Evaluation of dual BCL-2/BCL-XL inhibition in acute myeloid leukemia preclinical models with and without prior venetoclax therapy.

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy that relies heavily on the antiapoptotic protein B-cell lymphoma 2 (BCL-2) for survival. Venetoclax, a BCL-2 inhibitor, exploits this dependency and is currently approved for treatment of elderly patients with AML. BCL-XL, another prosurvival protein in the BCL-2 family, has been identified as a key driver of both intrinsic and acquired resistance to venetoclax. Patients often develop resistance to BCL-2 inhibition through upregulation of BCL-XL. This study investigates the efficacy of a dual BCL-2/BCL-XL inhibitor and its combination with standard-of-care (SOC) agents. Dual BCL-2/BCL-XL inhibitor demonstrates robust activity in AML cell lines and patient-derived models, including activity in samples from patients who relapsed following venetoclax therapy. Its combination with SOC agents deepens the antileukemic activity both in vitro and in vivo. Among the combination regimens tested, cytarabine or hypomethylating agents (HMAs) drive strong blast reduction in patient samples previously exposed to venetoclax and yield improved survival in xenograft models derived from patients with AML who underwent prior venetoclax/5-azacytidine treatment. These preclinical findings support the clinical evaluation of dual BCL-2/BCL-XL inhibition in patients with AML, particularly, those who do not respond to venetoclax.