TY - JOUR
T1 - BH3 profiling discriminates response to cytarabine-based treatment of acute myelogenous leukemia
AU - Pierceall, William E.
AU - Kornblau, Steven M.
AU - Carlson, Nicole E.
AU - Huang, Xuelin
AU - Blake, Noel
AU - Lena, Ryan
AU - Elashoff, Michael
AU - Konopleva, Marina
AU - Cardone, Michael H.
AU - Andreeff, Michael A.
PY - 2013/12
Y1 - 2013/12
N2 - As acute myelogenous 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 proapoptotic signaling BH3-only peptides as a surrogate for the function of Bcl-2 family proteins to address clinical response to cytarabinebased therapy in patients with AML (N = 62). Peripheral blood mononuclear cell (PBMC) or bone marrow aspirate specimens were obtained from newly diagnosed patients with AML, 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 [area under curve (AUC) = 0.83; 95% confidence interval (CI), 0.73-0.94; P = 2 × 10 -10]. Multivariate analysis indicates improved profiles for BIM readout patient age (AUC = 0.89; 95% CI, 0.81-0.97) and BIM patient age cytogenetic status (AUC = 0.91; 95% 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; 95% CI, 0.71-1.04) and unfavorable (P = 0.023; AUC = 0.79; 95% CI, 0.58-1.00) risk groups, demonstrating predictive power independent of cytogenetics. Additional analyses of secondary clinical endpoints displayed correlation between overall survival (P = 0.037) and event-free survival (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. Mol Cancer Ther; 12(12); 2940-9.
AB - As acute myelogenous 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 proapoptotic signaling BH3-only peptides as a surrogate for the function of Bcl-2 family proteins to address clinical response to cytarabinebased therapy in patients with AML (N = 62). Peripheral blood mononuclear cell (PBMC) or bone marrow aspirate specimens were obtained from newly diagnosed patients with AML, 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 [area under curve (AUC) = 0.83; 95% confidence interval (CI), 0.73-0.94; P = 2 × 10 -10]. Multivariate analysis indicates improved profiles for BIM readout patient age (AUC = 0.89; 95% CI, 0.81-0.97) and BIM patient age cytogenetic status (AUC = 0.91; 95% 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; 95% CI, 0.71-1.04) and unfavorable (P = 0.023; AUC = 0.79; 95% CI, 0.58-1.00) risk groups, demonstrating predictive power independent of cytogenetics. Additional analyses of secondary clinical endpoints displayed correlation between overall survival (P = 0.037) and event-free survival (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. Mol Cancer Ther; 12(12); 2940-9.
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U2 - 10.1158/1535-7163.MCT-13-0692
DO - 10.1158/1535-7163.MCT-13-0692
M3 - Article
C2 - 24092807
AN - SCOPUS:84890484192
SN - 1535-7163
VL - 12
SP - 2940
EP - 2949
JO - Molecular cancer therapeutics
JF - Molecular cancer therapeutics
IS - 12
ER -