Monitoring of clonal evolution of acute myeloid leukemia identifies the leukemia subtype, clinical outcome and potential new drug targets for post-remission strategies or relapse.
Monitoring of clonal evolution of acute myeloid leukemia identifies the leukemia subtype, clinical outcome and potential new drug targets for post-remission strategies or relapse.
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DOI：
10.3324/haematol.2020.254623
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发表时间：
2021-09-01
期刊：
影响因子：
10.1
通讯作者：
Ayala R
中科院分区：
文献类型：
--
作者：
Onecha E;Rapado I;Luz Morales M;Carreño-Tarragona G;Martinez-Sanchez P;Gutierrez X;Sáchez Pina JM;Linares M;Gallardo M;Martinez-López J;Ayala R
在急性髓性白血病（AML）治疗失败的情况下，突变谱在原发难治性和复发中的效用尚未确定。我们采用下一代测序技术（NGS）对23例阿糖胞苷联合伊达尔戈或氟达拉滨治疗失败的AML患者的临床随访样本（n=91）进行了前瞻性研究。与复发病例相比，原发性治疗无效病例在诊断时的DNA变异数较低（中位数分别为1.67和3.21，P=0.029）。原发性难治性肿瘤患者中最常受影响的途径是信号传导、转录和肿瘤抑制，而甲基化和剪接途径主要涉及复发患者。新的治疗靶点，无论是通过批准的药物或在临床试验中，没有确定在任何情况下的难治性（0/10）;然而，8个潜在的新靶点被发现在5例复发患者（5/13，P=0.027）：1 IDH 2，3 SF 3B 1，2 KRAS，1 KIT和1 JAK 2。在诊断时检测到的所有变异中，有65%在完全缓解时未检测到。具体而言，EZH 2、RUNX 1、VHL、FLT 3、ETV 6、U2 AF 1、PHF 6和SF 3B 1中100%的变异在完全缓解时消失，表明它们可能用作评估AML随访的微小残留病的标志物。在AML的治疗后评估中使用定制的32个基因的NGS髓样组进行分子随访，可以帮助对预后风险进行分层，选择最小残留疾病标志物以监测对治疗的反应并指导针对AML的缓解后策略，以及选择用于白血病复发的新药。
In cases of treatment failure in acute myeloid leukemia (AML), the utility of mutational profiling in primary refractoriness and relapse is not established. We undertook a perspective study using next-generation sequencing (NGS) of clinical follow-up samples (n=91) from 23 patients with AML with therapeutic failure to cytarabine plus idarubicin or fludarabine. Cases of primary refractoriness to treatment were associated with a lower number of DNA variants at diagnosis than cases of relapse (median 1.67 and 3.21, respectively, P=0.029). The most frequently affected pathways in patients with primary refractoriness were signaling, transcription and tumor suppression, whereas methylation and splicing pathways were mainly implicated in relapsed patients. New therapeutic targets, either by an approved drug or within clinical trials, were not identified in any of the cases of refractoriness (zero of ten); however, eight potential new targets were found in five relapsed patients (five of 13, P=0.027): one IDH2, three SF3B1, two KRAS, one KIT and one JAK2. Sixty-five percent of all variants detected at diagnosis were not detected at complete response. Specifically, 100% of variants in EZH2, RUNX1, VHL, FLT3, ETV6, U2AF1, PHF6 and SF3B1 disappeared at complete response, indicating their potential use as markers to evaluate minimal residual disease for follow-up of AML. Molecular follow-up using a custom NGS myeloid panel of 32 genes in the post-treatment evaluation of AML can help in the stratification of prognostic risk, the selection of minimal residual disease markers to monitor the response to treatment and guide post-remission strategies targeting AML, and the selection of new drugs for leukemia relapse.
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DOI：
10.1056/nejmoa1409405
发表时间：
2014-12-25
期刊：
The New England journal of medicine
影响因子：
--
作者：
Genovese G;Kähler AK;Handsaker RE;Lindberg J;Rose SA;Bakhoum SF;Chambert K;Mick E;Neale BM;Fromer M;Purcell SM;Svantesson O;Landén M;Höglund M;Lehmann S;Gabriel SB;Moran JL;Lander ES;Sullivan PF;Sklar P;Grönberg H;Hultman CM;McCarroll SA
通讯作者：
McCarroll SA
影响因子：
10.1
作者：
Onecha E;Linares M;Rapado I;Ruiz-Heredia Y;Martinez-Sanchez P;Cedena T;Pratcorona M;Oteyza JP;Herrera P;Barragan E;Montesinos P;Vela JAG;Magro E;Anguita E;Figuera A;Riaza R;Martinez-Barranco P;Sanchez-Vega B;Nomdedeu J;Gallardo M;Martinez-Lopez J;Ayala R
通讯作者：
Ayala R
影响因子：
45.3
作者：
Breems, DA;Van Putten, WLJ;Löwenberg, B
通讯作者：
Löwenberg, B
影响因子：
20.3
作者：
Metzeler, Klaus H.;Herold, Tobias;Spiekermann, Karsten
通讯作者：
Spiekermann, Karsten
影响因子：
8
作者：
Jan M;Majeti R
通讯作者：
Majeti R