细胞遗传学检测在慢性髓性白血病中的临床意义

Clinical significance of cytogenetic monitoring in chronic myeloid leukemia

目的探讨酪氨酸激酶抑制剂（TKI）时代，慢性髓性白血病（cML）病程演进与细胞遗传学的关系。方法应用骨髓细胞短期培养法，对387例初诊CML患者行染色体G显带技术核型分析，结合ABL激酶区点突变检测分析细胞遗传学变化与CML病程演进的关系。结果间接荧光原位杂交（FISH）技术检测387例CML患者BCR—ABL融合基因阳性，其中Ph’CML占94．1％（364／387），Ph—CML占5．9％（23／387）；标准易位t（9；22）（q34；q11）320例（87．9％），变异易位5例（1．4％），初诊Ph’合并额外染色体异常（ACA）39例（10．7％）。合并ACA中“主要路径”异常22例（56．4％），“次要路径”异常15例（38．5％），-Y异常2例（5．1％）。23．4％（71／303）标准易位患者在TKI治疗中出现ACA，主要为染色体数目异常，此类患者疾病进展比例高（X2=168．21，P〈0．001）、更易合并点突变（x2=29．04，P〈0．001）。初诊CML慢性期合并ACA患者与标准易位患者相比，有较低的无事件生存（EFS）及无病生存（DFS）率（P值分别为0．037和0．003），但总生存（OS）率差异无统计学意义（P=0．209）。CML慢性期患者TKI治疗过程中出现ACA者与无ACA者相比，OS、EFS、DFS率均降低（P值均〈0．001）。进展期合并ACA患者长期生存率下降（P=0．086）。结论CML在病程演进中往往合并ACA，此类患者更易发生不良事件或疾病进展，在TKI治疗过程中规律、及时行染色体核型分析及点突变检测对疗效评估及预后判断具有重要意义。

Objective To analyze the association of cytogenetic abnormalities with the prognosis of chronic myeloid leukemia （CML） patients in tyrosine kinase inhibitors （TKI） era. Methods Karyotype analysis of chromosome G-banding was carried out in 387 newly diagnosed CML patients by short-term culture of bone marrow cells. The correlation of cytogenetic abnormalities and CML progression was explored in combination with ABL tyrosine point mutations. Result Of 387 patients with positive BCR- ABL fusion gene assayed by fluorescence in situ hybridization （FISH） technique, 94.1% （364/387） patients were Ph positive and 5.9% （23/387） Ph negative; 320 patients （87.9%） had a translocation t（9; 22 ） （ q34;q 11 ） and 5 （ 1.4% ） a variant translocation t （v;22）. Additional cytogenetic aberrations （ACA） at diagnosis were found in 10.7% （39/387） Ph＋ patients, major route ACA in 22 （56.4 %） cases and minor route ACA in 15 （38.5%） cases and 2 patients （5.1%） lacked the Y chromosome （-Y）; 23.4%（71/303） patients occurred ACA during TKI treatment and the most frequent abnormalities were abnormal chromosome numbersd, which were likely associated with high proportion of disease progression （X2= 168.21, P〈0.001 ） and ABL tyrosine point mutations （x2=29.04, P〈0.001 ）. Newly diagnosed CML- CPpatients with t （9;22） （q34;q 11 ） had a longer event- free survival （EFS） and disease- free survival （DFS） rates than that of patients with ACA （P=0.037; P=0.003）, while the overall survival （OS） had no significant differences （P=0.209）. As for CML-CP patients that occurred ACA during TKI therapy would have a marked low OS, EFS and DFS （all P 〈 0.001 ） compared with no ACA occurred patients. Survival of advanced patients that occurred ACA were dramatically reduced. Conclusion ACA often emerged during the disease progress in CML patients, regular and timely detection of chromosomes karyotype and ABL tyrosine point mutations during TKI treatment was important for therapeutic evaluation, progress and prognosis of CML.