Max J Gordon1, Paul Tardi2, Marc M Loriaux3, Stephen E Spurgeon4, Elie Traer4, Tibor Kovacsovics5, Lawrence D Mayer2, Jeffrey W Tyner6. 1. Department of Internal Medicine, Oregon Health & Sciences University, Portland, OR, USA. 2. Jazz Pharmaceuticals, Suite 250 - 887 Great Northern Way, Vancouver, BC V5T 4T5, Canada. 3. Department of Pathology, Oregon Health & Science University, Portland, OR, USA; Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA. 4. Division of Hematology & Medical Oncology, Oregon Health & Science University, Portland, OR, USA; Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA. 5. Division of Hematology and Hematologic Malignancies, Huntsman Cancer Institute, Huntsman Cancer Hospital, The University of Utah, Salt Lake City, USA. 6. 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.
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.
PURPOSE: Identify AMLpatients 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 AMLpatients 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 AMLpatients. 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.
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