Abstract 907: Bcl-xL dependence predicts response to alvocidib in chronic lymphocytic leukemia patients
Authors: William E. Pierceall, Steven L. Warner, Ryan J. Lena, Camille Doykan, Noel Blake, Michael Elashoff, Daniel D. Von Hoff, David J. Bearss, Michael H. Cardone, Michael Grever, Mark C. Lanasa, John C. Byrd, Amy J. Johnson
Journal: Cancer Research (2014)

Abstract Introduction. Chronic lymphocytic leukemia (CLL) patients may benefit from personalized strategies targeting specific therapies to individuals with favorable molecular profiles. Many therapeutics exhibit response in a subset of patients, and factors such as age or cytogenetics are insufficient to predict treatment success with high accuracy. We assessed mitochondrial functionality in apoptosis signaling for identification of CLL patients likely to exhibit clinical response to treatment with alvocidib. Effects of this agent have been shown to involve pathways of apoptosis, providing the rationale for our study. Patients and Methods. Relapsed/refractory patients comprising OSU0055 and Sanofi EFC6663 clinical trials were analyzed. Pretreatment peripheral blood mononuclear cell (PBMC) specimens were divided into training and validation sets for response-correlative assessment. Blinded to outcomes, we analyzed specimens by flow cytometry-based BH3 profiling, indirectly measuring induction of mitochondrial outer membrane permeabilization in response to treatment with BH3-only peptides (Bim, Noxa, Bad, Bmf, Hrk) as surrogates for Bcl-2 family functions. Findings were correlated with disease characteristics and treatment outcome in the proof-of-principal set and tested for confirmation in the validation set. Results. Response data were available for 62 patients; training and test sets comprised 30 and 32 patients, respectively. Regression analyses indicated a correlation between clinical response (ordered 3 categories; PD, SD, PR) and priming in training set with Bim(0.1) (p=.014) and Hrk (p=.0098), that later validated in the test set for both markers (p=.0051 and p=.015, respectively). In total (n=62), Bim regression displayed a p=.0027 and Hrk regression a p=.00046. When analyzed as PD/SD vs PR, the combined cohort yielded Bim p=.04, and Hrk p=.0039 by logistic regression. Using area under the receiver operating curve (AUC) to quantify the accuracy of outcome prediction, Bim AUC = 0.73 (CI[.60-.85]; p=.0004) and Hrk AUC = .73 (CI[.61-.86]; p=.0002). Hrk benefitted from adjustment for trisomy12 status (AUC=0.83; CI[.71-.95]; p&amp;lt;.0001). Analysis of BH3 profiling and tumor lysis syndrome (TLS) indicated correlation between TLS and Bad priming (p=.012 log regression; AUC=.75; CI[.60-.89]; p=.0007) that benefitted from inclusion of ECOG status and patient age (AUC=.85; CI[.73-.97]; p&amp;lt;.0001). Conclusion. Bim and Hrk are significantly associated with response and, thus, engaging Bcl-xL dependence may be a component of response to alvocidib in relapsed CLL patients. Interestingly, TLS is predicted by a distinct BH3 profiling peptide readout, Bad, consistent with alvocidib-associated TLS driven by Bcl-2-dependency. Taken together, these biomarkers may predict patient response to investigational CDK inhibitors in CLL and concurrently identify patients at risk for treatment-related toxicity. Citation Format: William E. Pierceall, Steven L. Warner, Ryan J. Lena, Camille Doykan, Noel Blake, Michael Elashoff, Daniel D. Von Hoff, David J. Bearss, Michael H. Cardone, Michael Grever, Mark C. Lanasa, John C. Byrd, Amy J. Johnson. Bcl-xL dependence predicts response to alvocidib in chronic lymphocytic leukemia patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 907. doi:10.1158/1538-7445.AM2014-907