Evaluation of Navitoclax (ABT-263) as a promising Therapy for Pediatric Acute Myeloid Leukemia

Despite therapeutic advancements for pediatric AML, relapse rate remains high, particularly for leukemia with KMT2A aberration and Down syndrome-associated leukemia (ML-DS). This preclinical study explores Navitoclax (ABT-263) as a potential treatment for these vulnerable patient collectives. Four AML cell lines and leukemic blasts from eight pediatric AML patients underwent escalating ABT-263 exposure, resulting in significant growth reduction (EC50 values: 93 nM). A therapeutic range (EC50: 1.2 µM in CD34+ cells) was identified. Western blot and shRNA experiments unveiled variable BCL-2 family expression profiles, while BH3 profiling illuminated apoptotic interactions. In vivo experiments demonstrated a favorable response and survival advantage in KMT2A aberration after a 21-day treatment, while ML-DS remained unresponsive to ABT-263. ABT-263 emerges as a promising therapy for KMT2A aberration, with BH3 profiling aiding therapeutic response estimation. By highlighting apoptosis dysregulation in childhood AML, this study suggests unexplored therapeutic avenues, contributing to the optimization of treatments for high-risk pediatric AML.