BH3 profiling as a predictive biomarker for response to cytarabine-based treatment of acute myelogenous leukemia.

Abstract

7022 Background: Acute myelogenous leukemia (AML) is the most frequently diagnosed of the leukemias with approximately 13,000 new cases per year in the U.S. Although intense therapeutic discovery efforts have been directed towards AML, cytarabine-based treatment remains unchanged as the standard-of-care (SOC). As patient response to SOC is variable, segregating patients based on biomarker-driven predicted response may lead to improved clinical outcomes. One personalized diagnostic approach that may provide actionable information in patient management is BH3 profiling, a surrogate functional biomarker assay that assesses cell mitochondrial response to pro-apoptotic signaling. Methods: Blinded to outcomes, we profiled an AML cohort (n=63) treated with cytarabine-based therapy using a panel of BH3 peptides with response as a primary endpoint. Peripheral blood mononuclear cell (PBMC) or bone marrow aspirate (BM) specimens were obtained from newly diagnosed AML patients and viably preserved. Specimens were assayed by flow cytometry following cell permeabilization and incubation with potentiometric JC-1 mitochondrial dye and individual BH3 peptides. Results: Mann-Whitney analysis indicates BH3 profiling biomarkers are correlated with response to induction therapy. Among BH3 peptides, BIM was highly significant (p=2X10-6; CI[0.73,0.94]) with a notable sensitivity/specificity profile (AUC=0.84; p=2X10-10). Multivariate analysis indicates improved profiles for BIM + 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 was significant for both intermediate (p=0.0017; AUC=0.88; CI[0.71,1.04]) and unfavorable (p=0.016; AUC=0.80; CI[0.60,1.00]), demonstrating that the predictive power of the assay is independent of cytogenetics. Conclusions: Here, BH3 profiling predicts patient response to cytarabine-based treatment regimens with accuracies of 90%. Thus, patients may potentially benefit from being given alternate therapies while at the same time spared the toxicities, cost, and time lost associated with a therapy less likely to exhibit response.