954–5.
Wu M, Sun J, Zhang Y, Huang F, Zhou H, Fan Z, et al. Intrathecal rituximab for EBV-associated post-transplant lymphoproliferative disorder with central nervous system involvement unresponsive to intravenous rituximab-based treatments: a prospective study. Bone Marrow Transplant. 2016;51:456–8.
Maecker B, Jack T, Zimmermann M, Abdul-Khaliq H, Burdelski M, Fuchs A, et al. CNS or bone marrow involvement as risk factors for poor survival in post-transplantation lymphoproliferative disorders in children after solid organ transplantation. J Clin Clin Oncol. 2007;25:4902–8.
Kempf C, Tinguely M, Rushing EJ. Posttransplant lymphoproliferative disorder of the central nervous system. Pathobiology. 2013;80:310–8.
Carpenter B, Haque T, Dimopoulou M, Atkinson C, Roughton M, Grace S, et al. Incidence and dynamics of Epstein-Barr virus reactivation after alemtuzumab-based conditioning for allogeneic hematopoietic stem-cell transplantation. Transplantation. 2010;90:564–70.
Meij P, van Esser JW, Niesters HG, van Baarle D, Miedema F, Blake N, et al. Impaired recovery of Epstein-Barr virus (EBV)—specific CD8+ T lymphocytes after partially T-depleted allogeneic stem cell transplantation may identify patients at very high risk for progressive EBV reactivation and lymphoproliferative disease. Blood. 2003;101:4290–7.
Mahapatra S, Chin CC, Iagaru A, Heerema-McKenney A, Twist CJ. Successful treatment of systemic and central nervous system post-transplant lymphoproliferative disorder without the use of high-dose methotrexate or radiation. Pediatr Blood Cancer. 2014;61:2107–9.
Server A, Bargallo N, Floisand Y, Sponheim J, Graus F, Hald JK. Imaging spectrum of central nervous system complications of hematopoietic stem cell and solid organ transplantation. Neuroradiology. 2017;59:105–26.
Fox CP, Burns D, Parker AN, Peggs KS, Harvey CM, Natarajan S, et al. EBV-associated post-transplant lymphoproliferative disorder following in vivo T-cell-depleted allogeneic transplantation: clinical features, viral load correlates and prognostic factors in the rituximab era. Bone Marrow Transplant. 2014;49:280–6.
Gärtner BC, Fischinger J, Schäfer H, Einsele H, Roemer K, Müller-Lantzsch N. Epstein-Barr viral load as a tool to diagnose and monitor post-transplant lymphoproliferative disease. Recent Results Cancer Res. 2002;159:49–54.
Shimizu H, Saitoh T, Koya H, Yuzuriha A, Hoshino T, Hatsumi N, et al. Discrepancy in EBV-DNA load between peripheral blood and cerebrospinal fluid in a patient with isolated CNS post-transplant lymphoproliferative disorder. Int J Hematol. 2011;94:495–8.
Terasawa T, Ohashi H, Tsushita K, Utsumi M, Mukai E, Nakamura S, et al. Failure to detect Epstein-Barr virus (EBV) DNA in plasma by real-time PCR in a case of EBV-associated posttransplantation lymphoproliferative disorder confined to the central nervous system. Int J Hematol. 2002;75:416–20.
Barberi W, Perrone S, Iori AP, Torelli GF, Testi AM, Moleti ML, et al. Proven Epstein-Barr encephalitis with negative EBV-DNA load in cerebrospinal fluid after allogeneic hematopoietic stem cell transplantation in a child with acute lymphoblastic leukemia. Pediatr Transplant. 2015;19:E19–24.
Kittan NA, Beier F, Kurz K, Niller HH, Egger L, Jilg W, et al. Isolated cerebral manifestation of Epstein-Barr virus-associated post-transplant lymphoproliferative disorder after allogeneic hematopoietic stem cell transplantation: a case of clinical and diagnostic challenges. Transplant infectious disease: an official journal of the Transplantation. Society. 2011;13:524–30.
Styczynski J, Einsele H, Gil L, Ljungman P. Outcome of treatment of Epstein-Barr virus-related post-transplant lymphoproliferative disorder in hematopoietic stem cell recipients: a comprehensive review of reported cases. Transplant infectious disease: an official journal of the Transplantation. Society. 2009;11:383–92.
