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“Antivirals” in the Treatment of Adult T Cell Leukaemia– Lymphoma (ATLL)

  • T-Cell and Other Lymphoproliferative Malignancies (C Dearden, Section Editor)
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Abstract

Adult T cell leukaemia / lymphoma (ATLL) is a mature (post thymic) T cell lymphoma caused by the human T-lymphotropic virus type 1 (HTLV-1) infection. Overall survival in the aggressive subtypes (Acute Leukaemia and Lymphomatous) remains poor in part due to chemotherapy resistance. To improve treatment outcome for de novo disease, better induction therapies are required and since the pathogenic agent is known it would seem sensible to target the virus. In a recent meta-analysis the use of zidovudine and interferon alpha (ZDV/IFN) has been associated with improved response rates and prolonged overall survival in leukemic subtypes of ATLL (both acute and Chronic) confirmed in a multivariate analysis. In a more recent UK study the overall response rate for patients with aggressive ATLL treated with chemotherapy alone was 49 % compared to 81 % with combined first line therapy (chemotherapy with concurrent or sequential ZDV/IFN). Combined first line therapy prolonged median OS in acute (p = 0.0081) and lymphomatous ATLL (p = 0.001).These data support the use of low dose ZDV/IFN with chemotherapy as first line treatment for patients with newly diagnosed aggressive ATLL. Although the mechanisms of action are incompletely understood, some possible explanations for their efficacy will be discussed.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Mier JW, Gallo RC. Purification and some characteristics of human T-cell growth factor from phytohemagglutinin-stimulated lymphocyte-conditioned media. Proc Natl Acad Sci USA. 1980;77(10):6134–8.

    Article  PubMed  CAS  Google Scholar 

  2. Poiesz BJ, et al. Detection and isolation of type C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma. Proc Natl Acad Sci USA. 1980;77(12):7415–9.

    Article  PubMed  CAS  Google Scholar 

  3. Yoshida M, Miyoshi I, Hinuma Y. Isolation and characterization of retrovirus from cell lines of human adult T-cell leukemia and its implication in the disease. Proc Natl Acad Sci USA. 1982;79(6):2031–5.

    Article  PubMed  CAS  Google Scholar 

  4. IARC Monographs on the Evaluation of Carcinogenic Risk to Humans. Human immunodeficiency viruses and human T cell lymphotropic viruses. Lyon: IARC; 1996.

    Google Scholar 

  5. Murphy EL, et al. Modelling the risk of adult T-cell leukemia/lymphoma in persons infected with human T-lymphotropic virus type I. Int J Cancer. 1989;43(2):250–3.

    Article  PubMed  CAS  Google Scholar 

  6. Bazarbachi A, et al. New therapeutic approaches for adult T-cell leukaemia. Lancet Oncol. 2004;5(11):664–72.

    Article  PubMed  CAS  Google Scholar 

  7. Kondo T, et al. Age- and sex-specific cumulative rate and risk of ATLL for HTLV-I carriers. Int J Cancer. 1989;43(6):1061–4.

    Article  PubMed  CAS  Google Scholar 

  8. • Shimoyama M. Diagnostic criteria and classification of clinical subtypes of adult T-cell leukaemia-lymphoma. A report from the Lymphoma Study Group (1984–87). Br J Haematol. 1991;79(3):428–37. Original description of ATLL into disease subtypes.

    Article  PubMed  CAS  Google Scholar 

  9. Amano M, et al. New entity, definition and diagnostic criteria of cutaneous adult T-cell leukemia/lymphoma: human T-lymphotropic virus type 1 proviral DNA load can distinguish between cutaneous and smoldering types. J Dermatol. 2008;35(5):270–5.

    Article  PubMed  CAS  Google Scholar 

  10. Okayama A. Natural history of human T-lymphotropic virus type 1 (HTLV-1) infection. Rinsho Byori. 2005;53(9):837–44.

    PubMed  CAS  Google Scholar 

  11. Iwanaga M, et al. Human T-cell leukemia virus type I (HTLV-1) proviral load and disease progression in asymptomatic HTLV-1 carriers: a nationwide prospective study in Japan. Blood. 2010;116(8):1211–9.

    Article  PubMed  CAS  Google Scholar 

  12. Hodson et al. Pre Morbid Human T Lymphotropic virus type I proviral load, rather than percentage of abnormal lymphmocytes, is associated with an increased risk of Agressive T cell Leukamia/Lymphoma. In press Haematolgica; 2012.

  13. Matsuoka M, Jeang KT. Human T-cell leukaemia virus type 1 (HTLV-1) infectivity and cellular transformation. Nat Rev Cancer. 2007;7(4):270–80.

    Article  PubMed  CAS  Google Scholar 

  14. Afonso PV, et al. Centrosome and retroviruses: the dangerous liaisons. Retrovirology. 2007;4:27.

    Article  PubMed  Google Scholar 

  15. Mariner JM, et al. Human T cell lymphotropic virus type I Tax activates IL-15R alpha gene expression through an NF-kappa B site. J Immunol. 2001;166(4):2602–9.

