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Cardiovascular & Hematological Disorders-Drug Targets


ISSN (Print): 1871-529X
ISSN (Online): 2212-4063

Review Article

Clinical Post-Transplant Lymphoproliferative Disorders

Author(s): Ziba Aghsaeifard and Reza Alizadeh*

Volume 22, Issue 2, 2022

Published on: 09 September, 2022

Page: [96 - 103] Pages: 8

DOI: 10.2174/1871529X22666220804155810

Price: $65


Post-transplant lymphoproliferative disorders (PTLDs) are characterized by hyperproliferation of B cells due to solid organ or allogeneic hematopoietic stem cell transplant. Based on histological findings, it is divided into 4 categories. Most PTLD patients are Epstein–Barr virus (EBV) positive. Additionally, aggressive immunosuppressive therapies can also lead to PTLD. Reducing immunosuppressive regimes, antivirals, monoclonal antibodies, chemotherapy, and radiotherapy are available therapeutic options, depending on the nature and phase of the disease. This review briefly highlights pathogenesis, risk factors, prevention, and therapeutic strategies regarding PTLDs.

Keywords: Epstein-Barr virus (EBV), post-transplant lymphoproliferative disorders (PTLD), hematopoietic stem cell, immunosuppression, transplant recipients, lymphoma.

