Abstract
Adult T-cell leukemia (ATL) is an aggressive mature T-cell malignancy with a poor prognosis. The anti-C–C motif chemokine receptor 4 (CCR4) antibody mogamulizumab (moga) reduces ATL cells and induces reconstitution of polyclonal T cells; however, ATL cases often remain resistant and moga sometimes causes fatal immunopathology. Epstein–Barr virus (EBV)-related B-cell lymphoma develops in severely immunocompromised subjects, and is particularly associated with impaired T-cell immunity. Here, we report an ATL patient who had received conventional chemotherapy plus moga, and subsequently developed EBV-related diffuse large B-cell lymphoma (DLBCL) of the central nervous system. Next-generation sequencing-based T-cell receptor repertoire analyses identified residual abnormal clones and revealed that reconstitution of polyclonal T cells was incomplete, even after moga treatment. Furthermore, a skin rash that developed after moga treatment was found to contain ATL clones. This case suggests that the limited therapeutic effects of moga and incomplete T-cell reconstitution are associated with severely impaired T-cell immunity and subsequent development of EBV-related DLBCL.
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Verdonck K, Gonzalez E, Van Dooren S, Vandamme AM, Vanham G, Gotuzzo E. Human T-lymphotropic virus 1: recent knowledge about an ancient infection. Lancet Infect Dis. 2007;7(4):266–81.
Katsuki T, Katsuki K, Imai J, Hinuma Y. Immune suppression in healthy carriers of adult T-cell leukemia retrovirus (HTLV-I): impairment of T-cell control of Epstein-Barr virus-infected B-cells. Jpn J Cancer Res. 1987;78(7):639–42.
Sadahira Y, Nishihara H, Shimizu M, Hirokawa M, Wada H, Yamada O, et al. Epstein-Barr virus-associated Hodgkin’s disease in HTLV-I seropositive patients: a report of two cases. Pathol Int. 1998;48(1):67–73.
Yasunaga J, Sakai T, Nosaka K, Etoh K, Tamiya S, Koga S, et al. Impaired production of naive T lymphocytes in human T-cell leukemia virus type I-infected individuals: its implications in the immunodeficient state. Blood. 2001;97(10):3177–83.
Chen S, Ishii N, Ine S, Ikeda S, Fujimura T, Ndhlovu LC, et al. Regulatory T cell-like activity of Foxp3 + adult T cell leukemia cells. Int Immunol. 2006;18(2):269–77.
Ishida T, Joh T, Uike N, Yamamoto K, Utsunomiya A, Yoshida S, et al. Defucosylated anti-CCR4 monoclonal antibody (KW-0761) for relapsed adult T-cell leukemia-lymphoma: a multicenter phase II study. J Clin Oncol. 2012;30(8):837–42.
Fuji S, Shindo T. Friend or foe? Mogamulizumab in allogeneic hematopoietic stem cell transplantation for adult T-cell leukemia/lymphoma. Stem Cell Investig. 2016;3:70.
Ureshino H, Shindo T, Nishikawa H, Watanabe N, Watanabe E, Satoh H, et al. Effector regulatory T cells reflect the equilibrium between antitumor immunity and autoimmunity in adult T-cell leukemia. Cancer Immunol Res. 2016;4(8):644–9.
Shindo T, Kitaura K, Ureshino H, Kamachi K, Miyahara M, Doi K, et al. Deep sequencing of the T cell receptor visualizes reconstitution of T cell immunity in mogamulizumab-treated adult T cell leukemia. Oncoimmunol. 2017;7(3):e1405204.
Ellman MH, Hurwitz H, Thomas C, Kozloff M. Lymphoma developing in a patient with rheumatoid arthritis taking low dose weekly methotrexate. J Rheumatol. 1991;18(11):1741–3.
Castillo JJ, Beltran BE, Miranda RN, Young KH, Chavez JC, Sotomayor EM. EBV-positive diffuse large B-cell lymphoma of the elderly: 2016 update on diagnosis, risk-stratification, and management. Am J Hematol. 2016;91(5):;529–37.
