CPX-351 exhibits potent and direct ex vivo cytotoxicity against AML blasts with enhanced efficacy for cells harboring the FLT3-ITD mutation
CPX-351 exhibits potent and direct ex vivo cytotoxicity against AML blasts with enhanced efficacy for cells harboring the FLT3-ITD mutation
复制标题
DOI：
10.1016/j.leukres.2016.12.002
复制
发表时间：
2017-02-01
影响因子：
2.7
通讯作者：
Tyner, Jeffrey W.
中科院分区：
文献类型：
--
作者：
Gordon, Max J.;Tardi, Paul;Tyner, Jeffrey W.
目的：确定AML患者最有可能响应CPX-351，纳米级脂质体制剂含有阿糖胞苷和柔红霉素共封装在5：1的摩尔ratio.Methods：我们研究了体外细胞毒性活性的CPX-351对白血病细胞分离的53例AML患者和另外127个样本，包括急性淋巴细胞白血病，骨髓增生异常综合征/骨髓增生性肿瘤，或慢性淋巴细胞白血病/淋巴瘤。我们评估活动与常见的分子病变，并使用流式细胞术来评估CPX-351细胞uptake.Results：AML标本的敏感性CPX-351是相似的，在传统的风险组。FLT 3-ITD病例对CPX-351的敏感性高5倍。CPX-351在其他适应症中具有活性，几乎所有病例的IC 50值均显著低于接受CPX-351的患者报告的72小时血浆药物浓度。对于AML、CLL和ALL，CPX-351 IC 50值的范围和分布相当，而MDS/MPN病例的敏感性较低。CPX-351摄取分析显示摄取的CPX-351和细胞毒性potential.Conclusions之间的相关性：我们的研究结果是一致的临床数据，其中CPX-351活性保留在高风险AML患者。细胞毒性效价的离体分析可以提供一种鉴定特定AML亚群（如FLT 3-ITD）的方法，这些亚群从CPX-351中获益最大，并需要进行额外的临床评价。(C)2016爱思唯尔有限公司版权所有。
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. (C) 2016 Elsevier Ltd. All rights reserved.