Clinical features and outcomes of adult T-cell leukemia/lymphoma across world regions: An international retrospective cohort study

Abstract Background: Adult T-cell leukemia/lymphoma (ATL) has a dismal prognosis and disproportionately affects regions endemic in Human T-lymphotropic virus-1 (HTLV-1) infection. While treatment approaches vary globally due to differences in drug approvals and resource availability, the impact of these variations on outcomes remains poorly understood, and no direct multinational comparisons have been performed. We compared clinical features and overall survival (OS) across Japan, South America, the United States (US), and the United Kingdom (UK). Methods: We conducted a cohort study using hospital-based data from the Brazilian T-cell project (2015-2022 period), Grupo de Estudio Latinoamericano de Linfoproliferativos registry (GELL, 2000-2023 period), Japanese cohort (2000-2008 period), US centers (2000-2023 period), and UK center (2003-2023 period). We included adult patients (≥18 years) with ATL and pathologically diagnosed with a T-cell lymphoma and/or leukemia as well as those with a positive serum test for HTLV-1. All patients were enrolled consecutively, except in the UK, where only those who consented to data transfer were included. The study endpoints were the distribution of ATL subtypes and OS (defined from diagnosis to death from any cause) across world regions. A multivariable Poisson model was used to compare the distribution of ATL subtypes across regions (Japan as the reference), adjusting for age. The lowest median follow-up (reverse Kaplan-Meier method) from these regions was used to estimate OS. We used the Kaplan-Meier method and the Log-rank test. Results: A total of 1173 patients had available data for clinical description analysis (366 from Japan, 365 from South America, 354 from the US, and 88 from the UK). The median age at diagnosis was the highest in Japan (66 years vs. 52-57 years across all regions; P<0.001). Acute ATL was significantly more frequent in Japan (n=215; 59%, 95% confidence interval [CI]=54-64%) compared to the US (n=123; 45%, 95% CI=39-51%; P=0.016), South America (n=132; 36%, 95% CI=31-42%; P<0.0001), and the UK (n=20; 24%, 95% CI=14-35%; P<0.0001). In contrast, lymphomatous ATL was more frequently diagnosed in the UK (n=45; 53%, 95% CI=44-65%; P<0.0001), South America (n=186; 51%, 95% CI=46-57%; P<0.0001), and the US (n=125; 45%, 95% CI=39-52%; P<0.0001) compared to Japan (n=72; 20%, 95% CI=15-25%). The distribution of chronic (8-16%) and smoldering (2-8%) ATL was similar across regions, and sample sizes for these subtypes were <50 in most regions. Among 955 patients with available treatment and survival data, we observed distinct patterns. In acute ATL (n=418), chemotherapy alone was frequently used in Japan (97%), whereas chemotherapy was often combined with antiviral therapy plus interferon alpha (AI) in other regions (47-78%) (P<0.0001). For lymphomatous ATL (n=383), chemotherapy alone was favored in Japan (98%), the US (84%), and South America (61%), while chemotherapy with AI was more frequent in the UK (58%) (P<0.0001). Upfront hematopoietic cell transplantation use was the lowest in South America (1% vs. 11-15%; P=0.002) in acute ATL, while it was more frequently used for lymphomatous ATL in the UK (38% vs. 4-8%; P<0.001). For chronic ATL (n=107), AI alone was rarely used in Japan (4% vs. 21-64%; P<0.0001); and for smoldering ATL (n=47), a watchful waiting approach was used across all regions (25-61%; P=0.051). The median follow-up was 37 months (95% CI=30-46 months). The 3-year OS rates across regions were statistically similar and ranged 11-25% (P=0.050) for acute ATL, 15-34% (P=0.074) for lymphomatous ATL, and 60-83% (P=0.787) for smoldering ATL. Only the US (79%) and the UK (86%) had significantly higher 3-year OS rates compared to Japan (41%) and South America (49%) for chronic ATL (P=0.004). In sensitivity analysis, age-adjusted survival curves were consistent with the main findings. Conclusion: Despite regional variations in treatment approaches, OS remains poor for aggressive subtypes, underscoring the need to understand ATL biology and develop novel therapies through global collaboration. The distinct distribution of ATL subtypes, though requiring validation in population-based studies, could guide the design of international clinical studies by optimizing patient accrual for this rare disease.