TP53 and Decitabine in Acute Myeloid Leukemia and Myelodysplastic Syndromes.
TP53 and Decitabine in Acute Myeloid Leukemia and Myelodysplastic Syndromes.
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DOI：
10.1056/nejmoa1605949
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发表时间：
2016-11-24
期刊：
影响因子：
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通讯作者：
Ley TJ
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作者：
Welch JS;Petti AA;Miller CA;Fronick CC;O'Laughlin M;Fulton RS;Wilson RK;Baty JD;Duncavage EJ;Tandon B;Lee YS;Wartman LD;Uy GL;Ghobadi A;Tomasson MH;Pusic I;Romee R;Fehniger TA;Stockerl-Goldstein KE;Vij R;Oh ST;Abboud CN;Cashen AF;Schroeder MA;Jacoby MA;Heath SE;Luber K;Janke MR;Hantel A;Khan N;Sukhanova MJ;Knoebel RW;Stock W;Graubert TA;Walter MJ;Westervelt P;Link DC;DiPersio JF;Ley TJ
急性髓性白血病（AML）或骨髓增生异常综合征（MDS）患者对地西他滨治疗临床反应的分子决定因素尚不清楚。我们在一项地西他滨单机构试验中招募了84名患有AML或MDS的成年患者，以确定体细胞突变及其与临床反应的关系。地西他滨以每平方米体表面积每天20毫克的剂量给药，按月周期连续10天。我们对其中67名患者进行了增强外显子组或基因面板测序，并在多个时间点进行了序列测序，以评估54名患者的突变清除模式。扩展队列包括另外32名在不同方案中接受地西他滨治疗的患者。116例患者中，53例（46%）骨髓母细胞清除率（<5%）。不良风险细胞遗传谱患者的缓解率高于中度或良好风险细胞遗传谱患者（43例患者中有29例[67%]对71例患者中有24例[34%]，P<0.001）， TP53突变患者的缓解率高于野生型TP53患者（21例中有21例[100%]对78例中有32例[41%]，P<0.001）。先前的研究一致表明，具有不良风险细胞遗传学特征和TP53突变的患者接受常规化疗的结果较差。然而，在这项为期10天的地西他滨疗程的研究中，这两种危险因素都没有与具有中等风险细胞遗传学特征的研究患者的总生存率较低相关。AML和MDS患者在接受连续10天的地西他滨治疗后，具有与不利风险、TP53突变相关的细胞遗传学异常，或两者兼有良好的临床反应和强大的（但不完全的）突变清除。虽然这些反应不是持久的，但它们导致的总生存率与具有中等风险细胞遗传学特征并接受连续10天地西他滨疗程的AML患者相似。
The molecular determinants of clinical responses to decitabine therapy in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) are unclear. We enrolled 84 adult patients with AML or MDS in a single-institution trial of decitabine to identify somatic mutations and their relationships to clinical responses. Decitabine was administered at a dose of 20 mg per square meter of body-surface area per day for 10 consecutive days in monthly cycles. We performed enhanced exome or gene-panel sequencing in 67 of these patients and serial sequencing at multiple time points to evaluate patterns of mutation clearance in 54 patients. An extension cohort included 32 additional patients who received decitabine in different protocols. Of the 116 patients, 53 (46%) had bone marrow blast clearance (<5% blasts). Response rates were higher among patients with an unfavorable-risk cytogenetic profile than among patients with an intermediate-risk or favorable-risk cytogenetic profile (29 of 43 patients [67%] vs. 24 of 71 patients [34%], P<0.001) and among patients with TP53 mutations than among patients with wild-type TP53 (21 of 21 [100%] vs. 32 of 78 [41%], P<0.001). Previous studies have consistently shown that patients with an unfavorable-risk cytogenetic profile and TP53 mutations who receive conventional chemotherapy have poor outcomes. However, in this study of 10-day courses of decitabine, neither of these risk factors was associated with a lower rate of overall survival than the rate of survival among study patients with intermediate-risk cytogenetic profiles. Patients with AML and MDS who had cytogenetic abnormalities associated with unfavorable risk, TP53 mutations, or both had favorable clinical responses and robust (but incomplete) mutation clearance after receiving serial 10-day courses of decitabine. Although these responses were not durable, they resulted in rates of overall survival that were similar to those among patients with AML who had an intermediate-risk cytogenetic profile and who also received serial 10-day courses of decitabine.