Abstract 3400: Mitochondrial profiling in AML patients treated with an Alvocidib containing regimen reveals MCL1 dependency in responder bone marrow
Authors: Dettman Elisha J. , Warner Steven L. , Doykan Camille , Arn Melissa , Blake Noel , Bearss David J. , Cardone Michael , Smith Bruce D. 
Published: August 2015

Background.  Molecular profiles may provide insights into the likelihood of responding to traditional cytotoxic chemotherapy as well as important clues to the success of novel targeted agents.  The anti-apoptotic BCL-2 family proteins have previously been shown to facilitate pro-survival and resistance to chemotherapy in AML, multiple myeloma, as well as in other types of cancer. Measuring the function of these proteins using BH3 profiling has proven to provide useful information in predicting AML treatment response with traditional ara-c based treatment. Here, we sought to determine if such an approach might detect response with the addition of Alvocidib to ara-c-based chemotherapy. Mitochrondrial apoptosis signaling was assessed in AML patients treated with Alvocidib, ara-c and mitoxantrone (FLAM).  Methods.  Pretreatment peripheral blood mononuclear cell and bone marrow specimens from 63 patients treated with FLAM were measured for mitochondrial outer membrane permeabilization following incubation with BH3 peptides as a surrogate for BCL-2 protein family function. Results.  Analysis of the priming states (mitochondrial depolarization) in the patients who underwent complete remission (CR), compared with those who did not (NR), revealed that NOXA priming was significantly higher in CR bone marrow samples (median 44.5%) compared with NR samples (median 5.2%, p = 0.006). NOXA is known to interact most directly with MCL1, suggesting that these cancer cells may be MCL1 dependent. An additional multi-peptide algorithm using three BH3 members was also identified (involving BAD, PUMA, and BIM), which may also indirectly support MCL1 dependency. These BH3 priming profiles were both additive to known risk factors associated with clinical response to chemotherapy, including cytogenetic risk factors. Receiver operating characteristic (ROC) curve analysis of NOXA priming plus cytogenetics and MDS history indicated that these variables were highly predictive of response to FLAM (AUC-0.92, p = 0.0002). This correlation is distinct from our previous work which showed that the priming due to the BIM peptide predicts response to traditional ara-c based treatment. This work provides a basis for further studies into the MCL1 dependent action of Alvocidib, as well as a potential biomarker for identification of patients likely to respond to FLAM.

Citation Format: Elisha J. Dettman, Steven L. Warner, Camille Doykan, Melissa Arn, Noel Blake, David J. Bearss, Michael Cardone, Bruce D. Smith. Mitochondrial profiling in AML patients treated with an Alvocidib containing regimen reveals MCL1 dependency in responder bone marrow. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3400. doi:10.1158/1538-7445.AM2015-3400