Graphical Abstract
Petrara, M.R.; Giunco, S.; Serraino, D.; Dolcetti, R.; De Rossi, A. Post-transplant lymphoproliferative disorders: From epidemiology to pathogenesis-driven treatment. Cancer Lett., 2015, 369(1), 37-44.
[] [PMID: 26279520]
Singavi, A.K.; Harrington, A.M.; Fenske, T.S. Post-transplant lymphoproliferative disorders.In: Non-Hodgkin Lymphoma: Pathology, Imaging, and Current Therapy; Evens, A.M.; Blum, K.A., Eds.; Springer International Publishing: Cham, 2015, pp. 305-327.
La Rosa, C.S.; Rubulotta, E.; Beesley, A.H. Posttransplant Lymphoproliferative Disorders; Oncopaedia CEMIC: Buenos Aires, Argentina, 2017, pp. 1-29.
Tsuji, M.; Uchiyama, T.; Mizumoto, C.; Takeoka, T.; Tomo, K.; Ohno, T. Development of Hodgkin’s lymphoma-like post-transplant lymphoproliferative disorder after tandem autologous peripheral blood stem cell transplantation for multiple myeloma. Clin Hemat Res., 2017, 1(1), 10-15.
Romero, S.; Montoro, J.; Guinot, M.; Almenar, L.; Andreu, R.; Balaguer, A.; Beneyto, I.; Espí, J.; Gómez-Codina, J.; Iacoboni, G.; Jarque, I.; López-Andújar, R.; Mayordomo-Aranda, E.; Montalar, J.; Pastor, A.; Pastor, M.; Piñana, J.L.; Rojas-Ferrer, N.; Sánchez-Lázaro, I.; Sandoval, J.; Sanz, G.; Sanz, M.Á.; Solé, A.; Sanz, J. Post-transplant lymphoproliferative disorders after solid organ and hematopoietic stem cell transplantation. Leuk. Lymphoma, 2019, 60(1), 142-150.
[] [PMID: 29966464]
Fararjeh, F.A.; Mahmood, S.; Tachtatzis, P.; Yallop, D.; Devereux, S.; Patten, P.; Agrawal, K.; Suddle, A.; O’Grady, J.; Heaton, N.; Marcus, R.; Kassam, S. A retrospective analysis of post-transplant lymphoproliferative disorder following liver transplantation. Eur. J. Haematol., 2018, 100(1), 98-103.
[] [PMID: 29094407]
Mahanama, A.; Abeynayake, J.I. Post-Transplant Lymphoprolife-rative Disorder (PTLD); A descriptive cross sectional study describing the presence of associated factors for PTLD in a cohort of first year post renal transplant patients in Sri-Lanka. Transplantation, 2018, 102(Suppl. 7), S651.
Barış, Z.; Özçay, F.; Yılmaz Özbek, Ö.; Haberal, N.; Sarıalioğlu, F.; Haberal, M. A single-center experience of post-transplant lymphoproliferative disorder (PTLD) cases after pediatric liver transplantation: Incidence, outcomes, and association with food allergy. Turk. J. Gastroenterol., 2018, 29(3), 354-360.
[] [PMID: 29755021]
Bishnoi, R.; Bajwa, R.; Franke, A.J.; Skelton, W.P., IV; Wang, Y.; Patel, N.M.; Slayton, W.B.; Zou, F.; Dang, N.H. Post-transplant lymphoproliferative disorder (PTLD): Single institutional experience of 141 patients. Exp. Hematol. Oncol., 2017, 6(1), 26-26.
[] [PMID: 29021921]
AlDabbagh, M.A.; Gitman, M.R.; Kumar, D.; Humar, A.; Rotstein, C.; Husain, S. The role of antiviral prophylaxis for the prevention of Epstein-Barr virus-associated posttransplant lymphoproliferative disease in solid organ transplant recipients: A systematic review. Am. J. Transplant., 2017, 17(3), 770-781.
[] [PMID: 27545492]
De Paschale, M.; Clerici, P. Serological diagnosis of Epstein-Barr virus infection: Problems and solutions. World J. Virol., 2012, 1(1), 31-43.
[] [PMID: 24175209]
Adami, J.; Gäbel, H.; Lindelöf, B.; Ekström, K.; Rydh, B.; Glimelius, B.; Ekbom, A.; Adami, H.O.; Granath, F. Cancer risk following organ transplantation: A nationwide cohort study in Sweden. Br. J. Cancer, 2003, 89(7), 1221-1227.
