title: Mcl-1 dependence predicts response to vorinostat and gemtuzumab ozogamicin in acute myeloid leukemia.
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.
authors.affiliation: Eutropics Pharmaceuticals, Inc., Cambridge, MA, United States. Electronic address: wpierceall@eutropics.com.
authors.forename: William E
authors.initials: WE
authors.lastname: Pierceall
authors.affiliation: Eutropics Pharmaceuticals, Inc., Cambridge, MA, United States.
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Lena
authors.affiliation: Stanford University, Stanford, CA, United States.
authors.forename: Bruno C
authors.initials: BC
authors.lastname: Medeiros
authors.affiliation: Eutropics Pharmaceuticals, Inc., Cambridge, MA, United States.
authors.forename: Noel
authors.initials: N
authors.lastname: Blake
authors.affiliation: Eutropics Pharmaceuticals, Inc., Cambridge, MA, United States.
authors.forename: Camille
authors.initials: C
authors.lastname: Doykan
authors.affiliation: Eutropics Pharmaceuticals, Inc., Cambridge, MA, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Elashoff
authors.affiliation: Eutropics Pharmaceuticals, Inc., Cambridge, MA, United States.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Cardone
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States; Department of Medicine, Division of Hematology, University of Washington, Seattle, WA, United States; Department of Epidemiology, University of Washington, Seattle, WA, United States. Electronic address: rwalter@fhcrc.org.
authors.forename: Roland B
authors.initials: RB
authors.lastname: Walter
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000617:Aminoglycosides / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D005260:Female; D000079982:Gemtuzumab; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000401:mortality; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000502:physiology*; D010446:Peptide Fragments / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000494:pharmacology; D000077337:Vorinostat
chemical_list: D000617:Aminoglycosides; D061067:Antibodies, Monoclonal, Humanized; C474007:Bax protein (53-86); D006877:Hydroxamic Acids; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; C498702:PMAIP1 protein, human; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D000077337:Vorinostat; D000079982:Gemtuzumab
keywords: AML; Biomarker; Gemtuzumab ozogamicin; HDAC inhibitors; Personalized medicine