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Venetoclax plus hypomethylating agents (HMAs) is a standard therapy for older or unfit patients with acute myeloid leukemia (AML); however, some patients exhibit suboptimal responses, potentially associated with T-cell exhaustion. Our preclinical findings that statins enhance HMA efficacy by boosting anti-tumor T-cell responses prompted us to translate this strategy to the clinic. A multicenter phase II clinical trial (ChiCTR 2500111931) was conducted to evaluate the efficacy and safety of adding rosuvastatin to venetoclax and azacitidine (venetoclax-azacitidine) in older/unfit AML patients. After induction therapy with this triple combination, the cohort achieved a complete response (CR) rate of 55.5% and a composite complete remission (CRc) rate of 72.2%. Among patients who achieved CRc, 84.6% attained measurable residual disease (MRD) < 10^-3. With a median follow-up of 10 months, the median overall survival (OS) and relapse-free survival (RFS) were 18 and 14 months, respectively. Although no significant changes in lipid profiles were observed, multiparametric flow cytometry revealed significant reductions in PD-1⁺CD4⁺ T cells (p = 0.0137) and PD-1⁺CD8⁺ T cells (p = 0.0277) after therapy. In vitro experiments revealed that the addition of rosuvastatin diminished both early (PD-1⁺TIM-3⁻) and terminally (PD-1⁺TIM-3⁺) exhausted T cells, suggesting it prevents the development of T-cell exhaustion induced by venetoclax-azacitidine. Furthermore, functional assays confirmed that rosuvastatin addition significantly enhanced T cell cytotoxicity against leukemia cells. Collectively, our findings suggest that adding rosuvastatin to venetoclax-azacitidine shows preliminary clinical activity and acceptable safety, possibly by reducing T-cell exhaustion, thus supporting further study of this triple regimen in older/unfit AML patients.