Ohyama Y, Kumode T, Eguchi G, Yamaguchi T, Maeda Y. Induction of molecular remission by using anti-CC-chemokine receptor 4 (anti-CCR4) antibodies for adult T cell leukemia: a risk of opportunistic infection after treatment with anti-CCR4 antibodies. Ann Hematol. 2014;93:169–71.
Totani H, Kusumoto S, Ishida T, Masuda A, Yoshida T, Ito A, et al. Reactivation of hepatitis B virus (HBV) infection in adult T-cell leukemia-lymphoma patients with resolved HBV infection following systemic chemotherapy. Int J Hematol. 2015;101:398–404.
Tanaka H, Aoki H, Sugita Y, Shimizu R, Kiko K, Mochida H, et al. Development of Epstein-Barr Virus-related primary diffuse large B-cell lymphoma of the central nervous system in a patient with peripheral T-cell lymphoma, not otherwise specified after mogamulizumab treatment. Intern Med. 2017;56(20):2759–63.
Kitaura K, Shini T, Matsutani T, Suzuki R. A new high-throughput sequencing method for determining diversity and similarity of T cell receptor (TCR) α and β repertoires and identifying potential new invariant TCR α chains. BMC Immunol. 2016;17(1):38.
Teshima T, Akashi K, Shibuya T, Taniguchi S, Okamura T, Harada M, et al. Central nervous system involvement in adult T-cell leukemia/lymphoma. Cancer. 1990;15(65):327–32.
Kawasaki C, Ikeda H, Fukumoto T. Cerebral mass lesions associated with adult T-cell leukemia/lymphoma. Int J Hematol. 1995;61:97–102.
Beltran B, Salas R, Quinons P, Morales D, Hurtado F, Cotrina E, et al. EBV-positive diffuse large B-cell lymphoma in a human T-lymphotropic virus type 1 carrier. Infect Agent Cancer. 2009;4:10.
Tobinai K, Ohtsu T, Hayashi M, Kinoshita T, Matsuno Y, Mukai K, et al. Epstein-Barr virus (EBV) genome carrying monoclonal B-cell lymphoma in a patient with adult T-cell leukemia-lymphoma. Leuk Res. 1991;15:837–46.
Amano M, Marutsuka K, Sugimoto T, Todaka T, Setoyama M. Epstein-Barr virus-associated primary central nervous system lymphoma in a patient with adult T-cell leukemia/lymphoma. J Dermatol. 2011;38:575–80.
Talvensaari K, Clave E, Douay C, Rabian C, Garderet L, Busson M, et al. A broad T-cell repertoire diversity and an efficient thymic function indicate a favorable long-term immune reconstitution after cord blood stem cell transplantation. Blood. 2002;99(4):;1458–64.
Britanova OV, Putintseva EV, Shugay M, Merzlyak EM, Turchaninova MA, Staroverov DB, et al. Age-related decrease in TCR repertoire diversity measured with deep and normalized sequence profiling. J Immunol. 2014;192:2689–98.
Tu W, Rao S. Mechanisms Underlying T cell immunosenescence: aging and cytomegalovirus infection. Front Microbiol. 2016;7:2111.
Yager EJ, Ahmed M, Lanzer K, Randall TD, Woodland DL, Blackman MA. Age-associated decline in T cell repertoire diversity leads to holes in the repertoire and impaired immunity to influenza virus. J Exp Med. 2008;205:711–23.
Sugita Y, Furuta T, Ohshima K, Komaki S, Miyoshi J, Morioka M, et al. The perivascular microenvironment in Epstein-Barr virus positive primary central nervous system lymphoma: the role of programmed cell death 1 and programmed cell death ligand 1. Neuropathology. 2018;38:125–34.
Hashimoto A, Chiba N, Tsuno H, Komiya A, Furukawa H, Matsui T, et al. Incidence of malignancy and the risk of lymphoma in Japanese patients with rheumatoid arthritis compared to the general population. J Rheumatol. 2015;42:564–71.
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Kamachi, K., Shindo, T., Miyahara, M. et al. Epstein–Barr virus-related diffuse large B-cell lymphoma in mogamulizumab-treated adult T-cell leukemia with incomplete T-cell reconstitution. Int J Hematol 109, 221–227 (2019). https://doi.org/10.1007/s12185-018-2552-x
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DOI: https://doi.org/10.1007/s12185-018-2552-x