文章：

超精确双链测序评估Ph+ ALL患者治疗前ABL1激酶结构域突变

Ultra-accurate Duplex Sequencing for the assessment of pretreatment ABL1 kinase domain mutations in Ph+ ALL

原文发布日期：2020-05-26

DOI: 10.1038/s41408-020-0329-y

类型: Article

开放获取: 是

英文摘要：

Mutations of ABL1 are the dominant mechanism of relapse in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL). We performed highly accurate Duplex Sequencing of exons 4–10 of ABL1 on bone marrow or peripheral blood samples from 63 adult patients with previously untreated Ph + ALL who received induction with intensive chemotherapy plus a BCR-ABL1 TKI. We identified ABL1 mutations prior to BCR-ABL1 TKI exposure in 78% of patients. However, these mutations were generally present at extremely low levels (median variant allelic frequency 0.008% [range, 0.004%–3.71%] and did not clonally expand and lead to relapse in any patient, even when the pretreatment mutation was known to confer resistance to the TKI received. In relapse samples harboring a TKI-resistant ABL1 mutation, the corresponding mutation could not be detected pretreatment, despite validated sequencing sensitivity of Duplex Sequencing down to 0.005%. In samples under the selective pressure of ongoing TKI therapy, we detected low-level, emerging resistance mutations up to 5 months prior to relapse. These findings suggest that pretreatment ABL1 mutation assessment should not guide upfront TKI selection in Ph + ALL, although serial testing while on TKI therapy may allow for early detection of clinically actionable resistant clones.
 

摘要翻译： 

ABL1突变是费城染色体阳性急性淋巴细胞白血病（Ph + ALL）复发的主要机制。我们对63例既往未经治疗的成人Ph + ALL患者（接受强化化疗联合BCR-ABL1 TKI诱导治疗）的骨髓或外周血样本进行了ABL1基因第4-10外显子的高精度双链测序。在78%的患者开始BCR-ABL1 TKI治疗前，我们检测到了ABL1突变。然而这些突变通常以极低水平存在（中位变异等位基因频率为0.008%[范围：0.004%-3.71%]），且未在任何患者中发生克隆扩增导致复发——即使治疗前发现的突变已知会对所用TKI产生耐药性。在携带TKI耐药性ABL1突变的复发样本中，尽管双链测序已验证的灵敏度可达0.005%，但治疗前并未检测到相应突变。在持续TKI治疗的选择压力下，我们在复发前最长5个月即可检测到低水平的新兴耐药突变。这些研究结果表明，虽然TKI治疗过程中的连续监测可早期发现具有临床指导意义的耐药克隆，但治疗前ABL1突变评估不应作为Ph + ALL患者初始TKI选择的依据。

原文链接：

Ultra-accurate Duplex Sequencing for the assessment of pretreatment ABL1 kinase domain mutations in Ph+ ALL