FLT3基因在成人急性淋巴细胞白血病中突变的特征及临床意义

Characteristics and Clinical Significance of Mutation of FLT3 Gene in Adult Acute Lymphoblastic Leukemia

目的探讨成人急性淋巴细胞白血病(ALL)患者FLT3基因突变特征及其临床意义。方法选择2017年1月至2020年3月在郑州大学第一附属医院确诊的250例初治成人ALL患者,应用二代测序(NGS)技术检测FLT3基因并分析其突变率、突变类型、发生位点及患者临床特征,采用非参数检验分析FLT3突变组与无突变组临床特征的差异,Kaplan-Meier生存曲线及log-rank检验评估其临床预后。结果250例成人ALL患者中,11例发生FLT3突变,突变率为4.40%,包括2个内串联重复(ITD)突变、5个酪氨酸激酶结构域(TKD)突变(2个D835和Y842C、D839G、836_837del共3个非D835)、2个膜旁插入缺失突变(JM-InDel)(Y597delinsPY、598_600del)和3个膜旁点突变(JM-PM)(Y589H、F594I、V592A),部分存在与CREBBP/PAX5基因共突变;FLT3突变组与无突变组年龄、性别、白细胞计数(WBC)、血红蛋白(Hb)、血小板计数(PLT)、淋巴细胞绝对值(LYM)、乳酸脱氢酶(LDH)、骨髓及外周血原始细胞比率比较,差异均无统计学意义(P>0.05);FLT3突变组与无突变组总生存期(OS)及无进展生存期(PFS)比较,差异均无统计学意义(P>0.05)。1例初始高白细胞的急性T淋巴细胞白血病(T-ALL)患者化疗半疗程未缓解,加用索拉菲尼后持续缓解。结论本研究发现了2种FLT3的新基因突变位点及2种共突变基因,FLT3基因突变在成人ALL中不常见,与生存无显著相关,FLT3抑制剂可能对FLT3突变的难治ALL患者有利,需扩大样本量进一步明确FLT3基因突变对预后的影响。

Objective To investigate the FLT3 gene mutation and clinical features of adult patients with acute lymphoblastic leukemia(ALL).Methods Two hundred and fifty cases of newly-treated adult patients with ALL from January 2017 to March 2020 in the First Affiliated Hospital of Zhengzhou University were selected.FLT3 gene was detected by next generation sequencing(NGS),and its mutation rate,mutation type,mutation site and clinical characteristics were analyzed.Non-parametric tests were used to test the difference of clinical characteristics between FLT3 mutation group and non-mutation group.Kaplan-Meier survival curve and log-rank test were used to evaluate the clinical prognosis.Results FLT3 mutations occurred in 11 of 250 adult ALL patients with a mutation rate of 4.40%,including 2 internal tandem duplication(ITD)mutations,5 tyrosine kinase domain(TKD)mutations(2 D835 and Y842C,D839G,836_837del,3 non-D835),and 2 juxtamembrane indel(JM-InDel)mutations(Y597delinsPY,598_600del),3 juxtamembrane point mutations(JM-PM)(Y589H,F594I,V592A),and some of them were co-mutated with CREBBP or PAX5 gene.There were no significant differences in age,gender,white blood cell count(WBC),hemoglobin(Hb),platelet count(PLT),lymphocyte count(LYM),lactic dehydrogenase(LDH),bone marrow and peripheral blood primordial cells between FLT3 mutation group and non-mutation group(P>0.05).There was no-significant difference in overall survival(OS)and progression-free survival(PFS)between FLT3 mutation group and non-mutation group(P>0.05).One case of acute T-lymphoblastic leukemia(T-ALL)with initial high leukocyte count did not achieve remission after half a course of chemotherapy,and continued remission after addition of sorafenib.Conclusion This study found 2 novel FLT3 gene mutation sites and 2 co-mutation genes.FLT3 gene mutation is not common in adult ALL and has no significant correlation with survival.FLT3 inhibitors may be beneficial to refractory ALL patients with FLT3 mutation.It is necessary to expand the sample size to further clarify the impact of FLT3 gene mutation on prognosis.