[] [PMID: 14520450]
Heslop, H.E. How I treat EBV lymphoproliferation. Blood, 2009, 114(19), 4002-4008.
[] [PMID: 19724053]
McAulay, K.A.; Haque, T.; Crawford, D.H. Tumour necrosis factor gene polymorphism: A predictive factor for the development of post-transplant lymphoproliferative disease. Br. J. Cancer, 2009, 101(6), 1019-1027.
[] [PMID: 19738620]
Jeong, H.J.; Ahn, Y.H.; Park, E.; Choi, Y.; Yi, N.J.; Ko, J.S.; Min, S.I.; Ha, J.W.; Ha, I.S.; Cheong, H.I.; Kang, H.G. Posttransplantation lymphoproliferative disorder after pediatric solid organ transplantation: Experiences of 20 years in a single center. Korean J. Pediatr., 2017, 60(3), 86-93.
[] [PMID: 28392824]
Reshef, R.; Luskin, M.R.; Kamoun, M.; Vardhanabhuti, S.; Tomaszewski, J.E.; Stadtmauer, E.A.; Porter, D.L.; Heitjan, D.F.; Tsai, E. Association of HLA polymorphisms with post-transplant lymphoproliferative disorder in solid-organ transplant recipients. Am. J. Transplant., 2011, 11(4), 817-825.
[] [PMID: 21401872]
Zimmermann, H.; Babel, N.; Dierickx, D.; Morschhauser, F.; Mollee, P.; Zaucha, J.M.; Dreyling, M.H.; Dührsen, U.; Reinke, P.; Verhoef, G.; Subklewe, M.; Hüttmann, A.; Tousseyn, T.; Bachy, E.; Hauser, I.A.; Tarella, C.; Van Den Neste, E.; Gheysens, O.; Anagnostopoulos, I.; Leblond, V.; Riess, H.; Choquet, S.; Trappe, R.U. Immunosuppression is associated with clinical features and relapse risk of B cell posttransplant lymphoproliferative disorder: A retrospective analysis based on the prospective, international, multicenter PTLD-1 trials. Transplantation, 2018, 102(11), 1914-1923.
[] [PMID: 29757894]
Ferreiro, J.F.; Morscio, J.; Dierickx, D.; Vandenberghe, P.; Gheysens, O.; Verhoef, G.; Zamani, M.; Tousseyn, T.; Wlodarska, I. EBV-positive and EBV-negative posttransplant diffuse large B cell lymphomas have distinct genomic and transcriptomic features. Am. J. Transplant., 2016, 16(2), 414-425.
[] [PMID: 26780579]
Morscio, J.; Dierickx, D.; Tousseyn, T. Molecular pathogenesis of B-cell posttransplant lymphoproliferative disorder: What do we know so far? Clin. Dev. Immunol., 2013, 2013, 150835-35.
[] [PMID: 23690819]
Miyazono, A.; Okamoto, Y.; Nagasako, H.; Hamasaki, Y.; Shishido, S.; Yoshioka, T.; Kawano, Y. Multifocal Epstein-Barr virus-negative posttransplantation lymphoproliferative disorder treated with reduction of immunosuppression. Am. J. Kidney Dis., 2016, 68(3), 469-472.
[] [PMID: 27178679]
Liu, M.; Husain, S.; Famure, O.; Li, Y.; Kim, S.J. Incidence, risk factors, clinical management, and outcomes of posttransplant lymphoproliferative disorder in kidney transplant recipients. Prog. Transplant., 2019, 29(2), 185-193.
[] [PMID: 30845885]
Parker, A.; Bowles, K.; Bradley, J.A.; Emery, V.; Featherstone, C.; Gupte, G.; Marcus, R.; Parameshwar, J.; Ramsay, A.; Newstead, C. Diagnosis of post-transplant lymphoproliferative disorder in solid organ transplant recipients - BCSH and BTS Guidelines. Br. J. Haematol., 2010, 149(5), 675-692.
[] [PMID: 20408847]
Fujimoto, A.; Hiramoto, N.; Yamasaki, S.; Inamoto, Y.; Uchida, N.; Maeda, T.; Mori, T.; Kanda, Y.; Kondo, T.; Shiratori, S.; Miyakoshi, S.; Ishiyama, K.; Ikegame, K.; Matsuhashi, Y.; Tanaka, J.; Ichinohe, T.; Atsuta, Y.; Ogata, M.; Suzuki, R. Risk factors and predictive scoring system for post-transplant lymphoproliferative disorder after hematopoietic stem cell transplantation. Biol. Blood Marrow Transplant., 2019, 25(7), 1441-1449.
