{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T01:31:51Z","timestamp":1785461511304,"version":"3.56.0"},"reference-count":39,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2023,4,24]],"date-time":"2023-04-24T00:00:00Z","timestamp":1682294400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"name":"Practical Research Project"},{"name":"Medical Research and Development","award":["JP20ek0109346"],"award-info":[{"award-number":["JP20ek0109346"]}]},{"name":"Medical Research and Development","award":["JP22ek0109529"],"award-info":[{"award-number":["JP22ek0109529"]}]},{"name":"Health and Labour Sciences Research"},{"DOI":"10.13039\/501100003478","name":"Ministry of Health, Labour and Welfare of Japan","doi-asserted-by":"publisher","award":["JPMH22FC1013"],"award-info":[{"award-number":["JPMH22FC1013"]}],"id":[{"id":"10.13039\/501100003478","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Some carriers of human T-cell leukaemia virus type 1 (HTLV-1), a retrovirus that primarily infects CD4+ T cells and causes lifelong infection, develop HTLV-1-associated myelopathy\/tropical spastic paraparesis (HAM\/TSP). Current treatments for HAM\/TSP are insufficient with problematic long-term side effects. This study evaluated the long-term safety and efficacy of the anti-CCR4 antibody mogamulizumab in patients with HAM\/TSP over a 4-year period.<\/jats:p>\n               <jats:p>We conducted an open-label, extended long-term study (UMIN trial number: UMIN000019942) of a phase 1\u20132a trial with mogamulizumab for HAM\/TSP (UMIN000012655). The study participants were patients with corticosteroid-resistant HAM\/TSP who could walk 10 m with or without assistive tools. Mogamulizumab was administered at 0.01, 0.03, 0.1 or 0.3 mg\/kg at intervals of \u22658 weeks (0.01 and 0.03 mg\/kg) or \u226512 weeks (0.1 and 0.3 mg\/kg). HTLV-1 proviral load, CSF inflammatory markers and clinical symptoms were summarized by descriptive statistics. Missing observations were imputed using the last-observation-carried-forward method. As a post hoc analysis, we evaluated the therapeutic effect of mogamulizumab on gait function by comparing it with contemporary control data from a HAM\/TSP patient registry.<\/jats:p>\n               <jats:p>Of the 21 participants in the phase 1\u20132a, 18 (86%) enrolled in the long-term study and 15 (71%) continued repeated doses of mogamulizumab for 4 years. The median dose was 0.1 mg\/kg after 4 years. Seventeen of 21 participants (81%) experienced grade 1\u20132 skin-related adverse events. Observed grade 3 drug-related adverse effects included three cases of lymphopenia and one case each of microscopic polyangiitis, elevated levels of aspartate aminotransferase, and neutropenia. Four of 21 participants (19%) developed neutralizing antibodies. After 4 years, the peripheral blood proviral load and the number of infected cells in CSF decreased by 60.7% and 66.3%, respectively. Neopterin and CXCL10 CSF concentrations decreased by 37.0% and 31.0%, respectively. Among the 18 participants, spasticity and Osame Motor Disability Score (OMDS) improved in 17 (94%) and four (22%), respectively. However, 10 m walking time worsened by 7.3% on average. Comparison with the contemporary control group demonstrated that mogamulizumab inhibited OMDS progression (P = 0.02).<\/jats:p>\n               <jats:p>The results of the study suggest that mogamulizumab has long-term safety and inhibitory effects on lower limb motor disability progression in corticosteroid-treated patients with HAM\/TSP. This will provide a basis for the application of mogamulizumab in HAM\/TSP treatment.