Paper Details

ABSTRACT

INTRODUCTION

Adult T-cell leukemia/lymphoma (ATL) is a rare T-cell lymphoma with limited treatment options. The aggressive ATL subtypes (i.e., acute and lymphomatous) have dismal outcomes and typically progress before completion of planned therapy. As a result, early treatment failure may occur before standard assessment, limiting the utility of conventional clinical response endpoints. Therefore, we developed and externally validated a time-based endpoint to inform clinical decision-making.

METHODS

We conducted a retrospective cohort study of adults (≥18 years) with newly diagnosed acute or lymphomatous ATL during 2000-2023 who received first-line treatment with curative intent. The clinical endpoint was developed using data from a Latin American cohort (n=268) and was externally validated with cohorts from the United States (US; n=216) and Japan (n=246). The US and Japan cohorts were assessed separately due to the differences in ATL subtype prevalence and treatment approaches across regions.

Early treatment failure was defined as disease progression or death within 4 months of diagnosis (i.e., ATL4) and was selected as the clinical endpoint of interest. Alternative landmark definitions at 2, 3, 4, and 5 months were also tested, but the 4-month landmark was selected based on clinical applicability, sample size, and a trade-off between stable Hazard ratios (HRs) and observable events at each landmark. The primary endpoint was overall survival (OS). Survival estimates were assessed with the Kaplan-Meier method, and curves were compared with the Long-rank test. The effect of ATL4 on OS was assessed through a landmark analysis. Patients who died or whose follow-up time did not reach the landmark timepoint were excluded from this analysis. Multivariable Cox regressions were fitted, adjusting for age, sex, performance status, serum LDH values, and ATL subtypes. Likelihood ratio test were used to assess heterogeneity.

RESULTS

Of the 268 patients in the Latin American (i.e., training) cohort, the median age at diagnosis was 53 years (range 20-91 years), 53% were female, 63% had ECOG performance status score 0-1, 70% had B symptoms, 84% had high serum LDH values, 38% had hypercalcemia, and 63% had lymphomatous ATL. Chemotherapy alone was the most frequent first-line approach (57%), followed by chemotherapy with zidovudine/interferon alpha (AZT/IFN) (26%) and AZT/IFN alone (17%).

At 4 months after diagnosis in the training cohort, 177 patients were eligible for the landmark analysis. A total of 25 (9%) patients had a positive ATL4 (i.e., disease progression) and were alive. With a median follow-up of 33 months, ATL4 was associated with inferior 2-year OS (4% vs. 36%; adjusted Hazard Ratio [HR]=3.14, 95% confidence interval [CI]=1.77-5.56). The multivariable Cox model identified that B symptoms (HR=2.28, 95% CI=1.33-3.93), ECOG score of 2-4 (HR=1.78, 95% CI=1.18-2.68), and acute ATL (HR=1.56, 95% CI=1.01-2.40) were prognostic factors for ATL4.

In the validation cohorts, the proportion of patients with a positive ATL4 was 27% in the US and 39% in Japan. Similarly, ATL4 was associated with inferior 2-year OS in the US (20% vs. 37%; adjusted HR=1.90, 95% CI=1.12-3.21) and Japan (8% vs. 29%; adjusted HR=2.52, 95% CI=1.81-3.53) cohorts. The HRs across the training and validation cohorts were statistically similar (P _{for heterogeneity}=0.125), suggesting a constant effect across diverse populations

CONCLUSION

ATL4 consistently identified patients with early treatment failure and markedly inferior survival across three independent international cohorts, establishing its reproducibility and external validity. Given the aggressive natural history of ATL and the high frequency of progression before conventional response assessment, these findings question the suitability of objective response rate as the principal efficacy endpoint in aggressive ATL. Incorporating early time-based endpoints such as ATL4 into clinical trials may better reflect clinically meaningful benefit, facilitate earlier treatment modification, and improve the evaluation and approval of novel therapies in ATL management.