BH3 Profiling Discriminates Response to Cytarabine-based Treatment of Acute Myeloid Leukemia

摘要

As Acute Myeloid Leukemia (AML) patient response to cytarabine-based standard-of-care treatment is variable, stratification into subgroups by biomarker-predicted response may lead to improved clinical outcomes. Here we assess cell mitochondrial depolarization to pro-apoptotic signaling BH3-only peptides as a surrogate for the function of Bcl-2 family proteins to address clinical response to cytarabine-based therapy in AML patients (n=62). Peripheral blood mononuclear cell (PBMC) or bone marrow aspirate (BM) specimens were obtained from newly diagnosed AML patients, viably preserved, and assayed by flow cytometry following BH3 profile assay with individual BH3 peptides. Mann-Whitney analysis indicates biomarker correlation with response to induction therapy: notably BIM priming was highly significant (p=2×10⁻⁶) with a compelling sensitivity/specificity profile (AUC=0.83; CI[0.73,0.94]; p=2×10⁻¹⁰). Multivariate analysis indicates improved profiles for BIM readout + patient age (AUC=0.89; CI[0.81,0.97])and BIM + patient age +cytogenetic status (AUC=0.91; CI[0.83,0.98]). When patients were stratified by cytogenetic status, BIM readout was significant for both, intermediate (p=0.0017; AUC=0.88; CI[0.71,1.04]) and for unfavorable (p=0.023; AUC=0.79; CI[0.58,1.00]) risk groups, demonstrating predictive power independent of cytogenetics. Additional analyses of secondary clinical endpoints displayed correlation between overall survival (OS; p=0.037) and event-free survival (EFS; p=0.044) when patients were stratified into tertiles by BIM peptide response. Taken together, these results highlight the potential utility of BH3 profiling in personalized diagnostics of AML by offering actionable information for patient management decisions.