<\/jats:p>","DOI":"10.1093\/brain\/awad139","type":"journal-article","created":{"date-parts":[[2023,4,24]],"date-time":"2023-04-24T17:53:35Z","timestamp":1682358815000},"page":"3181-3191","source":"Crossref","is-referenced-by-count":11,"title":["Long-term safety and efficacy of mogamulizumab (anti-CCR4) for treating virus-associated myelopathy"],"prefix":"10.1093","volume":"146","author":[{"given":"Tomoo","family":"Sato","sequence":"first","affiliation":[{"name":"Department of Rare Diseases Research, Institute of Medical Science, St. Marianna University School of Medicine , Kawasaki, Kanagawa 216-8512 , Japan"},{"name":"Department of Neurology, St. Marianna University School of Medicine , Kawasaki, Kanagawa 216-8511 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junji","family":"Yamauchi","sequence":"additional","affiliation":[{"name":"Department of Rare Diseases Research, Institute of Medical Science, St. Marianna University School of Medicine , Kawasaki, Kanagawa 216-8512 , Japan"},{"name":"Department of Neurology, St. Marianna University School of Medicine , Kawasaki, Kanagawa 216-8511 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoko","family":"Yagishita","sequence":"additional","affiliation":[{"name":"Department of Rare Diseases Research, Institute of Medical Science, St. Marianna University School of Medicine , Kawasaki, Kanagawa 216-8512 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natsumi","family":"Araya","sequence":"additional","affiliation":[{"name":"Department of Rare Diseases Research, Institute of Medical Science, St. Marianna University School of Medicine , Kawasaki, Kanagawa 216-8512 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoki","family":"Takao","sequence":"additional","affiliation":[{"name":"Department of Neurology, St. Marianna University School of Medicine , Kawasaki, Kanagawa 216-8511 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuki","family":"Ohta","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, St. Marianna University School of Medicine , Kawasaki, Kanagawa 216-8511 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eisuke","family":"Inoue","sequence":"additional","affiliation":[{"name":"Showa University Research Administration Center, Showa University , Shinagawa-ku, Tokyo 142-8555 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaki","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Medical Informatics, St. Marianna University School of Medicine , Kawasaki, Kanagawa 216-8511 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makoto","family":"Yamagishi","sequence":"additional","affiliation":[{"name":"Laboratory of Tumor Cell Biology, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo , Minato-ku, Tokyo 108-8639 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yutaka","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Laboratory of Systems Genomics, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo , Kashiwa, Chiba 277-8561 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaoru","family":"Uchimaru","sequence":"additional","affiliation":[{"name":"Laboratory of Tumor Cell Biology, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo , Minato-ku, Tokyo 108-8639 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoki","family":"Matsumoto","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, St. Marianna University School of Medicine , Kawasaki, Kanagawa 216-8511 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuhiro","family":"Hasegawa","sequence":"additional","affiliation":[{"name":"Department of Neurology, St. Marianna University School of Medicine , Kawasaki, Kanagawa 216-8511 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshihisa","family":"Yamano","sequence":"additional","affiliation":[{"name":"Department of Rare Diseases Research, Institute of Medical Science, St. Marianna University School of Medicine , Kawasaki, Kanagawa 216-8512 , Japan"},{"name":"Department of Neurology, St. Marianna University School of Medicine , Kawasaki, Kanagawa 216-8511 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,4,24]]},"reference":[{"key":"2023080120202309000_awad139-B1","doi-asserted-by":"crossref","first-page":"7415","DOI":"10.1073\/pnas.77.12.7415","article-title":"Detection and isolation of type C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma","volume":"77","author":"Poiesz","year":"1980","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2023080120202309000_awad139-B2","doi-asserted-by":"crossref","first-page":"388","DOI":"10.3389\/fmicb.2012.00388","article-title":"Epidemiological aspects and world distribution of HTLV-1 infection","volume":"3","author":"Gessain","year":"2012","journal-title":"Front Microbiol"},{"key":"2023080120202309000_awad139-B3","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1016\/S0140-6736(85)92734-5","article-title":"Antibodies