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      Recent advances in the treatment of adult T-cell leukemia-lymphomas

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          Abstract

          Recent advances in treatment for adult T-cell leukemia-lymphoma (ATL) are reviewed herein. It is currently possible to select a therapeutic strategy for ATL and predict prognosis by classification of patients by clinical subtypes and clinicopathological factors. Although the overall survival (OS) of patients with ATL has increased marginally because of advances in chemotherapy, further prolongation of survival might be difficult with conventional chemotherapy alone. Promising results have been reported for antiviral therapy using zidovudine and interferon-α, and, indeed, antiviral therapy is currently the standard treatment for patients with ATL in western countries. Remarkably, the 5-year OS rates are 100% for both the smoldering-type and chronic-type ATL. Recently, treatments for ATL have included allogeneic hematopoietic stem cell transplantation and molecular targeted therapies. Furthermore, the anti-CCR4 monoclonal antibody mogamulizumab has been shown to have marked cytotoxic effects on ATL cells, especially in the leukemic type of ATL. In the lymphoma type of ATL, the response rate may be improved by combining mogamulizumab with chemotherapy. It should be recognized that prevention of infection from carriers of human T-cell leukemia virus type-I and transfer of the virus from mother to infant are crucial issues for the eradication of ATL.

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          Detection and isolation of type C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma.

          B Poiesz, F Ruscetti, A Gazdar … (1980)
          Retrovirus particles with type C morphology were found in two T-cell lymphoblastoid cell lines, HUT 102 and CTCL-3, and in fresh peripheral blood lymphocytes obtained from a patient with a cutaneous T-cell lymphoma (mycosis fungoides). The cell lines continuously produce these viruses, which are collectively referred to as HTLV, strain CR(HTLV(CR)). Originally, the production of virus from HUT 102 cells required induction with 5-iodo-2'-deoxyuridine, but the cell line became a constitutive producer of virus at its 56th passage. Cell line CTCL-3 has been a constitutive producer of virus from its second passage in culture. Both mature and immature extracellular virus particles were seen in thin-section electron micrographs of fixed, pelleted cellular material; on occasion, typical type C budding virus particles were seen. No form of intracellular virus particle has been seen. Mature particles were 100-110 nm in diameter, consisted of an electron-dense core surrounded by an outer membrane separated by an electron-lucent region, banded at a density of 1.16 g/ml on a continuous 25-65% sucrose gradient, and contained 70S RNA and a DNA polymerase activity typical of viral reverse transcriptase (RT; RNA-dependent DNA nucleotidyltransferase). Under certain conditions of assay, HTLV(CR) RT showed cation preference for Mg(2+) over Mn(2+), distinct from the characteristics of cellular DNA polymerases purified from human lymphocytes and the RT from most type C viruses. Antibodies to cellular DNA polymerase gamma and anti-bodies against RT purified from several animal retroviruses failed to detectably interact with HTLV(CR) RT under conditions that were positive for the respective homologous DNA polymerase, demonstrating a lack of close relationship of HTLV(CR) RT to cellular DNA polymerases gamma or RT of these viruses. Six major proteins, with sizes of approximately 10,000, 13,000, 19,000, 24,000, 42,000, and 52,000 daltons, were apparent when doubly banded, disrupted HTLV(CR) particles were chromatographed on a NaDodSO(4)/polyacrylamide gel. The number of these particle-associated proteins is consistent with the expected proteins of a retrovirus, but the sizes of some are distinct from those of most known retroviruses of the primate subgroups.
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            Diagnostic criteria and classification of clinical subtypes of adult T-cell leukaemia-lymphoma. A report from the Lymphoma Study Group (1984-87).

            M. Shimoyama (1991)
            The following diagnostic criteria are proposed to classify four clinical subtypes of HTLV-1 associated adult T-cell leukaemia-lymphoma (ATL): (1) Smouldering type, 5% or more abnormal lymphocytes of T-cell nature in PB, normal lymphocyte level (less than 4 x 10(9)/l), no hypercalcaemia (corrected calcium level less than 2.74 mmol/l), lactate dehydrogenase (LDH) value of up to 1.5 x the normal upper limit, no lymphadenopathy, no involvement of liver, spleen, central nervous system (CNS), bone and gastrointestinal tract, and neither ascites nor pleural effusion. Skin and pulmonary lesion(s) may be present. In case of less than 5% abnormal T-lymphocytes in PB, at least one of histologically-proven skin and pulmonary lesions should be present. (2) Chronic type, absolute lymphocytosis (4 x 10(9)/l or more) with T-lymphocytosis more than 3.5 x 10(9)/l, LDH value up to twice the normal upper limit, no hypercalcaemia, no involvement of CNS, bone and gastrointestinal tract, and neither ascites nor pleural effusion. Lymphadenopathy and involvement of liver, spleen, skin, and lung may be present, and 5% or more abnormal T-lymphocytes are seen in PB in most cases . (3) Lymphoma type, no lymphocytosis, 1% or less abnormal T-lymphocytes, and histologically-proven lymphadenopathy with or without extranodal lesions. (4) Acute type, remaining ATL patients who have usually leukaemic manifestation and tumour lesions, but are not classified as any of the three other types. A total of 818 ATL patients with a mean age of 57 years, newly diagnosed from 1983 to 1987, were analysed by this criteria. There were 448 males and 370 females, and 253 were still alive with a median follow-up time of 13.3 months from diagnosis, while 565 were dead with a median survival time (MST) of 5.4 months. MST was 6.2 months for acute type, 10.2 months for lymphoma type, 24.3 months for chronic type, and not yet reached for smouldering type. Projected 2- and 4-year survival rates were 16.7% and 5.0% for acute type, 21.3% and 5.7% for lymphoma type, 52.4% and 26.9% for chronic type, 77.7% and 62.8% for smouldering type, respectively. Distinct clinical features and laboratory findings of each clinical subtype are described.
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              Meta-analysis on the use of zidovudine and interferon-alfa in adult T-cell leukemia/lymphoma showing improved survival in the leukemic subtypes.

