分子遗传学联合骨髓象检测在正常核型急性髓系白血病预后判断中的价值

Value of molecular genetics combined with bone marrow imaging detection in the prognosis judgement of acute myeloid leukemia with normal karyotype

目的探讨NPM1和FLT3基因突变联合骨髓象检测对初治正常核型急性髓系白血病(CN-AML)患者预后判断的价值。方法回顾性分析2010年1月至2014年1月长治医学院附属和平医院的100例原发、初治CN-AML(非M3型)患者临床资料。入组患者均在诱导治疗结束当天或结束后第1天(T时间点)行骨髓象检查。根据FLT3和NPM1基因状态、T时间点骨髓幼稚细胞比例对AML患者分别进行单因素和多因素预后分析。结果100例患者中,36例发生FLT3基因突变,44例发生NPM1基因突变。FLT3+组和FLT3-组CN-AML患者的完全缓解(CR)率分别为13.9%(5/36)、71.9%(46/64)(P<0.01),2年无复发生存(RFS)率分别为5.6%、59.8%(P<0.01),2年总生存(OS)率分别为15.6%、66.2%(P<0.01),FLT3+组的中位RFS时间和中位OS时间分别为6.9、9.4个月,FLT3-组患者的中位RFS和中位OS时间均未达到,两组间各指标差异均有统计学意义(均P<0.01);NPM1+组与NPM1-组间CR率、2年RFS率及2年OS率差异均无统计学意义(均P>0.05)。NPM1+FLT3-组的CR率、2年RFS率及2年OS率高于NPM1-FLT3-、NPM1-FLT3+和NPM1+FLT3+组,NPM1-FLT3+组和NPM1+FLT3+组预后最差,且两组间CR率、RFS时间及OS时间差异均无统计学意义(均P>0.05)。T时间点骨髓幼稚细胞比例<0.05组患者预后均较≥0.05组好(均P<0.05)。根据FLT3和NPM1基因分为预后良好组(NPM1-FLT3-)、预后中等组(NPM1+FLT3-)及预后不良组(NPM1-FLT3+和NPM1+FLT3+)。预后良好+T时间点骨髓幼稚细胞比例<0.05组、预后良好+T时间点骨髓幼稚细胞比例≥0.05组、预后中等+T时间点骨髓幼稚细胞比例<0.05组CR率、2年RFS率及2年OS率差异均无统计学意义(均P>0.05);预后中等+T时间点骨髓幼稚细胞比例≥0.05组、预后不良+T时间点骨髓幼稚细胞比例<0.05组预后相当,均预后中等;预后不良+T时间点骨髓幼稚细胞比例≥0.05组预后最差。经过Cox多因素回归分析,FLT3基因突变和T时间点骨髓幼稚细胞比例均为影响CN-AML患者RFS和OS的独立影响因素(均P<0.05),NPM1是影响FLT3-患者RFS和OS的独立预后因素(均P<0.05)。结论诱导化疗结束后,根据分子遗传学和T时间点骨髓幼稚细胞比例,可以早期、客观地评估CN-AML患者对化疗方案的反应性及敏感性,对预后判断具有一定价值。

Objective To investigate the value of NPM1 and FLT3 gene mutation combined with bone marrow imaging detection in the prognosis judgement of initial treatment cytogenetically normal acute myeloid leukemia(CN-AML).Methods The clinical data of 100 patients(non-M3 type)with primary and initial treatment CN-AML from January 2010 to January 2014 in the Peace Hospital Affiliated of Changzhi Medical College were retrospectively analyzed.All patients were enrolled in the bone marrow imaging examination on the end day of induction treatment or the first day after the end of induction treatment(T time point).Univariate and multivariate prognostic analyses were performed on AML patients according to FLT3 and NPM1 gene status,bone marrow juvenile cell ratio at T time point.Results A total of 100 patients included 36 cases with FLT3 gene mutation and 44 cases with NPM1 gene mutation.The complete remission(CR)rate of CN-AML patients was 13.9%(5/36)and 71.9%(46/64),respectively(P<0.01),2-year recurrence-free survival(RFS)rate was 5.6%and 59.8%,respectively(P<0.01),2-year overall survival(OS)rate was 15.6%and 66.2%,respectively in FLT3+group and FLT3-group(P<0.01).The median RFS and median OS time in FLT3+group was 6.9 months and 9.4 months,respectively,and the median RFS and median OS time in FLT3-group had not yet reached.There were no significant differences of all the indexes between the two groups(all P<0.01).And there were no significant differences in CR rate,2-year RFS rate and 2-year OS rate between NPM1+group and NPM1-group(all P>0.05).The CR rate,2-year RFS rate and 2-year OS rate in NPM1+FLT3-group were better than those in NPM1-FLT3-,NPM1-FLT3+and NPM1+FLT3+groups;NPM1-FLT3+and NPM1+FLT3+groups had the worst prognosis,and there were no statistical differences in the CR rate,RFS and OS time between the two groups(all P>0.05).The prognosis of the patients in bone marrow juvenile cell ratio<0.05 group at T time point was better than that in ratio≥0.05 group(all P<0.05).CN-AML patients were classified into the good prognosis group(NPM1-FLT3-),the medium prognosis group(NPM1+FLT3-),and the poor prognosis group(NPM1-FLT3+and NPM1+FLT3+)according to the FLT3 and NPM1 genes.The good prognosis group+the ratio of bone marrow juvenile cells at T time point<0.05 group,the good prognosis group+the ratio of bone marrow juvenile cells at T time point≥0.05 group,the medium prognosis group+the ratio of bone marrow juvenile cells at T time point<0.05 group had no statistical differences in CR rate,2-year RFS rate and 2-year OS rate(all P>0.05).The medium prognosis group+the ratio of bone marrow juvenile cells at T time point≥0.05 group,the poor prognosis group+the ratio of bone marrow juvenile cells at T time point<0.05 group had the equivalent prognosis,and the average prognosis was moderate;the poor prognosis group+the ratio of bone marrow juvenile cells at T time point≥0.05 group had the worst prognosis.According to Cox multivariate regression analysis,FLT3 gene mutation and the ratio of bone marrow juvenile cells at T time point were independent influencing factors for RFS and OS in CN-AML patients(all P<0.05).NPM1 was an independent prognosis factor affecting RFS and OS of FLT3-patients(all P<0.05).Conclusions After induction chemotherapy,the responsiveness and sensitivity of AML patients to chemotherapy regimen can be assessed early and objectively according to molecular genetics and the ratio of bone marrow juvenile cells at T time point,which has a certain value in the prognosis judgement.