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Clinical Trial
. 2014 May;38(5):564-8.
doi: 10.1016/j.leukres.2014.02.007. Epub 2014 Feb 28.

Mcl-1 dependence predicts response to vorinostat and gemtuzumab ozogamicin in acute myeloid leukemia

William E Pierceall  1 , Ryan J Lena  2 , Bruno C Medeiros  3 , Noel Blake  2 , Camille Doykan  2 , Michael Elashoff  2 , Michael H Cardone  2 , Roland B Walter  4
Affiliations
Clinical Trial

Mcl-1 dependence predicts response to vorinostat and gemtuzumab ozogamicin in acute myeloid leukemia

William E Pierceall et al. Leuk Res. 2014 May.

Abstract

Older adults with acute myeloid leukemia (AML) are commonly considered for investigational therapies, which often only benefit subsets of patients. In this study, we assessed whether BH3 profiling of apoptotic functionality could predict outcomes following treatment with vorinostat (histone deacetylase inhibitor) and gemtuzumab ozogamicin (GO; CD33-targeted immunoconjugate). Flow cytometry of BH3 peptide priming with Noxa (anti-apoptotic protein Mcl-1 modulator) correlated with remission induction (p=.026; AUC=0.83 [CI: 0.65-1.00; p=.00042]: AUC=0.88 [CI:0.75-1.00] with age adjustment) and overall survival (p=.027 logistic regression; AUC=0.87 [0.64-1.00; p=.0017]). This Mcl-1-dependence suggests a pivotal role of Bcl-2 family protein-mediated apoptosis to vorinostat/GO in AML patients.

Keywords: AML; Biomarker; Gemtuzumab ozogamicin; HDAC inhibitors; Personalized medicine.

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Figures

Figure 1
Figure 1. Relationship between Noxa-induced priming and therapeutic response
(A) Dot-plot for the mean %priming (± S.D.) induced by Noxa comparing the 16 non-responder patients (“NR”) with those 7 responder patients who achieved a CR or CRp (“CR”) with vorinostat/GO. (B) ROC-plot of the sensitivity and specificity of Noxa as a predictor of therapeutic response for our study cohort, either when used alone or, in multivariate analysis, combined with age as additional predictive factor.
See this image and copyright information in PMC

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