Synergistic efficacy and preliminary molecular mechanisms of venetoclax combined with microtransplantation in the treatment of elderly patients with Acute Myeloid Leukemia

Abstract Background: Elderly patients with acute myeloid leukemia (AML) have poor prognosis, which is attributed to multiple factors including unique biological characteristics and high expression of adverse prognostic genes. Venetoclax combined with hypomethylating agents has shown potential efficacy in the first-line treatment of elderly AML patients, but its effectiveness remains limited in refractory/relapsed AML. Therefore, there is an urgent need to explore safer and more effective alternative regimens. Currently, the combination of targeted therapy and immunotherapy has become a research hotspot in the field of AML, providing a new direction for improving the treatment prognosis of elderly patients with intermediate and high-risk AML. Methods: A total of 18 elderly patients with intermediate and high-risk AML who achieved remission after induction therapy were enrolled from the Department of Hematology, Zhujiang Hospital, between January 2020 and July 2024. The safety and efficacy of venetoclax combined with microtransplantation as a consolidation therapy regimen were systematically evaluated. Meanwhile, using AML cell lines as target cells, flow cytometry was employed to assess the in vitro cytotoxicity of natural killer (NK) cells and CD8⁺T cells in combination with venetoclax. Additionally, flow cytometry was used to detect venetoclax-induced expression of NKG2D/NKG2DL (natural killer group 2 member D/ligand) receptor-ligand, aiming to explore the anti-AML effect and underlying mechanism of venetoclax in synergy with microtransplantation. Results: Survival analysis of 18 elderly AML patients receiving venetoclax combined with microtransplantation showed that the 2-year overall survival (OS) rate was 77.8%, with a median OS of 53.0 months. Most patients exhibited mild to moderate hematological and non-hematological toxicities, and no acute or chronic graft-versus-host disease (GVHD) occurred. Flow cytometric analysis revealed that the combination of venetoclax with NK cells or CD8⁺T cells produced a synergistic anti-leukemic effect, which was attributed to venetoclax-induced upregulation of NKG2DL in AML cells and NKG2D in effector cells. These findings suggest that venetoclax enhances the cytotoxic activity of NK cells and CD8⁺T cells by activating the NKG2D/NKG2DL receptor-ligand pathway. Conclusions: Venetoclax combined with microtransplantation is a safe and effective consolidation therapy regimen, which can prolong the survival of elderly AML patients. This combination regimen has the potential for synergistic anti-AML effects, and venetoclax can enhance the cytotoxic activity of NK cells and CD8⁺T cells by activating the NKG2D/NKG2DL receptor-ligand pathway.