    PubMed  CAS  Google Scholar 

  16. • Zhao T, Matsuoka M. HBZ and its roles in HTLV-1 oncogenesis. Front Microbiol. 2012;3:247. Importance of HBZ in the pathogenesis of ATLL.

    PubMed  Google Scholar 

  17. Okamoto T, et al. Multi-step carcinogenesis model for adult T-cell leukemia. Jpn J Cancer Res. 1989;80(3):191–5.

    Article  PubMed  CAS  Google Scholar 

  18. Moriyama K, et al. Immunodeficiency in preclinical smoldering adult T-cell leukemia. Jpn J Clin Oncol. 1988;18(4):363–9.

    PubMed  CAS  Google Scholar 

  19. Gabet AS, et al. High circulating proviral load with oligoclonal expansion of HTLV-1 bearing T cells in HTLV-1 carriers with strongyloidiasis. Oncogene. 2000;19(43):4954–60.

    Article  PubMed  CAS  Google Scholar 

  20. Sugata K, et al. HTLV-1 bZIP factor impairs cell-mediated immunity by suppressing production of Th1 cytokines. Blood. 2012;119(2):434–44.

    Article  PubMed  CAS  Google Scholar 

  21. Taylor GP, Matsuoka M. Natural history of adult T-cell leukemia/lymphoma and approaches to therapy. Oncogene. 2005;24(39):6047–57.

    Article  PubMed  CAS  Google Scholar 

  22. Yamada Y, et al. A new G-CSF-supported combination chemotherapy, LSG15, for adult T-cell leukaemia-lymphoma: Japan Clinical Oncology Group Study 9303. Br J Haematol. 2001;113(2):375–82.

    Article  PubMed  CAS  Google Scholar 

  23. Tsukasaki K, et al. VCAP-AMP-VECP compared with biweekly CHOP for adult T-cell leukemia-lymphoma: Japan Clinical Oncology Group Study JCOG9801. J Clin Oncol. 2007;25(34):5458–64.

    Article  PubMed  CAS  Google Scholar 

  24. Lewis JA, Mengheri E, Esteban M. Induction of an antiviral response by interferon requires thymidine kinase. Proc Natl Acad Sci USA. 1983;80(1):26–30.

    Article  PubMed  CAS  Google Scholar 

  25. • Shibata D, et al. Human T Cell lymphotropic virus type I (HTLV-1)-associated adult T Cell lymphoma in a patient infected with human immunodeficiency virus type −1(HIV-1). Ann Intern Med. 1989;111(11):871–5. First description of efficacy of AVT in ATLL.

    PubMed  CAS  Google Scholar 

  26. • Gill PS, et al. Treatment of adult T-cell leukemia-lymphoma with a combination of interferon alfa and zidovudine. N Engl J Med. 1995;332(26):1744–8. First reports of efficacy in AVT in ATLL patients.

  27. • Hermine O, et al. Treatment of adult T-cell leukemia-lymphoma with a combination of interferon alfa and zidovudine. N Engl J Med. 1995;332(26):1749–51. First reports of efficacy in AVT in ATLL patients.

    Article  PubMed  CAS  Google Scholar 

  28. Matutes E, et al. Interferon alpha and zidovudine therapy in adult T-cell leukaemia lymphoma: response and outcome in 15 patients. Br J Haematol. 2001;113(3):779–84.

    Article  PubMed  CAS  Google Scholar 

  29. Hermine O, et al. A prospective phase II clinical trial with the use of zidovudine and interferon-alpha in the acute and lymphoma forms of adult T-cell leukemia/lymphoma. Hematol J. 2002;3(6):276–82.

    Article  PubMed  CAS  Google Scholar 

  30. • Bazarbachi A, et al. Meta-analysis on the use of zidovudine and interferon-alfa in adult T-cell leukemia/lymphoma showing improved survival in the leukemic subtypes. J Clin Oncol. 2010;28(27):4177–83. Worldwide analysis of large series of patients confirming of AVT in Leukaemic forms of ATLL.

    Article  PubMed  CAS  Google Scholar 

  31. • Hodson A, et al. Use of zidovudine and interferon alfa with chemotherapy improves survival in both acute and lymphoma subtypes of adult T-cell leukemia/lymphoma. J Clin Oncol. 2011;29(35):4696–701. Further large series of patients confirming benefit of AVT in ATLL.

    Article  PubMed  CAS  Google Scholar 

  32. Ishitsuka K, et al. Interferon-alpha and zidovudine for relapsed/refractory adult T cell leukemia/lymphoma: case reports of Japanese patients. Int J Hematol. 2010;92(5):762–4.

    Article  PubMed  Google Scholar 

  33. Takasaki Y, et al. Long-term study of indolent adult T-cell leukemia-lymphoma. Blood. 2010;115(22):4337–43.

    Article  PubMed  CAS  Google Scholar 

  34. Goodbourn S, Didcock L, Randall RE. Interferons: cell signalling, immune modulation, antiviral response and virus countermeasures. J Gen Virol. 2000;81(Pt 10):2341–64.

