Prognostic significance of therapy-induced senescence and SASP dynamics in acute myeloid leukemia: a retrospective cohort study

Chemotherapy constitutes the backbone of Acute Myeloid Leukemia (AML) treatment but often induces cellular senescence. While senescence initially halts tumor proliferation, the accumulation of senescent cells and the Senescence-Associated Secretory Phenotype (SASP) may promote leukemic survival and relapse. The clinical correlation between post-treatment senescence burden and AML prognosis remains poorly characterized.

We conducted a single-center retrospective study analyzing 128 newly diagnosed AML patients treated with standard induction chemotherapy between January 2019 and December 2023. Bone marrow samples were assessed at diagnosis and post-induction. Senescent cell burden was quantified via p16^INK4a and p21^Cip1 expression, alongside Senescence-Associated β-galactosidase (SA-β-gal) activity using flow cytometry. Immune sub-clustering was performed to evaluate senescence in progenitor versus mature populations. SASP factors (IL-6, IL-8, TNF-α) were measured in bone marrow plasma by ELISA. Patients were stratified into High-Senescence and Low-Senescence groups based on median cut-off values.

Induction chemotherapy significantly increased the proportion of senescent cells and normalized SASP levels compared to baseline (P < 0.001), with LSC progenitors exhibiting the highest senescence burden. High post-induction senescence burden was positively correlated with adverse cytogenetics and minimal residual disease (MRD) positivity. Senescence markers strongly correlated with IL-6 and IL-8, but not TNF-α. Patients in the High-Senescence group exhibited significantly inferior Event-Free Survival (median EFS: 8.5 vs. 18.2 months, P = 0.002) and Overall Survival (median OS: 14.2 vs. 26.5 months, P = 0.004). Multivariate Cox regression identified high IL-6 levels (HR 2.14, 95% CI 1.32–3.48) and elevated p16^INK4a (HR 1.98, 95% CI 1.15–3.40) as independent predictors of poor prognosis.

Therapy-induced senescence creates a pro-tumoral microenvironment via SASP in AML. High senescence burden post-induction is a robust biomarker for poor outcomes, suggesting that senolytic strategies targeting these cells could improve therapeutic efficacy.