费城染色体阳性急性淋巴细胞白血病ABL激酶区突变的特征分析及其临床意义  

The characteristics and clinical significances of ABL kinase domain mutations in Philadelphia chromosome positive acute lymphoblastic leukemia

作　　者：傅维佳 胡晓霞[1] 王丽炳 黄爱杰 高磊[1] 倪雄 陈莉[1] 章卫平 王健民[1] 杨建民[1] FU Wei-jia;HU Xiao-xia;WANG Li-bing;HUANG Ai-jie;GAO Lei;NI Xiong;CHEN Li;ZHANG Wei-ping;WANG Jian-min;YANG Jian-min(Department of Hematology,Institute of Hematology,Changhai Hospital,Navy Military Medical University,Shanghai 200433,China)

机构地区：[1]海军军医大学长海医院血液科中国人民解放军血液病研究所

出　　处：《中国临床医学》2019年第5期703-709,共7页Chinese Journal of Clinical Medicine

基　　金：国家自然科学基金面上项目(81770160,81470321,81530047,81870143);上海市卫生计生委卫生系统优秀学科带头人培养计划(2017BR012)~~

摘　　要：目的:探讨酪氨酸激酶抑制剂(tyrosine kinase inhibitor, TKI)耐药的费城染色体阳性急性淋巴细胞白血病(philadelphia chromosome positive acute lymphoblastic leukemia, Ph +ALL)ABL激酶区突变的特征及其临床意义。方法:回顾性分析99例Ph +ALL患者临床特征、预后、分子遗传学以及ABL激酶区突变的特征。结果: 99例Ph +ALL患者共发生TKI耐药38例,发生耐药的中位时间为治疗后8个月。发生TKI耐药的患者5年总生存率(overall survival, OS)和无复发生存率(relapse free survival, RFS)均较未耐药者低[(34.2±8.0)% vs (61.4±6.7)%, P =0.044;(6.7±4.5)% vs (68.6±6.8)%, P <0.001]。32例患者于移植前发现TKI耐药,13例接受异基因造血干细胞移植(allogeneic hematopoietic stem cell transplantation, allo-HSCT);移植组与未移植组耐药后1年OS差异有统计学意义[(68.4±13.1)% vs (17.8±9.2)%, P < 0.001 ],RFS差异无统计学意义。38例患者中检测到ABL激酶区10个位点12种突变,突变比例为52.63%(20/38),其中T315I突变比例最高,占突变患者的45.00%(9/20),其次为E255K/V [40.00%(8/20)]和Y253H/F [15.00%(3/20)]。结论: Ph +ALL发生TKI耐药的主要机制为ABL激酶区突变,最常见的突变为T315I突变;发生ABL激酶区突变后,allo-HSCT仍是较为理想的治疗选择。Objective: To investigate the characteristics and clinical significances of ABL kinase domain mutations in tyrosine kinase inhibitor (TKI) resistant Philadelphia chromosome positive acute lymphoblastic leukemia (Ph +ALL). Methods: The clinical characteristics, prognosis, molecular genetic characteristics, and ABL kinase domain mutations of 99 patients with Ph +ALL were retrospectively analyzed. Results: Among the 99 Ph +ALL patients, TKI resistance was identified in 38 patients with median 8 months from treatment to resistant occurrence. The 5-year overall survival (OS) rate and relapse free survival (RFS) rate in TKI resistant group was lower than those in non-resistant group ([34.2±8.0]% vs [61.4± 6.7 ]%, P =0.044;[6.7±4.5]% vs [68.6±6.8]%, P =0.000). A total of 32 patients developed TKI resistance during consolidation, and 13 patients received allogeneic hematopoietic stem cell transplantation (allo-HSCT). Patients treated with allo-HSCT had better 1-year OS rate compared with patients without allo-HSCT ([68.4±13.1]% vs [17.8±9.2]%, P < 0.001 ), while patients in two groups had similar 1-year PFS. Twelve kinds of mutations were detected in 10 amino acid sites, and 52.63% patients (20/38) had ABL kinase domain mutations. The most frequent mutation was T315I (45%), followed by E255K/V (40%) and Y253H/F (15%). Conclusions: The primary mechanism of TKI resistant in Ph +ALL patients was ABL kinase domain mutations, and T315I mutation was the most frequent. For patients with ABL kinase domain mutations, allo-HSCT is still an ideal treatment option.

关 键 词：酪氨酸激酶抑制剂 白血病 耐药 突变 ABL激酶区 

分 类 号：R733.7[医药卫生—肿瘤]