Mortality and risk of progression to adult T cell leukemia/lymphoma in HTLV-1-associated myelopathy/tropical spastic paraparesis.

Human T cell leukemia virus 1 (HTLV-1) causes the functionally debilitating disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) as well as adult T cell leukemia lymphoma (ATLL). Although there were concerns that the mortality of HAM/TSP could be affected by the development of ATLL, prospective evidence was lacking in this area. In this 5-y prospective cohort study, we determined the mortality, prevalence, and incidence of ATLL in 527 HAM/TSP patients. The standard mortality ratio of HAM/TSP patients was 2.25, and ATLL was one of the major causes of death (5/33 deaths). ATLL prevalence and incidence in these patients were 3.0% and 3.81 per 1,000 person-y, respectively. To identify patients at a high risk of developing ATLL, flow cytometry, Southern blotting, and targeted sequencing data were analyzed in a separate cohort of 218 HAM/TSP patients. In 17% of the HAM/TSP patients, we identified an increase in T cells positive for cell adhesion molecule 1 (CADM1), a marker for ATLL and HTLV-1-infected cells. Genomic analysis revealed that somatic mutations of HTLV-1-infected cells were seen in 90% of these cases and 11% of them had dominant clone and developed ATLL in the longitudinal observation. In this study, we were able to demonstrate the increased mortality in patients with HAM/TSP and a significant effect of ATLL on their prognosis. Having dominant clonal expansion of HTLV-1-infected cells with ATLL-associated somatic mutations may be important characteristics of patients with HAM/TSP who are at an increased risk of developing ATLL.

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Copyright © 2020 the Author(s). Published by PNAS.

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Competing interest statement: M.N. reports personal fees from AstraZeneca and grants from Tempus, outside the submitted work. E.I. reports personal fees from Merck Bio Pharma Japan, outside the submitted work. Y.Y. reports grants from Japan Agency for Medical Research and Development, grants from Ministry of Health, Labour and Welfare, and Japan Society for the Promotion of Science KAKENHI during the conduct of the study; grants from Daiichi Sankyo Co., Ltd.; grants from ONO Pharmaceutical Co., Ltd.; and grants from Kyowa Hakko Kirin, Japan, outside the submitted work; In addition, Y.Y. and N.A. have a patent “Medicine for Treating or Preventing HTLV-I-Related Myelopathy, and Method for Forecasting the Effect of Antibody Therapy for Patient of HTLV-I-Related Myelopathy” (Japan Patent 5552630 licensed to St. Marianna University School of Medicine). Y.Y. has a patent “Therapeutic Method and Medicament for HTLV-1-Associated Myelopathy (HAM)” (Japan Patent 6310845, US9,642,910, AUS2013285970 licensed to St. Marianna University School of Medicine, Kyowa Hakko Kirin, Japan); and a patent “Preventive or Therapeutic Agent for HTLV-1-Associated Myelopathy Using Low-Dose Anti-CCR4 Antibody” (Japan Patent 6430082 licensed to St. Marianna University School of Medicine, Kyowa Hakko Kirin, Japan). All other authors have no competing interests to disclose.