CPX-351 exhibits potent and direct ex vivo cytotoxicity against AML blasts with enhanced efficacy for cells harboring the FLT3-ITD mutation

Leuk Res. 2017 Feb:53:39-49. doi: 10.1016/j.leukres.2016.12.002. Epub 2016 Dec 12.

Abstract

Purpose: 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.

Methods: 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.

Results: 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 IC50 values markedly lower than reported 72-h plasma drug concentration in patients receiving CPX-351. The range and distribution of CPX-351 IC50 values 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.

Conclusions: 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.

Keywords: CPX-351; Cytarabine; Cytotoxicity; Daunorubicin; Leukemia.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibiotics, Antineoplastic / administration & dosage
  • Antimetabolites, Antineoplastic / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage
  • Blast Crisis / drug therapy*
  • Cytarabine / administration & dosage*
  • Daunorubicin / administration & dosage*
  • Humans
  • Inhibitory Concentration 50
  • Liposomes / administration & dosage*
  • Mutation
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
  • Tumor Cells, Cultured
  • fms-Like Tyrosine Kinase 3 / genetics

Substances

  • Antibiotics, Antineoplastic
  • Antimetabolites, Antineoplastic
  • Liposomes
  • Cytarabine
  • fms-Like Tyrosine Kinase 3
  • Daunorubicin