Analysis Of Common Genetic Mutation Profiling And Its Clinical Significance In Patients With Acute Myeloid Leukemia

A.ObjectiveIn this study,we analyze the gene mutations,clinical features and laboratory characteristics and risk features of treatment response and prognosis in acute myeloid leukemia(AML)patients.B.MethodsClinical data of 384 newly diagnosed AML patients who are hospitalized in Qilu Hospital of Shandong University from Mar 1,2017 to Jun 20,2022 are retrospectively analyzed.The prognostic classification ability of European Leukemia Net(ELN)in 2022 is validated and characteristics of clinical,gene mutation and cytogenetic and their effects to the response of chemotherapy,disease progress and prognosis are further explored.C.Resultsa.Clinical featuresIn this study,384 newly diagnosed patients with non acute promyelocytic leukemia(non-M3 AML)are analyzed.The median age of patients is 52.5 years old and the account of patients of primary AML is 90.6%.Male patients are slightly more than female patients,and the ratio is 1:0.89.The disease is characterized as higher bone marrow primitive cells and white blood cell counts,anemia,thrombocytopenia and normal karyotype.The account of patients treated with tensive chemotherapy is 59.4%.b.Gene mutation profilesHigh gene mutation frequencies and co-mutations are usually observed in AML patients.Mutations are presented in 87.1%of AML patients.AML patients are characterized by higher mutation frequency rates of FLT3-ITD,NPM1 and DNMT3A,while the lowest mutation frequency is SETBP1.Co-mutations is detected in 57.8%of patients and those three genes with high mutation frequency have higher co-mutation frequencies.Higher mutation frequency of FLT3-ITD is found in female,NRAS and AML1 are found in secondary or treatment-related AML(s/t-AML)patients,NPM1 is found in gender and primitive patients and SRSF2 is found in male and elder patients.The variant allele frequencies(VAF)of DNMT3A,CEBPA and TET2 are higher which indicates that those mutations occur in early stage.c.Re-classification of ELN risk classificationThe patient number ratio of favorable,intermediate and poor groups is 40.5%,36%and 23.5%,respectively,in 2017ELN risk class classification and is 37.2%,35.8%and 27.1%in 2022ELN risk class classification.The proportion of patients in poor group is increased after re-classification.The risk group is changed in 13.1%of patients and most of them are re-classified as intermediate(40.4%)and poor(38.3%)groups.d.Response assessmentSince efficacy evaluation point,the complete remission(CR)rate is 73.6%,and higher CR ratio is observed in patients treated with intensive chemotherapy(81.6%)than patients treated with low-intensive chemotherapy(61.2%).S/T-AML and U2AF1 mutation is blocking factor of CR in all patients while female and CEBPA mutation is found as motivational factor.Mutation of IDH1 is also identified as interfering factor in patients treated with intensive chemotherapy.In patients treated with low-intensive chemotherapy,no CR-related mutations are noted.The CR rate showed consistent trends in all patients,patients treated with intensive chemotherapy and low-intensive chemotherapy.The rank of CR rate in risk classification,from high to low,is poor,intermediate and favorable.ELN risk classification exhibits stronger classification effect on response in all patients and patients treated with intensive chemotherapy.Until the last follow-up date,31.7%of patients suffer from disease recurrence and higher recurrence rate is observed in patients treated with low-intensive chemotherapy.Positive minimal residual disease(MRD-positive)and higher age are independent relevant factors that influenced recurrence.TP53 mutation is relevant to recurrence.e.Survival analysisWe observe worse relapse-free survival(RFS)in patients with MRD-positive.The statistically differences of overall survival(OS)among ELN risk classification are observed in all patients and patients treated with intensive chemotherapy,but no statistically significance is observed in intermediate and poor groups.The statistically difference of progression free survival(PFS)among 2022ELN risk classification is observed in all patients,but no statistically significance is among 2017ELN risk classification.The study demonstrates that age,white blood cell count,complex karyotype and gene mutations of IDH1,JAK2 and PFH6 are determined as independent risk factors that affects OS in AML patients.Age and white blood cell count are independent risk factors for PFS and IDH1 exhibited borderline significance(p=0.051).Age,white blood cell count,MRD and TP53 mutation are independent risk factors affecting RFS.The prognostic significance of the FLT3-ITD mutation with mutated or non-mutated NPM1 is observed in patients with normal karyotype.D.Conclusion1.The molecular mechanisms underlying the pathogenesis of AML are intricate.High gene mutation frequency and co-mutations are usually observed in AML patients.With a high response and recurrence rate,AML patients are characteristic as normal karyotype.2.AML patients are characterized by higher mutation frequency rates of FLT3-ITD,NPM1 and DNMT3A and 57.8%of patients are observed co-mutation.The variant allele frequencies(VAF)of DNMT3A,CEBPA and TET2 are higher which indicates that those mutations occur in early stage.3.Re-classification of patients in 2017ELN risk classification is conducted by 2022ELN risk classification.The number of patients in poor group is increased after re-classification.ELN demonstrates stronger prognostic stratification capability in patients treated with intensive chemotherapy and 2022ELN shows stronger stratification ability than 2017ELN for OS and PFS.4.Clinical variables such as age and type and gene mutations of CEBPA and U2AF1 are identified as independent risk factors for CR in all patients.In patients treated with intensive chemotherapy,IDH1 mutation is regarded as an independent risk factor for CR.MRD-positive and higher age are recognized as risk factors for recurrence.TP53 mutation is relevant to recurrence.5.Age,white cell counts,complex karyotype and gene mutations of IDH1,JAK2 and PFH6 are determined as independent risk factors that affected OS in AML patients.Age and white blood cell count are independent risk factors for PFS and IDH1 exhibited borderline significance.Age,white blood cell count,MRD and TP53 mutation are independent risk factors for RFS.The prognostic significance of the FLT3-ITD independently of NPM1 mutation is only observed in patients with normal karyotype but not all patients.