核心结合因子相关急性髓系白血病的缓解和预后异质性多因素分析

A multivariate model for predicting induction response and prognosis in core binding factor acute myeloid leukemia

目的综合运用传统细胞形态学、免疫学、细胞遗传学和分子生物学(MICM)分型结合二代测序,评价当前诱导和巩固模式下,核心结合因子相关急性髓系白血病(CBF-AML)的疗效和预后因素,以进一步优化CBF-AML的治疗选择。方法收集206例成人初治CBF-AML患者,年龄16~65岁,包括152例t(8;21)AML和54例inv(16)AML。采用多因素logistic和Cox回归模型,分析MICM分型结合51种二代测序基因突变特征对完全缓解(CR)率、无病生存(DFS)和总生存(OS)的影响。结果标准方案诱导1个疗程后,inv(16)AML患者的CR率为100%(54/54),显著高于t(8;21)AML患者的86.4%(127/147)(P=0.005)。融合转录本水平和KIT突变是t(8;21)AML患者CR率的独立影响因素(P值分别为0.044和0.027)。inv(16)AML患者的DFS和OS有优于t(8;21)AML患者的趋势,但尚无统计学意义(P值分别为0.066和0.306)。多因素Cox分析显示,CD19^-和女性是t(8;21)AML患者不良DFS的独立预测因素(CD19:P=0.000;性别:P=0.006)。CD19和性别结合的分析显示,女性CD19^-患者的DFS显著差于男性CD19^+患者(Bonferroni检验,P<0.00001)。每例患者基因突变个数、FLT3-ITD和附加核型异常不影响CR率和DFS(P值均>0.05)。结论inv(16)AML患者的诱导疗效优于t(8;21)AML患者。t(8;21)AML患者高融合转录本水平或阳性KIT突变与低CR率有关,且CD19阴性表达、女性因素可预测复发增加。

Objective To evaluate the efficacy and prognostic factors in core binding factor(CBF)acute myeloid leukemia(AML)under current therapy modalities,therefore optimizing the treatment strategies.Methods Standard cytological and immune methods including next generation sequencing(NGS)were used for risk stratification.Complete remission(CR)rate,disease-free survival(DFS)and overall survival(OS)were assessed by multivariate Logistic and Cox regression models in a total of 206 adults(aged 16-65 years)with CBF-AML,including 152 AML patients with t(8;21)and 54 with inv(16).Results The CR rate of inv(16)patients after first course was 54/54(100%),significantly higher than that of t(8;21)patients[127/147(86.4%),P=0.005].The fusion transcript level and KIT mutation were independent factors related to CR rate in t(8;21)patients(P=0.044 and 0.027;respectively).DFS and OS in inv(16)patients tended to be more superior than that in t(8;21)patients(P=0.066 for DFS;P=0.306 for OS;respectively).Multivariate Cox identified negative expression of CD19 and female gender the independent predictors of inferior DFS in t(8;21)patients(P=0.000 for CD19;P=0.006 for sex;respectively).Analysis of combining CD19 with gender indicated that females/CD19^- subpopulation had significantly poor DFS than did males/CD19^+ ones(Bonferroni-P<0.00001).The number of mutations in each patient,FLT3-ITD and additional karyotype abnormalities did not affect CR rate and DFS(all P>0.05).Conclusions Patients with inv(16)have better induction response than those with t(8;21).High level of fusion transcripts and positive KIT mutation are associated with low CR rate in t(8;21)patients.Negative CD19 expression and female gender are independent predictors of inferior DFS in t(8;21)patients.