              Ali Bazarbachi, Yves Plumelle, Juan Carlos Ramos … (2010)
              Human T-cell lymphotropic virus type-I-associated adult T-cell leukemia/lymphoma (ATL) is an aggressive, chemotherapy-resistant malignancy. Multiple small studies using zidovudine (AZT) and interferon-alfa (IFN-α) have shown response in patients with ATL. However, the impact of this innovative antiviral treatment strategy on long-term survival remains undetermined. We report a meta-analysis of antiviral therapy of ATL. Medical records of 254 patients with ATL who were treated in the United States, the United Kingdom, Martinique, and continental France were individually reviewed. According to Shimoyama classification, there were 116 patients with acute ATL, 18 patients with chronic ATL, 11 patients with smoldering ATL, and 100 patients with ATL lymphoma. In 231 patients with available survival data, first-line therapy was recorded in 207 patients. Five-year overall survival rates were 46% for 75 patients who received first-line antiviral therapy (P = .004), 20% for 77 patients who received first-line chemotherapy, and 12% for 55 patients who received first-line chemotherapy followed by antiviral therapy. Patients with acute, chronic, and smoldering ATL significantly benefited from first-line antiviral therapy, whereas patients with ATL lymphoma experienced a better outcome with chemotherapy. In acute ATL, achievement of complete remission with antiviral therapy resulted in 82% 5-year survival. Antiviral therapy in chronic and smoldering ATL resulted in 100% 5-year survival. Multivariate analysis confirmed that first-line antiviral therapy significantly improves overall survival of patients with ATL (hazard ratio, 0.47; 95% CI, 0.27 to 0.83; P = .021). These results confirm the high efficacy of AZT and IFN, which should now be considered the gold standard first-line therapy in leukemic subtypes of ATL.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Cancer Sci
                Journal ID (iso-abbrev): Cancer Sci
                Journal ID (publisher-id): cas
                Title: Cancer Science
                Publisher: BlackWell Publishing Ltd (Oxford, UK )
                ISSN (Print): 1347-9032
                ISSN (Electronic): 1349-7006
                Publication date (Print): April 2015
                Publication date (Electronic): 06 March 2015
                Volume: 106
                Issue: 4
                Pages: 344-351
                Affiliations
                [1 ]Department of Hematology, Imamura Bun-in Hospital Kagoshima, Japan
                [2 ]Department of Hematology, National Kyushu Cancer Center Fukuoka, Japan
                [3 ]Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute Nagoya, Japan
                [4 ]Department of Pathology, Kurume University School of Medicine Kurume, Japan
                [5 ]Department of Pharmaceutical Development, Immuno-Biological Laboratories Fujioka, Japan
                Author notes
                Correspondence Atae Utsunomiya, Department of Hematology, Imamura Bun-in Hospital, 11-23 Kamoikeshinmachi, Kagoshima 890-0064, Japan., Tel: +81-99-251-2221; Fax: +81-99-250-6181;, E-mail: autsunomiya@ 123456jiaikai.jp

                Funding Information Ministry of Health, Labor, and Welfare of Japan and Japan Society for the Promotion of Science.

                Article
                DOI: 10.1111/cas.12617
                PMC ID: 4409876
                PubMed ID: 25613789
                SO-VID: 22d7716c-b27e-4ccd-9e56-b06e69453341
                Copyright © © 2015 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.
                License:

                This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                History
                Date received : 29 October 2014
                Date revision received : 14 January 2015
                Date accepted : 16 January 2015
                Categories
                Subject: Review Articles

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: adult t-cell leukemia-lymphoma,allogeneic hematopoietic stem cell transplantation,antiviral therapy,chemotherapy,molecular targeted therapy
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: adult t-cell leukemia-lymphoma, allogeneic hematopoietic stem cell transplantation, antiviral therapy, chemotherapy, molecular targeted therapy

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