Background

Anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapy received its first U.S. approval for relapsed/refractory acute lymphoblastic leukemia (ALL) in late 2017. The extent to which this innovation reduced population-level mortality is unknown.

Methods

Multiple-cause-of-death data for ALL (ICD-10 C91.0), acute myeloid leukemia (AML, C92.), malignant brain tumors (C71), and malignant bone tumors (C40–C41) were extracted from CDC WONDER (query 10 July 2025). Sex-specific mortality rates per 100 000 were calculated for three age bands (0-14, 15-39, ≥40 years), yielding 12 prespecified strata. A pre-CAR-T era (1999-2016) and post-CAR-T era (2018-2023) were defined; 2017 was treated as the transition year. Post-2018 counterfactuals were generated with a gradient-boosted quantile-regression time-series model (LightGBM; 2.5th/97.5th quantiles). Causal attribution was assessed using (i) pairwise difference-in-differences (DiD) between ALL and each control tumor type and (ii) a synthetic triple-difference estimator that combined AML, brain, and bone mortality with non-negative weights learned from pre-period data (Σw = 1). Ninety-five-percent prediction intervals were reported for the machine-learning model.

Results

Between 1999 and 2023, the United States recorded 152 983 deaths from ALL (114 013 during the pre-CAR-T era and 38 970 after approval). Mean annual mortality fell in 11 of the 12 predefined age-and-sex strata; the steepest absolute decline occurred in men aged 40 years or older, dropping by 1.37 per 100 000 (an 18 percent reduction). Synthetic triple-difference testing confirmed a significant post-approval decrease across every stratum, with point estimates spanning 0.06 to 1.84 fewer deaths per 100 000. The largest effect again appeared in older men (1.84 per 100 000; donor mix AML 54 percent, bone 46 percent), while even the smallest subgroup, boys aged 0 to 14 years, showed a clear reduction of 0.057 per 100 000 (weights AML 51 percent, brain 21 percent, bone 29 percent).

Conclusions

U.S. nationwide mortality data show a rapid and clinically meaningful decline in ALL deaths temporally aligned with CAR-T dissemination, greatest among adults ≥ 40 years. Concordant findings from machine-learning forecasts, DiD, and synthetic triple-difference analyses using biologically related malignancies strengthen causal inference and support the real-world effectiveness of CAR-T therapy. Continued surveillance is warranted to evaluate durability and equitable access.

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2025
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