Analysis Of Clinical Characteristics And Prognostic Factors Of Acute Myeloid Leukemia Patients With CEBPA Double Mutations

Objective:Acute myeloid leukemia(AML)is a malignant hematopoietic proliferative disease marked by the accumulation of myeloid precursor cells in the bone marrow.With the progress of sequencing,molecular biomarkers in AML prognosis are becoming increasingly important when making treatment decisions.AML with double mutation of CEBPA gene has become an independent subtype in WHO.Although it is a group with favorable prognosis,about 40% of patients with double mutation of CEBPA still have a recurrence,suggesting that this is a group of diseases with high heterogeneity,and the prognostic factors affecting patients with double mutation of CEBPA are still worth further investigation.To further clarify the clinical characteristics and prognostic risk factors of AML patients with double mutation of CEBPA gene,this study retrospectively analyzed 101 newly diagnosed AML patients with double mutation of CEBPA gene in our center,and explored the clinical characteristics and prognostic factors of AML patients with double mutation of CEBPA gene.Methods:We retrospectively analyzed 101 patients with AML with double mutation of CEBPA gene(excluding APL patients)who were initially diagnosed on December 31,2012 at the department of hematology,cancer center of Bethune first hospital,Jilin University.The bone marrow fluid of AML patients was collected for morphological analysis,immunological analysis,cytogenetic analysis.Second-generation sequencing methods was used to detect the mutation status of the patients' genes and to screen for AML related gene mutations.Clinical data including age,sex,immune typing,peripheral blood leukocyte count,hemoglobin number,platelet number,bone marrow primitive cell ratio,fusion gene,chromosome karyotype,gene mutation,induction chemotherapy regimen,and follow-up data were collected.Patients who completed 2 courses of high-dose cytidine consolidation were included in the survival analysis to analyze the clinical characteristics and prognostic factors of CEBPA gene mutation.Results:A total of 101 patients with AML with CEBPA double mutation were included,including 53 males and 48 females,with ages ranging from 9 to 79 years and a median age of 43 years.According to FAB classification,M2(54.46%,55/101)was the main type.According to cytogenetic analysis,the proportion of normal karyotype was 92.3%(72/78),and the patients with abnormal karyotype were all in the intermediate prognosis group.A total of 38 co-mutated genes were detected,with a total mutation rate of 85.15%(86/101).The most frequent co-mutated genes were WT1(23.76%),GATA2(20.79%),CSF3R(19.80%),NRAS(16.83%),FLT3-ITD(9.90%),TET2(9.90%),EZH2(7.92%),DNMT3A(6.93%),RAD21(5.94%)and KIT(4.95%).In terms of the number of co-mutated genes,the most common was 1 co-mutation(35.64%,36/101),followed by 2 co-mutations(20.79%,21/101)and 3 co-mutations(16.83%,17/101).From a functional perspective,the most common co-mutated gene types were signaling pathway-related mutations(50.5%)and methylation-related gene mutations(39.6%),followed by tumor suppressor genes(24.75%)and transcription factor related mutations(23.76%).In addition,chromatin modification gene(9.9%),viscoprotein complex(6.93%)and spliceosome complex gene(2.97%)were also seen.A total of 82 cases of patients with CR rate can be analyzed,CR rate after one course of treatment was 80.49%(66/82),CR rate after one or two courses of treatment was 95.12%(78/82).The CR rate of patients with common comutations was analyzed,and the results suggest patients with GATA2 co-mutation had a CR rate of 55.56%,significantly lower than that of GATA2 wild-type patients,the result was statistically significant(P = 0.003).In terms of the number of co-mutated genes,patients with 3 or more co-mutated genes had a significantly lower CR rate after one course of treatment(P=0.001).Seventy-two patients who completed at least two courses of high-dose cytarabine intensive therapy were followed for a long period of time,ranging from 3 months to 78 months,with a median follow-up time of 18.5 months.Seven patients received hematopoietic stem cell transplantation.This study analyzed 66 patients with complete sequence MRD information.In this group,the median OS was 53.2 months,and the 1-,3-and 5-year OS rates were 96.7%,67.8% and 50.8%,respectively.The median RFS was 44.0 months,and the 1-,3-and 5-year RFS rates were 92.0%,62.5% and 42.6%.Age,sex,peripheral leukocyte,hemoglobin,platelet and bone marrow cell number at the time of initial diagnosis had no effect on the prognosis of the patients.In this study,the prognosis of common co-mutations in AML patients with CEBPA double mutation was analyzed,and the results indicated that OS and RFS were significantly reduced in patients with 3 or more co-mutations.Patients with CSF3 R mutations had lower OS and RFS.RFS was significantly reduced in patients with WT1 and NRAS mutations.The prognosis of AML patients with CEBPA double mutation was analyzed with MRD level as the monitoring index,and the OS and RFS of patients with 2 courses of MRD negative were significantly better than those with MRD positive.The factors affecting prognosis were included in COX multivariate analysis,and the results suggested that the independent prognostic factors affecting RFS were the number of co-mutations,combined with the co-mutations of WT1 and NRAS.Conclusion:1.Double mutations of CEBPA gene were mostly found in FAB type M2,and was mainly found in chromosome normal karyotype.A few abnormal karyotypes were also found in the middle group of cytogenetic prognosis.2.38 co-mutations were found in 86 patients,the incidence of co-mutations was 85.15%.The genes associated with tyrosine kinase signaling pathway were the most frequently associated with gene mutations,while WT1 was the most frequently associated with gene mutations.3.The CR rate of patients with double mutation combined with GATA2 for one course of treatment was significantly lower than that of patients with GATA2 wild type.Patients with 3 or more co-mutated genes had a significantly reduced CR rate during a course of treatment.4.OS and RFS were significantly reduced in patients with 3 or more co-mutations.Patients with CSF3 R mutations had lower OS and RFS.RFS was significantly reduced in patients with WT1 and NRAS mutations.5.2 OS and RFS of MRD-negative patients with a course of treatment were significantly better than that of MRD-positive patients.