Temporal trends and future projections of sepsis mortality in leukemia: A nationwide analysis of demographic and geographic disparities (1999–2030)

Abstract Background: Leukemia is a hematologic malignancy characterized by the uncontrolled proliferation of leukocytes, and it is broadly classified as myeloid or lymphoid based on its cellular origin.Patients with leukemia are at increased risk of sepsis due to disease-related and treatment-induced immunosuppression, making sepsis a significant contributor to morbidity and mortality in this population. Understanding trends in sepsis-related mortality among leukemia patients is critical for early recognition, timely intervention, and improved survival outcomes. Methods: We conducted a retrospective, population-based analysis using the CDC WONDER Multiple Cause of Death database to examine sepsis-related mortality among leukemia patients in the United States from 1999 to 2023. Age-adjusted mortality rates (AAMRs) were calculated per million population using U.S. Census data as the denominator. Temporal trends were assessed using Joinpoint regression models to estimate the average annual percent change (AAPC). To forecast future mortality trends from 2024 to 2030, we applied autoregressive integrated moving average (ARIMA) models with Box-Cox transformation, following stationarity tests using the Augmented Dickey-Fuller (ADF) and Kwiatkowski–Phillips–Schmidt–Shin (KPSS) methods. Model performance was validated through residual diagnostics. Subgroup analyses were stratified by sex, race, ethnicity, geographic region, and urbanization level. Results: Between 1999 and 2023, the overall age-adjusted mortality rate (AAMR) in the United States declined from 4.9 to 4.1 per million. Both genders experienced decreases, with AAMR in females falling from 3.4 to 2.7 per million, a 20% reduction, and in males from 7.1 to 5.9 per million, marking a 16.9% decline. By race and ethnicity, White individuals saw a decrease from 4.9 to 4.2 per million, while Black individuals experienced a decline from 5.5 to 4.2 per million, with a notable drop to 3.7 in 2015 (a 32.7% decrease) and 3.9 in 2020 (a 29% decrease). The Asian or Pacific Islander population showed a decline from 3.3 to 2.6 per million. Hispanic or Latino individuals saw their AAMR fall from 3.8 to 3.2, reaching a significant low of 2.5 in 2004. Non-Hispanic individuals also showed a decrease from 4.9 to 4.2 per million. Regionally, the Northeast experienced the greatest improvement, with AAMR dropping from 6.0 to 4.0 per million. The Midwest declined from 4.5 to 3.9, the South from 4.8 to 4.3, and the West showed a modest decrease from 4.3 to 4.1 per million. Urbanization trends revealed increases in AAMRs in non-metro areas (from 4.0 to 4.6 per million) and medium metro areas (from 4.2 to 4.5), while central metro areas experienced a notable decline, from 5.4 to 4.3. Micropolitan regions saw a slight decrease from 4.7 to 4.5, and small metro areas experienced a minor increase from 4.5 to 4.6. Based on ARIMA modeling, the AAMR for sepsis-related mortality in Leukemia is projected to continue rising steadily. Forecasted rates include 4.3 per million in 2024, 2026, 2028, and 2030 (95% CI: 3.91–5.17), suggesting a persistent trend. Conclusions: The Mortality rates due to Leukemia associated sepsis have declined over the past two decades. However, there were significant disparities observed across genders, races, geographic regions, and urbanization levels. Particularly, rural and certain suburban populations have experienced rising or stagnant rates, highlighting areas of concern. Furthermore, projected forecasts exhibited a rising trend till 2030. These findings emphasize the need for targeted interventions in high-risk areas and improved social determinants of health.