[] [PMID: 30794929]
Hertig, A.; Zuckermann, A. Rabbit antithymocyte globulin induction and risk of post-transplant lymphoproliferative disease in adult and pediatric solid organ transplantation: An update. Transpl. Immunol., 2015, 32(3), 179-187.
[] [PMID: 25936966]
Bachier Rodriguez, L.; Shore, T.B.; Gergis, U. Novel risk factors for Epstein-Barr virus (EBV) reactivation and post-transplant lymphoproliferative disorder (PTLD) after allogeneic hematopoietic stem cell transplant. Blood, 2017, 130(Suppl. 1), 1949-49.
Engels, E.A.; Jennings, L.W.; Everly, M.J.; Landgren, O.; Murata, K.; Yanik, E.L.; Pfeiffer, R.M.; Onaca, N.; Klintmalm, G.B. Donor-specific antibodies, immunoglobulin-free light chains, and BAFF levels in relation to risk of late-onset PTLD in liver recipients. Transplant. Direct, 2018, 4(6), e353-e53.
[] [PMID: 30123826]
Kinch, A.; Sundström, C.; Tufveson, G.; Glimelius, I. Association between HLA-A1 and -A2 types and Epstein-Barr virus status of post-transplant lymphoproliferative disorder. Leuk. Lymphoma, 2016, 57(10), 2351-2358.
[] [PMID: 27104753]
Mbulaiteye, S.M.; Clarke, C.A.; Morton, L.M.; Gibson, T.M.; Pawlish, K.; Weisenburger, D.D.; Lynch, C.F.; Goodman, M.T.; Engels, E.A. Burkitt lymphoma risk in U.S. solid organ transplant recipients. Am. J. Hematol., 2013, 88(4), 245-250.
[] [PMID: 23386365]
Funch, D.P.; Walker, A.M.; Schneider, G.; Ziyadeh, N.J.; Pescovitz, M.D. Ganciclovir and acyclovir reduce the risk of post-transplant lymphoproliferative disorder in renal transplant recipients. Am. J. Transplant., 2005, 5(12), 2894-2900.
[] [PMID: 16303002]
Worth, A.; Conyers, R.; Cohen, J.; Jagani, M.; Chiesa, R.; Rao, K.; Goulden, N.; Veys, P.; Amrolia, P.J. Pre-emptive rituximab based on viraemia and T cell reconstitution: A highly effective strategy for the prevention of Epstein-Barr virus-associated lymphoproliferative disease following stem cell transplantation. Br. J. Haematol., 2011, 155(3), 377-385.
[] [PMID: 21910716]
Braconnier, P.; Del Marmol, V.; Broeders, N.; Kianda, M.; Massart, A.; Lemy, A.; Ghisdal, L.; Le Moine, A.; Madhoun, P.; Racapé, J.; Abramowicz, D.; Wissing, K.M. Combined introduction of anti-IL2 receptor antibodies, mycophenolic acid and tacrolimus: Effect on malignancies after renal transplantation in a single-centre retrospective cohort study. Nephrol. Dial. Transplant., 2012, 27(6), 2547-2553.
[] [PMID: 22123748]
Alizadeh, R.; Aghsaie Fard, Z. Renal impairment and analgesia: From effectiveness to adverse effects. J. Cell. Physiol., 2019, 234(10), 17205-17211.
[] [PMID: 30916404]
Alizadeh, R.; Fard, Z.A. Renal effects of general anesthesia from old to recent studies. J. Cell. Physiol., 2019, 234(10), 16944-16952.
[] [PMID: 30843210]
Aghsaiefard, Z.; Hossenifard, Z.; Alizadeh, R.; Ramim, T. The relationship between hemoglobin level with PTH level and dialysis adequacy in chronic hemodialysis patients. Tehran Univ. Med. J., 2018, 76(4), 257-264.
Gill, H.; Hwang, Y-Y.; Chan, T.S.Y.; Pang, A.W.; Leung, A.Y.; Tse, E.; Kwong, Y.L. Valganciclovir suppressed Epstein-Barr virus reactivation during immunosuppression with alemtuzumab. J. Clin. Virol., 2014, 59(4), 255-258.
[] [PMID: 24507802]
