克拉屈滨、阿糖胞苷、粒细胞集落刺激因子（CLAG方案）与米哚妥林及全反式维甲酸用于复发/难治性急性髓系白血病的I期研究。
Phase I study of cladribine, cytarabine, granulocyte colony stimulating factor (CLAG regimen) and midostaurin and all-trans retinoic acid in relapsed/refractory AML.
作者信息
Ramsingh Giridharan, Westervelt Peter, McBride Ali, Stockerl-Goldstein Keith, Vij Ravi, Fiala Mark, Uy Geoffrey, Cashen Amanda, Dipersio John F, Abboud Camille N
机构信息
Jane Anne Nohl Division of Hematology, Department of Medicine, University of Southern California, Los Angeles, CA, USA.
出版信息
Int J Hematol. 2014 Mar;99(3):272-8. doi: 10.1007/s12185-014-1503-4. Epub 2014 Feb 2.
Abstract
We conducted a phase I study using midostaurin (25 or 50 mg orally twice daily), all-trans retinoic acid (ATRA) and CLAG chemotherapy to target multiple pathways in relapsed/refractory AML. 10 patients received the combination and no dose-limiting toxicities were observed. Two patients (22 %) achieved complete remission and 1 patient (11 %) achieved complete remission with incomplete count recovery. Pharmacokinetic data showed that the 25 mg dosing of midostaurin achieved therapeutic levels with no significant interaction between midostaurin and ATRA. With evidence of activity of ATRA in NPM1-mutated AML and midostaurin in FLT3-ITD AML, this combination warrants further investigation.
摘要
我们开展了一项I期研究，使用米哚妥林（口服25或50毫克，每日两次）、全反式维甲酸（ATRA）和CLAG化疗来靶向复发/难治性急性髓系白血病（AML）的多种信号通路。10名患者接受了联合治疗，未观察到剂量限制性毒性。2名患者（22%）实现完全缓解，1名患者（11%）实现完全缓解但血细胞计数未完全恢复。药代动力学数据显示，25毫克剂量的米哚妥林达到了治疗水平，且米哚妥林与ATRA之间无显著相互作用。鉴于ATRA在NPM1突变型AML中以及米哚妥林在FLT3-ITD AML中均有活性证据，该联合治疗值得进一步研究。
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本文引用的文献
1
The bone marrow microenvironment as niche retreats for hematopoietic and leukemic stem cells.作为造血干细胞和白血病干细胞生态位的骨髓微环境。
Adv Hematol. 2013;2013:953982. doi: 10.1155/2013/953982. Epub 2013 Jan 10.
2
Phase IB study of the FLT3 kinase inhibitor midostaurin with chemotherapy in younger newly diagnosed adult patients with acute myeloid leukemia.一项在年轻初诊成人急性髓系白血病患者中进行的与化疗联用的 FLT3 激酶抑制剂米哚妥林的 Ib 期研究。
Leukemia. 2012 Sep;26(9):2061-8. doi: 10.1038/leu.2012.115. Epub 2012 Apr 27.
3
Cladribine, but not fludarabine, added to daunorubicin and cytarabine during induction prolongs survival of patients with acute myeloid leukemia: a multicenter, randomized phase III study.克拉屈滨，而非氟达拉滨，在诱导缓解治疗中联合柔红霉素和阿糖胞苷可延长急性髓系白血病患者的生存：一项多中心、随机 III 期研究。
J Clin Oncol. 2012 Jul 10;30(20):2441-8. doi: 10.1200/JCO.2011.37.1286. Epub 2012 Apr 16.
4
Prognostic value of FLT3 mutations among different cytogenetic subgroups in acute myeloid leukemia.FLT3 突变在急性髓系白血病不同细胞遗传学亚组中的预后价值。
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