CPX-351 exhibits potent and direct ex vivo cytotoxicity against AML blasts with enhanced efficacy for cells harboring the FLT3-ITD mutation. (February 2017)

• Record Type: Journal Article
• Authors: Gordon, Max J.; Tardi, Paul; Loriaux, Marc M.; Spurgeon, Stephen E.; Traer, Elie; Kovacsovics, Tibor; Mayer, Lawrence D.; Tyner, Jeffrey W.
• Is Part Of: Leukemia research. Volume 53(2017:Feb.)
• Page Start: 39
• Page End: 49
• Publication Date: 2017-02
• Subjects: CPX-351 -- Cytarabine -- Daunorubicin -- Leukemia -- Cytotoxicity; Leukemia -- Periodicals; Leukemia -- Periodicals; Leucémie -- Périodiques; Leukemia; Periodicals; Electronic journals; Electronic journals; 616.9941905
• DOI: 10.1016/j.leukres.2016.12.002
• Languages: English
• ISSNs: 0145-2126

Abstract

Highlights: CPX-351 is a liposome formulation of cytarabine and daunorubicin in 5:1 molar ratio. CPX-351 has ex vivo activity against a broad range of hematologic malignancies. Consistent with clinical data, CPX-351 activity is retained in high-risk AML blasts. Ex vivo analysis of AML blasts with FLT3-ITD shows increased sensitivity to CPX-351. Ex vivo analysis identifies AML subgroups warranting further clinical investigation. 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.