to human T-lymphotropic virus type-I in patients with tropical spastic paraparesis","volume":"2","author":"Gessain","year":"1985","journal-title":"Lancet"},{"key":"2023080120202309000_awad139-B4","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1016\/S0140-6736(86)91298-5","article-title":"HTLV-I associated myelopathy, a new clinical entity","volume":"1","author":"Osame","year":"1986","journal-title":"Lancet"},{"key":"2023080120202309000_awad139-B5","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1182\/blood.V50.3.481.481","article-title":"Adult T-cell leukemia: Clinical and hematologic features of 16 cases","volume":"50","author":"Uchiyama","year":"1977","journal-title":"Blood"},{"key":"2023080120202309000_awad139-B6","doi-asserted-by":"crossref","first-page":"6476","DOI":"10.1073\/pnas.78.10.6476","article-title":"Adult T-cell leukemia: Antigen in an ATL cell line and detection of antibodies to the antigen in human sera","volume":"78","author":"Hinuma","year":"1981","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2023080120202309000_awad139-B7","doi-asserted-by":"crossref","first-page":"1211","DOI":"10.1182\/blood-2009-12-257410","article-title":"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","volume":"116","author":"Iwanaga","year":"2010","journal-title":"Blood"},{"issue":"1\u20132","key":"2023080120202309000_awad139-B8","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.jns.2005.05.010","article-title":"HTLV-1 proviral load in peripheral blood mononuclear cells quantified in 100 HAM\/TSP patients: A marker of disease progression","volume":"237","author":"Olindo","year":"2005","journal-title":"J Neurol Sci"},{"key":"2023080120202309000_awad139-B9","doi-asserted-by":"crossref","first-page":"586","DOI":"10.3109\/13550289809114225","article-title":"Analysis of HTLV-I proviral load in 202 HAM\/TSP patients and 243 asymptomatic HTLV-I carriers: High proviral load strongly predisposes to HAM\/TSP","volume":"4","author":"Nagai","year":"1998","journal-title":"J Neurovirol"},{"key":"2023080120202309000_awad139-B10","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1080\/13550280152403272","article-title":"HTLV-I proviral load correlates with progression of motor disability in HAM\/TSP: Analysis of 239 HAM\/TSP patients including 64 patients followed up for 10 years","volume":"7","author":"Matsuzaki","year":"2001","journal-title":"J Neurovirol"},{"key":"2023080120202309000_awad139-B11","doi-asserted-by":"crossref","first-page":"15012","DOI":"10.1038\/nrdp.2015.12","article-title":"HTLV-1-associated myelopathy\/tropical spastic paraparesis","volume":"1","author":"Bangham","year":"2015","journal-title":"Nat Rev Dis Primers"},{"key":"2023080120202309000_awad139-B12","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1186\/s13023-019-1212-4","article-title":"Real-world clinical course of HTLV-1-associated myelopathy\/tropical spastic paraparesis (HAM\/TSP) in Japan","volume":"14","author":"Tsutsumi","year":"2019","journal-title":"Orphanet J Rare Dis"},{"key":"2023080120202309000_awad139-B13","doi-asserted-by":"crossref","first-page":"1207","DOI":"10.3389\/fmicb.2020.01207","article-title":"Diagnostic approaches and established treatments for adult T cell leukemia lymphoma","volume":"11","author":"Tsukasaki","year":"2020","journal-title":"Front Microbiol"},{"key":"2023080120202309000_awad139-B14","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1080\/14712598.2019.1572746","article-title":"Development of new agents for peripheral T-cell lymphoma","volume":"19","author":"Ito","year":"2019","journal-title":"Expert Opin Biol Ther"},{"key":"2023080120202309000_awad139-B15","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1002\/hon.2850","article-title":"Cutaneous T-cell lymphomas-an update 2021","volume":"39","author":"Kempf","year":"2021","journal-title":"Hematol Oncol"},{"key":"2023080120202309000_awad139-B16","doi-asserted-by":"crossref","first-page":"2876","DOI":"10.1093\/brain\/awt183","article-title":"Positive feedback loop via astrocytes causes chronic inflammation in virus-associated