Kinch, A.; Hallböök, H.; Arvidson, J.; Sällström, K.; Bondeson, K.; Pauksens, K. Long-term outcome of Epstein-Barr virus DNAemia and PTLD with the use of preemptive rituximab following allogeneic HSCT. Leuk. Lymphoma, 2018, 59(5), 1172-1179.
[] [PMID: 28831836]
Prockop, S.; Reshef, R.; Tsai, D.E.; Bunin, N.; Abu-Arja, R.; Mahadeo, K.M.; Weng, W-K.; Van Besien, K.; Loeb, D.; Dwivedy Nasta, S.; Nemecek, E.R.; Hiremath, M.; Yue, S.; Sun, Y.; Navarro, W.; Nikiforow, S. Long-term outcomes of subjects with Epstein-Barr virus-driven post-transplant lymphoproliferative disorder (EBV+PTLD) following solid organ (SOT) or allogeneic hematopoietic cell transplants (HCT) treated with tabelecleucel on an expanded access program. Blood, 2019, 134(Suppl. 1), 4071-71.
Ghosh, S.K.; Perrine, S.P.; Williams, R.M.; Faller, D.V. Histone deacetylase inhibitors are potent inducers of gene expression in latent EBV and sensitize lymphoma cells to nucleoside antiviral agents. Blood, 2012, 119(4), 1008-1017.
[] [PMID: 22160379]
Perrine, S.P.; Hermine, O.; Small, T.; Suarez, F.; O’Reilly, R.; Boulad, F.; Fingeroth, J.; Askin, M.; Levy, A.; Mentzer, S.J.; Di Nicola, M.; Gianni, A.M.; Klein, C.; Horwitz, S.; Faller, D.V. A phase 1/2 trial of arginine butyrate and ganciclovir in patients with Epstein-Barr virus-associated lymphoid malignancies. Blood, 2007, 109(6), 2571-2578.
[] [PMID: 17119113]
Malouf, M.; Chhajed, P.; Hopkins, P.; Plit, M.; Turner, J.; Glanville, A. Anti-viral prophylaxis reduces the incidence of lymphoproliferative disease in lung transplant recipients. J. Heart Lung Transplant., 2002, 21, 547-554.
Ballen, K.K.; Cutler, C.; Yeap, B.Y. Donor-derived second hematologic malignancies after cord blood transplantation. Biol. Blood Marrow Transplant., 2010, 16(7), 1025-1031.
Baldanti, F.; Rognoni, V.; Cascina, A.; Oggionni, T.; Tinelli, C.; Meloni, F. Post-transplant lymphoproliferative disorders and Epstein-Barr virus DNAemia in a cohort of lung transplant recipients. Virol. J., 2011, 8(1), 421.
[] [PMID: 21892950]
McDiarmid, S.V.; Jordan, S.; Kim, G.S.; Toyoda, M.; Goss, J.A.; Vargas, J.H.; Martín, M.G.; Bahar, R.; Maxfield, A.L.; Ament, M.E.; Busuttil, R.W. Prevention and preemptive therapy of postransplant lymphoproliferative disease in pediatric liver recipients. Transplantation, 1998, 66(12), 1604-1611.
[] [PMID: 9884246]
Zimmermann, H.; Denecke, T.; Dreyling, M.H.; Franzius, C.; Reinke, P.; Subklewe, M.; Amthauer, H.; Kneba, M.; Riess, H.; Trappe, R.U. End-of-treatment positron emission tomography after uniform first-line therapy of B-cell posttransplant lymphoproliferative disorder identifies patients at low risk of relapse in the prospective German PTLD registry. Transplantation, 2018, 102(5), 868-875.
[] [PMID: 29189632]
Summers, J; Mongelluzzo, G; Leese, E. Primary CNS posttransplant lymphoproliferative disease (PCNS-PTLD): Diagnosis, minimal treatment toxicity, and surveillance in renal transplant patients (P1.6-015). Neurology, 2019, 92(15 Supplement)), P1.6-015.
Martinez, O.M. Biomarkers for PTLD diagnosis and therapies. Pediatr. Nephrol., 2020, 35(7), 1173-1181.
[] [PMID: 31240394]
Sullivan, B.J.; Kim, G.J.; Sara, G. Treatment dilemma for survivors of rituximab-induced bowel perforation in the setting of post-transplant lymphoproliferative disorder. BMJ Case Rep., 2018, 11(1), e226666.
[] [PMID: 30567238]
