| Objectives: To evaluate the clinical characteristics and outcomes of cytogenetically normal acute myeloid leukemia(CN-AML)patients with double mutations in NPM1 and DNMT3 A.Methods: We retrospectively reviewed the clinical data of adult patients who were firstly diagnosed with AML(non-APL)in Fujian Medical University Union Hospital from January 1st,2013 to June 30 th,2016.And a total of 317 CN-AML patients were included in this study.These patients were classified into four groups according to NPM1 and DNMT3 A mutation status: those with double mutant(NPM1+/DNMT3A+),those with NPM1 single mutant(NPM1+/DNMT3A-),those with DNMT3 A single mutant(NPM1-/DNMT3A+),and those with wide-type(NPM1-/DNMT3A-).We then compared the clinical characteristics and survival outcomes of these four groups to evaluate the effects of co-occurrence mutations in both NPM1 and DNMT3 A on the treatment outcomes of CN-AML patients.Results: 1.Among these 317 CN-AML patients,NPM1 mutations and DNMT3 A mutations were detected in 82(25.9%)and 72(22.7%)cases,respectively.Among them,35 cases(11.0%)had mutations in both NPM1 and DNMT3A(NPM1+/DNMT3A+).2.The age,WBC count and lactate dehydrogenase(LDH)at onset in double mutant group(NPM1+/DNMT3A+)were significantly higher than in wide-type group(NPM1-/DNMT3A-)(P=0.006,0.044,0.023 respectively).And there were no statistically significant differences in gender distribution,HGB,PLT count,blast percentage in blood,uric acid(UA),and alpha-hydroxybutyric dehydrogenase(α-HBDH)among four groups(P>0.05).3.No significant differences were found in complete remission(CR)rate between double mutant group(NPM1+/DNMT3A+)and other groups.But the relapse frequency was significantly higher in double mutant group(NPM1+/DNMT3A+)than in NPM1 single mutant(NPM1+/DNMT3A-)group(P=0.023).4.NPM1+/DNMT3A+ group had a shorter relapse-free survival(RFS)than wide-type(NPM1-/DNMT3A-)or NPM1+/DNMT3A-groups(P=0.014,0.001 respectively),although no significant difference was found between NPM1+/DNMT3A+ group and NPM1-/DNMT3A+ group.There were no significant differences in overall survival(OS)(P=0.175)among four groups.5.Among the patients without FLT3-ITD mutation,RFS was significantly shorter in NPM1+/DNMT3A+ group than in NPM1+/DNMT3A-or NPM1-/DNMT3A-groups(P=0.033,P=0.026 respectively);similarly,RFS was significantly shorter in NPM1-/DNMT3A+ group than in NPM1+/DNMT3A-or NPM1-/DNMT3A-groups(P=0.011,P=0.024 respectively).OS was significantly shorter in both NPM1+/DNMT3A+ and NPM1-/DNMT3A+ groups than in NPM1+/DNMT3Agroup(P=0.034,0.037,respectively).6.The triple mutant group(NPM1+/DNMT3A+/FLT3-ITD+)had a shorter RFS than in NPM1+/FLT3-ITD+ group(P=0.008).But there were no significant differences in OS between triple mutant group(NPM1+/DNMT3A+/FLT3-ITD+)group and double mutant groups(NPM1+/DNMT3A+ or NPM1+/FLT3-ITD+)(P=0.832,0.685 respectively).7.Multivariate survival analysis using Cox’s regression model showed that DNMT3 A mutations was an independent unfavorable factor for RFS(HR=4.289);both age(≥60)and FLT3-ITD mutation were independent unfavorable factors for OS(HR=3.812,2.817 respectively).Conclusion: 1.The double mutation of NPM1 and DNMT3 A is associated with higher age,WBC count and LDH level at onset.2.No significant differences exist in complete remission(CR)rate between double mutant group(NPM1+/DNMT3A+)and other groups.3.CN-AML patients with double mutations in NPM1 and DNMT3 A have higher relapse frequency and shorter RFS.4.Two types of double mutant,NPM1+/DNMT3A+ and NPM1+/FLT3-ITD+ are unfavorable prognostic factors for CN-AML.5.CN-AML patients with triple mutations in NPM1,DNMT3 A and FLT3-ITD have worse prognosis.6.In CN-AML patients,DNMT3 A mutation is an independent unfavorable factor for RFS in CN-AML patients;both age(≥60)and FLT3-ITD mutation are independent unfavorable factors for OS. |
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