myelopathy","volume":"136","author":"Ando","year":"2013","journal-title":"Brain"},{"key":"2023080120202309000_awad139-B17","doi-asserted-by":"crossref","first-page":"3431","DOI":"10.1172\/JCI75250","article-title":"HTLV-1 induces a Th1-like state in CD4 + CCR4+ T cells","volume":"124","author":"Araya","year":"2014","journal-title":"J Clin Invest"},{"key":"2023080120202309000_awad139-B18","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.jneuroim.2016.08.012","article-title":"HTLV-1 induces a Th1-like state in CD4 + CCR4+ T cells that produces an inflammatory positive feedback loop via astrocytes in HAM\/TSP","volume":"304","author":"Yamano","year":"2017","journal-title":"J Neuroimmunol"},{"key":"2023080120202309000_awad139-B19","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1093\/infdis\/jiu438","article-title":"Mogamulizumab, an anti-CCR4 antibody, targets human T-lymphotropic virus type 1-infected CD8 + and CD4+ T cells to treat associated myelopathy","volume":"211","author":"Yamauchi","year":"2015","journal-title":"J Infect Dis"},{"key":"2023080120202309000_awad139-B20","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1056\/NEJMoa1704827","article-title":"Mogamulizumab (anti-CCR4) in HTLV-1-associated myelopathy","volume":"378","author":"Sato","year":"2018","journal-title":"N Engl J Med"},{"key":"2023080120202309000_awad139-B21","doi-asserted-by":"crossref","first-page":"11685","DOI":"10.1073\/pnas.1920346117","article-title":"Mortality and risk of progression to adult T cell leukemia\/lymphoma in HTLV-1-associated myelopathy\/tropical spastic paraparesis","volume":"117","author":"Nagasaka","year":"2020","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2023080120202309000_awad139-B22","first-page":"191","volume-title":"Human retrovirology: HTLV","author":"Osame","year":"1990"},{"key":"2023080120202309000_awad139-B23","doi-asserted-by":"crossref","first-page":"1549","DOI":"10.1016\/S0022-5347(17)36966-5","article-title":"The American urological association symptom index for benign prostatic hyperplasia. The Measurement Committee of the American Urological Association","volume":"148","author":"Barry","year":"1992","journal-title":"J Urol"},{"key":"2023080120202309000_awad139-B24","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1016\/j.urology.2006.02.042","article-title":"Symptom assessment tool for overactive bladder syndrome--overactive bladder symptom score","volume":"68","author":"Homma","year":"2006","journal-title":"Urology"},{"key":"2023080120202309000_awad139-B25","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1002\/nau.20041","article-title":"ICIQ: A brief and robust measure for evaluating the symptoms and impact of urinary incontinence","volume":"23","author":"Avery","year":"2004","journal-title":"Neurourol Urodyn"},{"key":"2023080120202309000_awad139-B26","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1016\/j.urology.2003.10.019","article-title":"Development and validation of a quality-of-life measure for men with nocturia","volume":"63","author":"Abraham","year":"2004","journal-title":"Urology"},{"key":"2023080120202309000_awad139-B27","doi-asserted-by":"crossref","first-page":"2851","DOI":"10.1158\/1078-0432.CCR-13-3169","article-title":"CADM1 Expression and stepwise downregulation of CD7 are closely associated with clonal expansion of HTLV-I-infected cells in adult T-cell leukemia\/lymphoma","volume":"20","author":"Kobayashi","year":"2014","journal-title":"Clin Cancer Res"},{"key":"2023080120202309000_awad139-B28","doi-asserted-by":"crossref","DOI":"10.1371\/journal.ppat.1005560","article-title":"CADM1\/TSLC1 Identifies HTLV-1-infected cells and determines their susceptibility to CTL-mediated lysis","volume":"12","author":"Manivannan","year":"2016","journal-title":"PLoS Pathog"},{"key":"2023080120202309000_awad139-B29","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1186\/s13023-016-0451-x","article-title":"Nation-wide epidemiological study of Japanese patients with rare viral myelopathy using novel registration system (HAM-net)","volume":"11","author":"Coler-Reilly","year":"2016","journal-title":"Orphanet J Rare Dis"},{"key":"2023080120202309000_awad139-B30","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1111\/cas.12116","article-title":"Stevens-Johnson syndrome associated with mogamulizumab