Background: Myelodysplastic syndromes (MDS) are clonal hematopoietic disorders characterized by ineffective hematopoiesis and a risk of progression to acute myeloid leukemia (AML). Approximately 30% of MDS cases transform into AML, with transformation rates ranging from about 20% in lower-risk subtypes to over 40% in higher-risk MDS subtypes. AML arising in the context of prior MDS (secondary AML) is associated with poorer prognosis and increased resistance to therapy. These challenges underscore the need for population-level analyses to better understand mortality outcomes in this high-risk group. Methods: Using the CDC WONDER Multiple Cause of Death database, we identified individuals with AML (ICD-10: C92.0) and MDS (ICD-10: D46). Age-adjusted mortality rates (AAMR), standardized to the 2000 U.S. population, were calculated per million individuals. Temporal trends were assessed using Joinpoint regression to estimate Average Annual Percent Change (AAPC) and determine statistical significance. For future projections, ARIMA models with Box-Cox transformation were applied after testing for stationarity using ADF/KPSS tests. Models were validated using residual diagnostics and cross-validation. Subgroup analyses were conducted on the basis of sex, race/ethnicity, U.S. census region, and urbanicity.Results: Between 1999 and 2023, a total of 17,387 deaths in the U.S. were attributed to coexisting MDS and AML among patients. The AAMR declined from 14.7 per million in 1999 to 12.4 per million in 2023, reflecting a net decrease of 15.6%. However, the trend was not uniform; the AAMR increased steadily during 2007–2013, peaking at 20.0 per million in 2009, before stabilizing in the mid-2010s and declining throughout the 2020s.

Gender-specific analyses revealed a consistently higher mortality burden among males, who accounted for 10,767 deaths compared to 6,620 among females. The AAMR for males declined from 22.5 to 17.4 per million (22.7% decrease), while the female AAMR decreased more modestly, from 9.6 to 8.6 per million (10.4% reduction). Despite these declines, male mortality remained nearly twice that of females in 2023.

White individuals accounted for the majority of deaths, with AAMR declining slightly from 14.2 to 12.5 per million. Black or African American individuals had persistently higher rates, increasing marginally from 17.1 to 17.4 per million. Asian or Pacific Islanders maintained stable and comparatively lower AAMRs throughout the study period, while American Indian/Alaska Native populations experienced fluctuating but overall rising trends, with rates increasing from 7.7 to 10.6 per million.

Ethnicity-specific trends showed a mild overall decline in AAMR among Hispanic patients, decreasing from 13.2 to 12.1 per million (8.3% reduction), despite fluctuations including a mid-period peak to 15.6 in 2018. In contrast, Non-Hispanic individuals had a more consistent downward trend, with AAMR decreasing from 15.7 to 13.4 per million (14.6% reduction).

The Midwest maintained the highest regional burden, with an AAMR of 15.1 per million in 2023, a slight decrease from 16.0 in 1999. The South and West regions experienced more pronounced declines, with AAMRs falling from 13.7 to 11.2 and from 22.5 to 12.8 per million, respectively. The Northeast remained relatively stable, with AAMR changing modestly from 12.6 to 11.8 per million. These findings highlight persistent regional disparities in care delivery and outcomes.

Lowest AAMRs were seen in large central metropolitan areas, decreasing from 14.5 to 11.8 per million. In contrast, rural non-core and micropolitan regions experienced higher mortality burdens, with AAMRs of 14.3 and 13.7, respectively, in 2023.

ARIMA forecasting through 2030 projects a gradual increase in AAMR for AML and MDS-related mortality, with expected rates of 15.68 per million in 2026, 15.82 in 2028, and 15.93 in 2030. These projections suggest a persistent and slowly increasing disease burden over the coming decade.

Conclusions: Overall, AML-related mortality among MDS patients has declined. However, significant disparities persist across gender, race, geography, and urbanization. Males, Black individuals, and rural populations continue to face elevated risks. Forecasting indicates that, without targeted interventions, this mortality burden may begin to rise again, reinforcing the urgent need for focused public health strategies.

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2025
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