Shi D Y, Qin Y Z, Lai Y Y, Shi H X, Huang X J, Jiang Q
Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing 100044, China.
Zhonghua Xue Ye Xue Za Zhi. 2020 Jun 14;41(6):469-476. doi: 10.3760/cma.j.issn.0253-2727.2020.06.006.
To explore BCR-ABL kinase domain mutation profiles and clinical variables associated with them in tyrosine kinase inhibitor (TKI) -resistant patients with chronic myeloid leukemia (CML) . Imatinib-, nilotinib-, and/or dasatinib-resistant patients with CML who screened BCR-ABL mutation (s) in Peking University People's Hospital between June 2001 and September 2019 were retrospectively reviewed. BCR-ABL mutation was analyzed by Sanger sequencing. Binary logistic regression model was built to identify independent clinical variables associated with developing BCR-ABL mutation (s) . Data of 1 093 TKI-resistant cases in 804 patients who experienced resistance to imatinib (=576, 52.7%) , nilotinib (=238, 21.8%) , and dasatinib (=279, 25.5%) were analyzed. In total, 291 (50.5%) imatinib-, 152 (63.9%) nilotinib-, and 160 (57.3%) dasatinib-resistant cases developed BCR-ABL mutation (s) . T315I mutation was the most frequent mutation detected in imatinib-, nilotinib-, and dasatinib-resistant cases, accounting for 12.3%, 27.3%, and 34.1%, respectively. Y253F/H (7.5%) and F359V/C/I (5.6%) were the mutation detected in ≥5% imatinib-resistant cases; F359V/C/I (12.2%) , Y253F/H (11.8%) , and E255K/V (10.5%) in nilotinib-resistant cases; and F317L/V/I/C (11.5%) and E255K/V (5.4%) in dasatinib-resistant cases. In multivariate analyses, no TKI dose reduction or discontinuation of TKI therapy was the common variable associated with developing BCR-ABL mutation (s) . Other variables associated with developing BCR-ABL mutation (s) in imatinib-, nilotinib-, or dasatinib-resistant cases included male gender, younger age, no comorbidity, advanced phase before starting current TKI therapy, longer interval from diagnosis to starting current TKI therapy, acquired resistance, and TKI resistance due to progression to advanced phase or hematologic failure. In addition, interval from TKI failure to BCR-ABL mutation detection, starting initial TKI therapy to TKI failure, and starting current TKI therapy to TKI failure were associated with the frequency of developing BCR-ABL mutation. Dasatinib and nilotinib use and acquired resistance were identified to be associated with the development of T315I mutation in multivariate analyses. More than half of TKI-resistant CML patients developed BCR-ABL mutation (s) by Sanger sequencing. T315I mutation was the most frequently detected. Clinical variables significantly associated with developing BCR-ABL mutation (s) should be used not only as basis for the choice of subsequent TKIs but also the understanding of TKI-resistant mechanisms.
探索慢性髓性白血病（CML）酪氨酸激酶抑制剂（TKI）耐药患者的BCR-ABL激酶结构域突变谱及其相关临床变量。回顾性分析2001年6月至2019年9月期间在北京大学人民医院筛查BCR-ABL突变的伊马替尼、尼洛替尼和/或达沙替尼耐药的CML患者。采用桑格测序法分析BCR-ABL突变。构建二元逻辑回归模型以确定与BCR-ABL突变发生相关的独立临床变量。分析了804例经历伊马替尼（n = 576，52.7%）、尼洛替尼（n = 238，21.8%）和达沙替尼（n = 279，25.5%）耐药的1093例TKI耐药病例的数据。总共，291例（50.5%）伊马替尼耐药、152例（63.9%）尼洛替尼耐药和160例（57.3%）达沙替尼耐药病例发生了BCR-ABL突变。T315I突变是在伊马替尼、尼洛替尼和达沙替尼耐药病例中检测到的最常见突变，分别占12.3%、27.3%和34.1%。Y253F/H（7.5%）和F359V/C/I（5.6%）是在≥5%伊马替尼耐药病例中检测到的突变；F359V/C/I（12.2%）、Y253F/H（11.8%）和E255K/V（10.5%）在尼洛替尼耐药病例中；F317L/V/I/C（11.5%）和E255K/V（5.4%）在达沙替尼耐药病例中。在多变量分析中，未进行TKI剂量减少或未停用TKI治疗是与BCR-ABL突变发生相关的常见变量。在伊马替尼、尼洛替尼或达沙替尼耐药病例中与BCR-ABL突变发生相关的其他变量包括男性、年龄较小、无合并症、开始当前TKI治疗前处于晚期、从诊断到开始当前TKI治疗的间隔时间较长、获得性耐药以及因进展到晚期或血液学衰竭导致的TKI耐药。此外，从TKI失败到检测到BCR-ABL突变的间隔时间、从开始初始TKI治疗到TKI失败以及从开始当前TKI治疗到TKI失败与BCR-ABL突变发生的频率相关。在多变量分析中，确定使用达沙替尼和尼洛替尼以及获得性耐药与T315I突变的发生相关。超过一半的TKI耐药CML患者通过桑格测序发生了BCR-ABL突变。T315I突变是最常检测到的。与BCR-ABL突变发生显著相关的临床变量不仅应用于作为选择后续TKI的依据，还应用于理解TKI耐药机制。