Volpi A. Epstein-Barr virus and human herpesvirus type 8 infections of the central nervous system. Herpes. 2004;11:120A–7A.
Vickers MA, Wilkie GM, Robinson N, Rivera N, Haque T, Crawford DH, et al. Establishment and operation of a Good Manufacturing Practice-compliant allogeneic Epstein-Barr virus (EBV)-specific cytotoxic cell bank for the treatment of EBV-associated lymphoproliferative disease. Br J Haematol. 2014;167:402–10.
Heslop HE, Slobod KS, Pule MA, Hale GA, Rousseau A, Smith CA, et al. Long-term outcome of EBV-specific T-cell infusions to prevent or treat EBV-related lymphoproliferative disease in transplant recipients. Blood. 2010;115:925–35.
Harjunpaa A, Wiklund T, Collan J, Janes R, Rosenberg J, Lee D, et al. Complement activation in circulation and central nervous system after rituximab (anti-CD20) treatment of B-cell lymphoma. Leuk & Lymphoma. 2001;42:731–8.
van de Glind G, de Graaf S, Klein C, Cornelissen M, Maecker B, Loeffen J. Intrathecal rituximab treatment for pediatric post-transplant lymphoproliferative disorder of the central nervous system. Pediatr Blood Cancer. 2008;50:886–8.
Czyzewski K, Styczynski J, Krenska A, Debski R, Zajac-Spychala O, Wachowiak J, et al. Intrathecal therapy with rituximab in central nervous system involvement of post-transplant lymphoproliferative disorder. Leuk & Lymphoma. 2013;54:503–6.
Meuleman N, Ahmad I, Duvillier H, Lemort M, Bennani J, Martiat M, et al. Intrathecal donor lymphocyte infusion for the treatment of suspected refractory lymphomatous meningitis: a case report. Eur J Haematol. 2006;77:523–6.
Neumann M, Blau IW, Burmeister T, Tietze-Buerger C, Blau O, Gerbitz A, et al. Intrathecal application of donor lymphocytes in leukemic meningeosis after allogeneic stem cell transplantation. Ann Hematol. 2011;90:911–6.
Yanagisawa R, Nakazawa Y, Sakashita K, Saito S, Tanaka M, Shiohara M, et al. Intrathecal donor lymphocyte infusion for isolated leukemia relapse in the central nervous system following allogeneic stem cell transplantation: a case report and literature review. Int J Hematol. 2016;103:107–11.
Acknowledgements
This work was supported by the National Natural Science Foundation of China(Grant N0.81470827). The authors thank for every faculty member of Department of Hematology of the Affiliated Cancer Hospital of Zhengzhou University who had participant in the study.
Author contributions
Jian Zhou, Yongping Song, Yanli Zhang, Quande Lin, Baijun Fang and Juanjuan Zhao designed the research. Juanjuan Zhao, Yingling Zu, Lijie Han, Ruirui Gui, Fengkuan Yu, acquired the clinical data. Juanjuan Zhao, Zhen Li, and Huifang Zhao analyzed data and wrote the manuscript. Jian Zhou and Yongping Song supervised the study.
Funding
This study was funded by National Nature Science Foundation of China (grant number 81470827).
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Clinical responsibilities and informed consent
We conducted thoroughly comprehensive communication with three patients and their families to get them informed of the possible efficacy and adverse reactions of this procedure. Informed consent was obtained from individual participants (Cases 1 and 3) or their guardians (Case 2). The patients and/or their families take full responsibilities for any problem resulting from this procedure.
Ethical approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Rights and permissions
About this article
Cite this article
Zhao, J., Zu, Y., Han, L. et al. Treatment of Epstein–Barr virus associated central nervous system diseases after allogeneic hematopoietic stem cell transplantation with intrathecal donor lymphocyte infusion. Bone Marrow Transplant 54, 821–827 (2019). https://doi.org/10.1038/s41409-018-0409-9
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41409-018-0409-9
This article is cited by
-
Immunosuppressants
Reactions Weekly (2019)