title: CPX-351 exhibits potent and direct ex vivo cytotoxicity against AML blasts with enhanced efficacy for cells harboring the FLT3-ITD mutation.
abstract: Identify AML patients most likely to respond to CPX-351, a nano-scale liposome formulation containing cytarabine and daunorubicin co-encapsulated at a 5:1 molar ratio.
  
  
  
  We examined the ex vivo cytotoxic activity of CPX-351 against leukemic cells isolated from 53 AML patients and an additional 127 samples including acute lymphoblastic leukemia, myelodysplastic syndrome/myeloproliferative neoplasms, or chronic lymphocytic leukemia/lymphoma. We assessed activity with respect to common molecular lesions and used flow cytometry to assess CPX-351 cellular uptake.
  
  
  
  AML specimen sensitivity to CPX-351 was similar across conventional risk groups. FLT3-ITD cases were five-fold more sensitive to CPX-351. CPX-351 was active across other indications with nearly all cases exhibiting IC50values markedly lower than reported 72-h plasma drug concentration in patients receiving CPX-351. The range and distribution of CPX-351 IC50values were comparable for AML, CLL, and ALL, whereas MDS/MPN cases were less sensitive. CPX-351 uptake analysis revealed a correlation between uptake of CPX-351 and cytotoxic potency.
  
  
  
  Our findings are consistent with clinical data, in which CPX-351 activity is retained in high-risk AML patients. Ex vivo analysis of cytotoxic potency may provide a means to identify specific AML subsets, such as FLT3-ITD, that benefit most from CPX-351 and warrant additional clinical evaluation.
authors.affiliation: Department of Internal Medicine, Oregon Health & Sciences University, Portland, OR, USA.
authors.forename: Max J
authors.initials: MJ
authors.lastname: Gordon
authors.affiliation: Jazz Pharmaceuticals, Suite 250 - 887 Great Northern Way, Vancouver, BC V5T 4T5, Canada.
authors.forename: Paul
authors.initials: P
authors.lastname: Tardi
authors.affiliation: Department of Pathology, Oregon Health & Science University, Portland, OR, USA; Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
authors.forename: Marc M
authors.initials: MM
authors.lastname: Loriaux
authors.affiliation: Division of Hematology & Medical Oncology, Oregon Health & Science University, Portland, OR, USA; Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Spurgeon
authors.affiliation: Division of Hematology & Medical Oncology, Oregon Health & Science University, Portland, OR, USA; Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
authors.forename: Elie
authors.initials: E
authors.lastname: Traer
authors.affiliation: Division of Hematology and Hematologic Malignancies, Huntsman Cancer Institute, Huntsman Cancer Hospital, The University of Utah, Salt Lake City, USA.
authors.forename: Tibor
authors.initials: T
authors.lastname: Kovacsovics
authors.affiliation: Jazz Pharmaceuticals, Suite 250 - 887 Great Northern Way, Vancouver, BC V5T 4T5, Canada.
authors.forename: Lawrence D
authors.initials: LD
authors.lastname: Mayer
authors.affiliation: Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, OR, USA; Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA. Electronic address: tynerj@ohsu.edu.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Tyner
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D001752:Blast Crisis / Q000188:drug therapy*; D003561:Cytarabine / Q000008:administration & dosage*; D003630:Daunorubicin / Q000008:administration & dosage*; D006801:Humans; D020128:Inhibitory Concentration 50; D008081:Liposomes / Q000008:administration & dosage*; D009154:Mutation; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D014407:Tumor Cells, Cultured; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics
chemical_list: D000903:Antibiotics, Antineoplastic; D000964:Antimetabolites, Antineoplastic; D008081:Liposomes; D003561:Cytarabine; D051941:fms-Like Tyrosine Kinase 3; D003630:Daunorubicin
keywords: CPX-351; Cytarabine; Cytotoxicity; Daunorubicin; Leukemia