    PubMed  CAS  Google Scholar 

  35. Oliere S, et al. HTLV-1 evades type I interferon antiviral signaling by inducing the suppressor of cytokine signaling 1 (SOCS1). PLoS Pathog. 2010;6(11):e1001177.

    Article  PubMed  Google Scholar 

  36. Feng X, Heyden NV, Ratner L. Alpha interferon inhibits human T-cell leukemia virus type 1 assembly by preventing Gag interaction with rafts. J Virol. 2003;77(24):13389–95.

    Article  PubMed  CAS  Google Scholar 

  37. Isono T, Ogawa K, Seto A. Antiviral effect of zidovudine in the experimental model of adult T cell leukemia in rabbits. Leuk Res. 1990;14(10):841–7.

    Article  PubMed  CAS  Google Scholar 

  38. Taylor GP, et al. Effect of lamivudine on human T-cell leukemia virus type 1 (HTLV-1) DNA copy number, T-cell phenotype, and anti-tax cytotoxic T-cell frequency in patients with HTLV-1-associated myelopathy. J Virol. 1999;73(12):10289–95.

    PubMed  CAS  Google Scholar 

  39. Macchi B, et al. Susceptibility of primary HTLV-1 isolates from patients with HTLV-1-associated myelopathy to reverse transcriptase inhibitors. Viruses. 2011;3(5):469–83.

    Article  PubMed  CAS  Google Scholar 

  40. Afonso PV, et al. Highly active antiretroviral treatment against STLV-1 infection combining reverse transcriptase and HDAC inhibitors. Blood. 2010;116(19):3802–8.

    Article  PubMed  CAS  Google Scholar 

  41. Datta A, Nicot C. Telomere attrition induces a DNA double-strand break damage signal that reactivates TP53 transcription in HTLV-I leukemic cells. Oncogene. 2008;27(8):1135–41.

    Article  PubMed  CAS  Google Scholar 

  42. • Datta A, et al. Persistent inhibition of telomerase reprograms adult T-cell leukemia to TP53-dependent senescence. Blood. 2006;108(3):1021–9. Mechanism of AZT in ATLL and requirement for wild type TP53 status.

    Article  PubMed  CAS  Google Scholar 

  43. Tawara M, et al. Impact of TP53 aberration on the progression of Adult T-cell Leukemia/Lymphoma. Cancer Lett. 2006;234(2):249–55.

    Article  PubMed  CAS  Google Scholar 

  44. • Ramos JC, et al. IRF-4 and c-Rel expression in antiviral-resistant adult T-cell leukemia/lymphoma. Blood. 2007;109(7):3060–8. Disease resistance to AVT by recogntion of overexpression of IRF-4.

    PubMed  CAS  Google Scholar 

  45. Alizadeh AA, et al. Expression profiles of adult T-cell leukemia-lymphoma and associations with clinical responses to zidovudine and interferon alpha. Leuk Lymphoma. 2010;51(7):1200–16.

    Article  PubMed  CAS  Google Scholar 

  46. Hermine O, et al. Phase II trial of arsenic trioxide and alpha interferon in patients with relapsed/refractory adult T-cell leukemia/lymphoma. Hematol J. 2004;5(2):130–4.

    Article  PubMed  CAS  Google Scholar 

  47. Kchour G, et al. Phase 2 study of the efficacy and safety of the combination of arsenic trioxide, interferon alpha, and zidovudine in newly diagnosed chronic adult T-cell leukemia/lymphoma (ATL). Blood. 2009;113(26):6528–32.

    Article  PubMed  CAS  Google Scholar 

  48. El Hajj H, et al. Therapy-induced selective loss of leukemia-initiating activity in murine adult T cell leukemia. J Exp Med. 2010;207(13):2785–92.

    Article  PubMed  CAS  Google Scholar 

  49. • Ishida T, et al. Defucosylated anti-CCR4 monoclonal antibody(KW-0761) for relapsed adult T cell leukaemia -lymphhoma: a multicenter phase II study. J Clin Oncol. 2012;30:837–42. This paper decribes a phase II study of anti CCR4 antibody in relapsed ATLL patients reporting an overall response rate of 50 %.

    Article  PubMed  CAS  Google Scholar 

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Disclosure

P. Fields: received funding support from Kings Health Partners AHSC; G. Taylor: institution received grant from National Institute for Health Research

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Authors and Affiliations

  1. Department of Haematology, Guys and St Thomas’, Kings College Hospitals, London, SE1 9RT, UK

    Paul A. Fields

  2. Section of Infectious Diseases, Department of Medicine, Imperial College, London, W2 1PG, UK

    Graham P. Taylor

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Correspondence to Paul A. Fields.

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Fields, P.A., Taylor, G.P. “Antivirals” in the Treatment of Adult T Cell Leukaemia– Lymphoma (ATLL). Curr Hematol Malig Rep 7, 267–275 (2012). https://doi.org/10.1007/s11899-012-0139-9

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  • DOI: https://doi.org/10.1007/s11899-012-0139-9

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