Park, S-G. Is there a relationship between the infusion-related reaction and effect of rituximab in the treatment of patients with diffuse large B-cell lymphoma? Korean J. Intern. Med. (Korean. Assoc. Intern. Med.), 2019, 34(4), 775-776.
[] [PMID: 31272144]
Pilch, N.A.; Meadows, H.B.; Alloway, R.R. Monoclonal antibodies in solid organ transplantation.In: Pharmaceutical Biotechnology: Fundamentals and Applications; Crommelin, D.J.A.; Sindelar, R.D.; Meibohm, B., Eds.; Springer International Publishing: Cham, 2019, pp. 537-555.
Seto, W-K.; Chan, T.S.; Hwang, Y-Y.; Wong, D.K.; Fung, J.; Liu, K.S.; Gill, H.; Lam, Y.F.; Lie, A.K.; Lai, C.L.; Kwong, Y.L.; Yuen, M.F. Hepatitis B reactivation in patients with previous hepatitis B virus exposure undergoing rituximab-containing chemotherapy for lymphoma: A prospective study. J. Clin. Oncol., 2014, 32(33), 3736-3743.
[] [PMID: 25287829]
Sahu, K.K.; Petrou, N.; Cohn, Z.; Khanna, S. Rituximab-induced late-onset neutropenia. BMJ Case Rep., 2019, 12(12), e233569.
[] [PMID: 31888912]
Huang, Q.; Yang, T.; Jin, X.; Ni, X.; Qi, H.; Yan, Z. Remission of late-onset post-heart transplantation lymphoproliferative disorder following treatment with rituximab and modified mini-CHOP chemotherapy: A case report. Exp. Ther. Med., 2016, 12(1), 262-266.
[] [PMID: 27347047]
Bollard, C.M.; Gottschalk, S.; Torrano, V.; Diouf, O.; Ku, S.; Hazrat, Y.; Carrum, G.; Ramos, C.; Fayad, L.; Shpall, E.J.; Pro, B.; Liu, H.; Wu, M.F.; Lee, D.; Sheehan, A.M.; Zu, Y.; Gee, A.P.; Brenner, M.K.; Heslop, H.E.; Rooney, C.M. Sustained complete responses in patients with lymphoma receiving autologous cytotoxic T lymphocytes targeting Epstein-Barr virus latent membrane proteins. J. Clin. Oncol., 2014, 32(8), 798-808.
[] [PMID: 24344220]
Blaes, A.H.; Hammerschmidt, D.E.; Peterson, B.A. Bortezomib and rituximab in the treatment of post-transplant lymphoproliferative disorders. Blood, 2011, 118(21), 4947-47.
Abdulsalam, M.; Manimoliyan, D. Therapeutic benefits of lenalidomide in hematological malignancies. Indian J. Med Special, 2019, 10(2), 61-65.
Läubli, H.; Tzankov, A.; Juskevicius, D.; Degen, L.; Rochlitz, C.; Stenner-Liewen, F. Lenalidomide monotherapy leads to a complete remission in refractory B-cell post-transplant lymphoproliferative disorder. Leuk. Lymphoma, 2016, 57(4), 945-948.
[] [PMID: 26295731]
Trappe, R.; Oertel, S.; Leblond, V.; Mollee, P.; Sender, M.; Reinke, P.; Neuhaus, R.; Lehmkuhl, H.; Horst, H.A.; Salles, G.; Morschhauser, F.; Jaccard, A.; Lamy, T.; Leithäuser, M.; Zimmermann, H.; Anagnostopoulos, I.; Raphael, M.; Riess, H.; Choquet, S. Sequential treatment with rituximab followed by CHOP chemotherapy in adult B-cell post-transplant lymphoproliferative disorder (PTLD): The prospective international multicentre phase 2 PTLD-1 trial. Lancet Oncol., 2012, 13(2), 196-206.
[] [PMID: 22173060]
Said-Conti, V.; Amrolia, P.J.; Gaze, M.N.; Stoneham, S.; Sebire, N.; Shroff, R.; Marks, S.D. Successful treatment of central nervous system PTLD with rituximab and cranial radiotherapy. Pediatr. Nephrol., 2013, 28(10), 2053-2056.
[] [PMID: 23743853]
Knight, J.S.; Tsodikov, A.; Cibrik, D.M.; Ross, C.W.; Kaminski, M.S.; Blayney, D.W. Lymphoma after solid organ transplantation: Risk, response to therapy, and survival at a transplantation center. J. Clin. Oncol., 2009, 27(20), 3354-3362.
[] [PMID: 19451438]

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