BH3 profiling discriminates response to cytarabine-based treatment of acute myelogenous leukemia

William E. Pierceall, Steven M. Kornblau, Nicole E. Carlson, Xuelin Huang, Noel Blake, Ryan Lena, Michael Elashoff, Marina Konopleva, Michael H. Cardone, Michael A. Andreeff

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)2940-2949
Number of pages10
JournalMolecular Cancer Therapeutics
Volume12
Issue number12
DOIs
StatePublished - Dec 2013
Externally publishedYes

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