Global, regional, and national burden of acute leukemia and its risk factors from 1990 to 2021 and predictions to 2040: findings from the global burden of disease study 2021

Background Despite therapeutic advances, acute leukemia (AL) continues to impose a substantial global health burden, with persistently high incidence and mortality rates. Notably, the prediction is that the number of incidence and mortality of acute myeloid leukemia (AML) cases will continue to increase to 184,287.88 and 165,537.59, respectively, by 2040. Using Global Burden of Disease Study (GBD) 2021 data, we assessed the worldwide AL burden from 1990 to 2021, analyzing trends by sex to inform public health strategies. Methods To delineate the burden of AL, we reported incidence, prevalence, mortality, and disability-adjusted life year (DALY) rates at global, regional, and national levels, with these estimates including age-standardized rates (ASRs) per 100,000 population and average annual percentage changes (AAPCs) from 1990 to 2021 which were stratified by age, sex, and socio-demographic index (SDI), and computed ASRs and AAPCs using linear regression. Temporal trends were analyzed using an age-period-cohort (APC) model with intrinsic estimation (principal component regression). Risk factor attribution quantified contributions of 21 behavioral, environmental, and metabolic exposures to AL-related DALYs. For inequality assessment, we applied the Slope Index of Inequality and Concentration Index to evaluate absolute and relative disparities in AL burden across regions and countries. Future projections (2040) were modeled via a Bayesian APC framework with Integrated Nested Laplace Approximation. All statistical analyses were performed using R software (version R 4.4.1). The GATHER (Guidelines for Accurate and Transparent Health Estimates Reporting) statement provides a framework to ensure the transparency, reproducibility, and quality of health estimates reporting. Results Between 1990 and 2021, global ASRs of AL declined, except for acute lymphoblastic leukemia (ALL) age-standardized prevalence rates (ASPR) (AAPC 0.84, 95% CI 0.59-1.10). Case numbers rose overall, though ALL mortality and DALYs decreased. AML burden correlated positively with SDI (rho > 0, P < 0.001), with the highest number of incident and mortality cases in Western Europe. For ALL, SDI showed positive associations with ASIR and ASPR (rho > 0, P < 0.001) but negative correlations with ASMR and ASDALR (rho < 0, P < 0.001), with East Asia being the most severely affected region. High body mass index (BMI), smoking, and benzene/formaldehyde exposure were key AL DALY risk factors. High BMI and smoking predominate in developed countries, and the proportion of DALYs decreases progressively as SDI decreases. Occupational exposures prevailed in developing countries. Population growth drove most absolute increases. Males bore a greater AL burden. AML risk rose with age, whereas ALL displayed bimodal peaks (< 5 and > 40 years). Notably, while ASRs in AL are projected to decline slightly and the number of ALL to decrease by 2040, the number of AML is expected to increase, with the number of incidence and mortality cases increasing by 41.56% and 27.16%, respectively. Conclusion As a major public health concern, despite declining ALL-related mortality and DALYs (1990-2021), AL remains a growing global health challenge, with AML cases projected to rise significantly by 2040. Region-specific intervention strategies are required: high-SDI nations should prioritize smoking cessation and metabolic control to address smoking and high BMI-related AML risks while preparing for aging populations, whereas low/middle-SDI countries urgently need enhanced pediatric ALL diagnosis, treatment capacity, and occupational safety measures. Effective mitigation demands evidence-based health planning, including resource allocation guided by projected AL burden trends and targeted policy interventions to reduce healthcare disparities.