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

Abstract

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.

Keywords: ATLL; HAM/TSP; HTLV-1; SMR; prognosis.

Fig. 1.

Representative expression patterns of CADM1/CD7 and Southern blot analysis in patients with HAM/TSP. Each Left panel shows a representative flow cytometric plot of CADM1 and CD7 expression in CD4⁺ T cells among PBMCs. Each Right panel shows a Southern blot analysis using the HTLV-1 probe. Patients with HAM/TSP tend to have the flow cytometry pattern (CADM1⁺CD7^dim > CADM1⁺CD7^neg) shown in A with a smear Southern blot pattern. B and C represent patients with HAM/TSP at a potential risk for ATLL who have a positive clonal band. D shows the flow-cytometric pattern of the patient in C who developed ATLL after 2 y and 4 mo. The arrows point to the major clone. E, EcoRI digestion; F, flanking band; P, PstI digestion; S, smear. (A) HAM/TSP, (B and C) HAM/TSP at potential risk for ATLL, and (D) both HAM/TSP and ATLL.

Fig. 2.

Clonality analysis of HTLV-1–infected cells using next-generation sequencing. The pie charts show the relative frequency of each integrations site (n = 27). For example, the percentage of the major clone (shown in blue) found in HAM1 patient was 41.3% and was located on chromosome 16. *For HAM25 post ATLL, the cells for analysis were gated for CADM1-positive, CD7-negative cells. Chr of MC, chromosomal location of the major clone.