Venetoclax and new BCL-2 inhibitors in acute myeloid leukemia

The development of B-cell lymphoma-2 (BCL-2) inhibitors has totally revolutionized the management of acute myeloid leukemia (AML). These highly effective, small molecules trigger apoptosis in leukemia cells by specifically targeting the BCL-2 protein. Notably, venetoclax, an extremely high-affinity BCL-2 inhibitor, stands out particularly for its high therapeutic index, especially when combined with hypomethylating agents like azacytidine and decitabine, among older patients and even young patients with comorbidities that preclude intensive chemotherapy regimens. Once more, because the new AML model is evolving, venetoclax is being used more with high-intensity chemotherapy even in young patients, at any age.

This review summarizes the progress in AML targeting the intrinsic apoptosis pathway with current and developing BCL-2 inhibitors, as well as their clinical applications in combination therapies.

While venetoclax has made significant progress in treating AML, ongoing clinical research is moving this agent into first-line combination treatments. Notably, the lack of response to this agent and the development of acquired resistance remain significant concerns. Although specific gene mutations strongly predict clinical response, research is ongoing into predictive biomarkers and new drug combinations that work synergistically. Emerging therapies targeting BCL-2 also aim to maximize treatment benefits and address issues related to venetoclax resistance.