Abstract
Predictive biomarkers can potentially meet the need for improved drug assignment in acute myeloid leukemia (AML). Fewer than half of AML patients have actionable mutations: consequently, targeted therapy achieves remission in only a fraction of those who have them. Dynamic BH3 Profiling (DBP), a functional assay, can measure changes in ex vivo drug-induced apoptotic priming in multiple cancers. To assess the feasibility and predictive capacity of DBP in AML, we prospectively tested DBP using a fixed-drug panel in myeloblasts from 92 patients. We generated a database combining genetic and functional annotation. Established AML clinical and genetic prognostic characteristics were associated with drug-induced apoptotic priming. We observed distinct inter patient sensitivities to single drugs or combinations with the BCL2-inhibitor venetoclax, and intra patient apoptotic priming differences based on CD123-expression within distinct cell subpopulations. DBP further predicted the likelihood of remission to chemotherapy and targeted agents, supporting its use to identify optimal personalized therapy. STATEMENT OF SIGNIFICANCE: Dynamic BH3 profiling provides patient-specific drug vulnerability data in real-time to inform prognosis and therapy selection. KEY TAKEAWAYS: Dynamic BH3 profiling can be performed on bone marrow and leukemic blood from AML patients in 48 hours.Known clinical prognostic factors associate with drug-induced apoptotic priming in AML.Drug-induced apoptotic priming identifies drug vulnerabilities in individual patients and predicts clinical response to chemotherapy and small molecule inhibitors.