treatment of adult T-cell leukemia \/ lymphoma","volume":"104","author":"Ishida","year":"2013","journal-title":"Cancer Sci"},{"key":"2023080120202309000_awad139-B31","doi-asserted-by":"crossref","first-page":"17945","DOI":"10.1073\/pnas.1316796110","article-title":"Anti-CCR4 mAb selectively depletes effector-type FoxP3 + CD4 + regulatory T cells, evoking antitumor immune responses in humans","volume":"110","author":"Sugiyama","year":"2013","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2023080120202309000_awad139-B32","doi-asserted-by":"crossref","first-page":"4388","DOI":"10.1158\/1078-0432.CCR-18-2575","article-title":"Mogamulizumab treatment elicits autoantibodies attacking the skin in patients with adult T-cell leukemia-lymphoma","volume":"25","author":"Suzuki","year":"2019","journal-title":"Clin Cancer Res"},{"key":"2023080120202309000_awad139-B33","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/j.neurol.2011.12.006","article-title":"Tropical spastic paraparesis and HTLV-1 associated myelopathy: Clinical, epidemiological, virological and therapeutic aspects","volume":"168","author":"Gessain","year":"2012","journal-title":"Rev Neurol (Paris)"},{"key":"2023080120202309000_awad139-B34","doi-asserted-by":"crossref","first-page":"136","DOI":"10.3390\/v14010136","article-title":"Efficacy of corticosteroid therapy for HTLV-1-associated myelopathy: A randomized controlled trial (HAMLET-P)","volume":"14","author":"Yamauchi","year":"2022","journal-title":"Viruses"},{"key":"2023080120202309000_awad139-B35","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1136\/jnnp-2019-321955","article-title":"Use of cerebrospinal fluid CXCL10 and neopterin as biomarkers in HTLV-1-associated myelopathy\/tropical spastic paraparesis treated with steroids","volume":"91","author":"Yamauchi","year":"2020","journal-title":"J Neurol Neurosurg Psychiatry"},{"key":"2023080120202309000_awad139-B36","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1002\/ijc.20144","article-title":"Role of HTLV-1 proviral DNA load and clonality in the development of adult T-cell leukemia\/lymphoma in asymptomatic carriers","volume":"110","author":"Okayama","year":"2004","journal-title":"Int J Cancer"},{"key":"2023080120202309000_awad139-B37","doi-asserted-by":"crossref","first-page":"3925","DOI":"10.1182\/blood-2014-02-553602","article-title":"The role of HTLV-1 clonality, proviral structure, and genomic integration site in adult T-cell leukemia\/lymphoma","volume":"123","author":"Cook","year":"2014","journal-title":"Blood"},{"key":"2023080120202309000_awad139-B38","doi-asserted-by":"crossref","first-page":"1195","DOI":"10.1182\/bloodadvances.2017005900","article-title":"Clonality of HTLV-1-infected T cells as a risk indicator for development and progression of adult T-cell leukemia","volume":"1","author":"Firouzi","year":"2017","journal-title":"Blood Adv"},{"key":"2023080120202309000_awad139-B39","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1038\/s42003-022-03467-w","article-title":"RAISING Is a high-performance method for identifying random transgene integration sites","volume":"5","author":"Wada","year":"2022","journal-title":"Commun Biol"}],"container-title":["Brain"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/brain\/advance-article-pdf\/doi\/10.1093\/brain\/awad139\/50424095\/awad139.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/brain\/article-pdf\/146\/8\/3181\/51018504\/awad139.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/brain\/article-pdf\/146\/8\/3181\/51018504\/awad139.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,1]],"date-time":"2023-08-01T20:35:54Z","timestamp":1690922154000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/brain\/article\/146\/8\/3181\/7137401"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,24]]},"references-count":39,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2023,4,24]]},"published-print":{"date-parts":[[2023,8,1]]}},"URL":"https:\/\/doi.org\/10.1093\/brain\/awad139","relation":{},"ISSN":["0006-8950","1460-2156"],"issn-type":[{"value":"0006-8950","type":"print"},{"value":"1460-2156","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2023,8]]},"published":{"date-parts":[[2023,4,24]]}}}