Mortality and risk of progression to adult T cell leukemia/lymphoma in HTLV-1–associated myelopathy/tropical spastic paraparesis
Menée au Japon à partir de données portant sur 527 patients atteints d'une paraparésie spastique tropicale associée au virus T-lymphotropique humain et menée à partir d'échantillons sanguins prélevés sur une cohorte de 228 patients complémentaires, cette étude évalue le risque de progression de la maladie vers
une leucémie-lymphome à cellules T de l'adulte (ATLL), identifie les caractéristiques biologiques associées à cette progression et évalue l'effet d'une ATLL sur le pronostic
HTLV-1 manifests many diseases, which cause morbidity and mortality in 5
∼
10% of infected individuals, including the fatal adult T cell leukemia/lymphoma (ATLL) and debilitating myelopathy (HAM/TSP). However, the rarity of these diseases had made it prohibitory to conduct large-scale prospective observational studies. This work enabled calculating the standard mortality ratio of HAM/TSP patients and also identified ATLL as one of the major causes of death among these patients. We also identified the features that lead HAM/TSP patients to develop ATLL: having dominant clonal expansion of HTLV-1–infected cells with ATLL-associated somatic mutations. Furthermore, this manuscript describes genomic changes occurring in HAM/TSP patients at the actual time of their ATLL transformation.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.
Proceedings of the National Academy of Sciences , Article en libre accès, 2019