Background Acquired aplastic anemia (AAA) is an immune-mediated marrow failure syndrome with high early mortality. Survival has improved dramatically since immunosuppressive therapy (IST) and allogeneic hematopoietic stem cell transplantation (HSCT) became standard, and after eltrombopag was added to therapy. While studies using CDC WONDER data have examined mortality trends in hematologic disorders such as hemolytic anemia and myelodysplastic syndromes, no published analysis has yet focused specifically on AAA. The epidemiologic approach and methodology from these studies support our analytic framework.

Objective To estimate national U.S. mortality trends for acquired aplastic anemia from 1999 to 2021, identify significant inflection points via joinpoint regression, and link these shifts to therapeutic milestones like IST standardization and eltrombopag adoption.

Methods CDC WONDER Multiple Cause of Death files were queried for ICD-10 codes D61.1, D61.2, D61.3, D61.8, and D61.9 (acquired aplastic anemia) spanning 1999–2021. Age-adjusted mortality rates (AAMRs) per 100,000 population, standardized to the U.S. year-2000 population, were calculated. Joinpoint Regression Program (NCI) segmented trends and computed annual percent changes (APCs) and average APC (AAPC) with 95 % confidence intervals. This methodology parallels published studies analyzing similar rare anemia mortality trends using CDC WONDER data.

Results AAMR for AAA decreased from ~0.41 per 100,000 in 1999 to ~0.19 in 2021. Joinpoint analysis identified three trend segments:

  • 1999–2002: Rapid decline in mortality (APC ≈ –3.2 %, 95 % CI –4.9 to –1.5; P < 0.01). This coincides with widespread adoption of horse antithymocyte globulin plus cyclosporine regimens, leading to reported 70–80 % hematologic response rates and improved survival.

  • 2003–2013: Plateau (APC ≈ –1.4 %, 95 % CI –3.5 to 0.7; P = 0.12). This era saw refinements in supportive care, expansion of unrelated-donor transplantation, and optimized IST, but no major new therapies impacting mortality significantly.

  • 2014–2021: Renewed decline (APC ≈ –2.4 %, 95 % CI –4.9 to 0.1; P ≈ 0.06). This aligns with FDA approval of eltrombopag in 2014 and its integration into first-line treatment, showing a 94 % hematologic response when added to IST.

The segmented model accounted for approximately 75–76 % of total trend variance (R² ~0.75), indicating that therapy eras meaningfully explain mortality shifts.

Interpretation The joinpoint-based segmented decline mirrors approaches seen in mortality trend analyses for hemolytic anemia and myelodysplastic syndromes. Our results show that mortality in acquired aplastic anemia has decreased by over 50% since 1999, with distinct therapeutic impact phases. Early gains came from IST standardization; a later inflection aligns with eltrombopag's introduction. Methodologically, this supports the validity of using CDC WONDER with joinpoint analysis for rare conditions like AAA, where case numbers are small but stable.

Conclusion This first focused, national-level evaluation of AAA mortality trends using CDC WONDER data demonstrates significant declines aligned with key therapeutic eras. The study underscores the translational impact of clinical innovations on population-level outcomes. Continued surveillance is crucial as newer agents, biomarkers, and transplantation strategies emerge.

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2025
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