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TP53突变与地西他滨治疗急性髓系白血病和骨髓增生异常综合征关系的研究
TP53 and Decitabine in Acute Myeloid Leukemia and Myelodysplastic Syndromes


John S. Welch ... 肿瘤 • 2016.11.24
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TP53与地西他滨治疗AML及MDS临床研究述评


王婷

上海交通大学医学院附属仁济医院血液科

 

预后不良核型急性髓系白血病(AML)与老年AML(≥60岁)预后差,应用传统的AML标准蒽环类与阿糖胞苷为基础的诱导方案,中位生存期1年左右。而具有TP53突变的AML患者多为老年,且几乎均为不良核型,预后尤其差,应用传统诱导化疗方案,中位生存期仅为4~6个月。目前治疗老年AML以及骨髓增生异常综合征(MDS)亦常用含地西他滨(DNA甲基转移酶抑制剂)的方案,地西他滨单药应用(5天方案)治疗AML缓解率相对较低,延长地西他滨用药时间(10天方案)能明显改善疗效。

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摘要


背景

急性髓系白血病(AML)或骨髓增生异常综合征(MDS)患者接受地西他滨治疗后,临床应答情况的分子决定因素仍然不明。

 

方法

我们在对地西他滨进行的一项单一机构试验中纳入了84例成年AML或MDS患者,目的是鉴定体细胞突变及它们与临床应答情况之间的关系。地西他滨在每个周期以每日20 mg/m2体表面积的剂量连续给药10天,每月一个周期。我们对上述患者中的67例进行了增强外显子组或基因面板测序,并且对54例患者在多个时间点进行了系列测序,以评价其突变清除(mutation clearance)模式。扩展队列纳入了另外32例在不同研究方案中接受地西他滨的患者。

 

结果

116例患者中,有53例(46%)达到骨髓母细胞清除(母细胞<5%)。有高危(unfavorable-risk)细胞遗传学特征的患者的有效率高于有中危或低危(favorable-risk)细胞遗传学特征的患者(29/43例患者[67%]对24/71例患者[34%],P<0.001),有TP53突变的患者的有效率高于有野生型TP53的患者(21/21 [100%]对32/78[41%],P<0.001)。之前的研究一致表明,有高危细胞遗传学特征和TP53突变的患者接受常规化疗后结局较差。然而,在此项对地西他滨10天疗程进行的研究中,与具有中危细胞遗传学特征的患者相比,这些危险因素均未伴有总生存率的降低。

 

结论

有细胞遗传学异常伴高危险度、TP53突变或两者兼有的AML和MDS患者接受地西他滨以10天为一疗程的系列治疗后,产生了良好的临床应答和强效(但不完全)的突变清除。虽然这些应答不持久,但产生的总生存率仍然与有中危细胞遗传学特征的AML患者接受系列地西他滨10天疗程后达到的总生存率相似(由美国国立癌症研究所[National Cancer Institute]和其他机构提供资助;ClinicalTrials.gov注册号为NCT01687400)。





作者信息

John S. Welch, M.D., Ph.D., Allegra A. Petti, Ph.D., Christopher A. Miller, Ph.D., Catrina C. Fronick, B.S., Michelle O’Laughlin, B.S., Robert S. Fulton, M.S., Richard K. Wilson, Ph.D., Jack D. Baty, B.A., Eric J. Duncavage, M.D., Bevan Tandon, M.D., Yi-Shan Lee, M.D., Ph.D., Lukas D. Wartman, M.D., Geoffrey L. Uy, M.D., Armin Ghobadi, M.D., Michael H. Tomasson, M.D., Iskra Pusic, M.D., Rizwan Romee, M.D., Todd A. Fehniger, M.D., Ph.D., Keith E. Stockerl-Goldstein, M.D., Ravi Vij, M.B., B.S., Stephen T. Oh, M.D., Ph.D., Camille N. Abboud, M.D., Amanda F. Cashen, M.D., Mark A. Schroeder, M.D., Meagan A. Jacoby, M.D., Ph.D., Sharon E. Heath, Kierstin Luber, B.S., Megan R. Janke, Ph.D., Andrew Hantel, M.D., Niloufer Khan, M.D., Madina J. Sukhanova, Ph.D., Randall W. Knoebel, Pharm.D., Wendy Stock, M.D., Timothy A. Graubert, M.D., Matthew J. Walter, M.D.,aa Peter Westervelt, M.D., Ph.D., Daniel C. Link, M.D., John F. DiPersio, M.D., Ph.D., and Timothy J. Ley, M.D.
Address reprint requests to Dr. Ley at the Department of Internal Medicine, Washington University School of Medicine, 660 S. Euclid Ave., Box 8007, St. Louis, MO 63110, or at timley@wustl.edu.

 

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