| Objective:Next-generation sequencing(NGS)technology has greatly improved the understanding of genetic changes in AML from diagnosis to relapse and enhanced the dynamic assessment of the disease,which may intervene in the clinical management and prolong the survival of these patients.In this paper,we explore the changes in gene mutation profiles before and after relapse in patients with relapsed AML and assess their clinical significance.Methods:Retrospective analysis of gene mutations in AML patients between January 2018 and June 2022 at the Department of Hematology,Oncology Center,First Hospital of Jilin University,who relapsed after remission with initial treatment and underwent second-generation sequencing at both initial diagnosis and relapse.General clinical characteristics(including gender,age,initial white blood cell count,bone marrow primitive cell count,chromosomes,fusion genes,induction and consolidation regimens,duration of remission,hematopoietic stem cell transplantation,etc.),second-generation sequencing mutations before and after relapse,and treatment and survival after relapse were collected.We compared the gene mutation characteristics of patients before and after relapse to investigate the effect of pre-relapse treatment on the pattern of gene mutation changes and the effect of post-relapse gene changes on the remission rate and survival.Results:1.Comparing the gene mutation characteristics of 90 relapsed AML patients before treatment with all primary AML patients who were admitted to our center during the same period,we found that the relapsed patients had a lower proportion of DNA methylation gene mutations,a higher proportion of signal transduction factor and chromatin modification gene mutations.Among them,NRAS gene mutations accounted for 28.9% of the relapsed population,while only 14.7% of the overall population,with a statistically significant difference(P=0.008).2.Comparing the gene mutations in 90 patients before and after relapse,we found that the number of gene mutations decreased after relapse compared with the initial diagnosis(2.5(0～6)vs.3(0～6),P=0.022);the proportion of DNA methylation,myeloid transcription factor and chromatin modification gene mutations increased,while the proportion of signaling pathway gene and nucleophosmin gene mutations decreased during relapse.Comparing of the mutation changes in each gene before and after relapsed,we suggested that the mutation rate of nucleophosmin gene NPM1 decreased significantly(P=0.028).3.Among the 90 patients,20 patients(22.22%)showed new mutations at the time of relapse,24 patients(26.67%)had reduced mutations(loss group),29 patients(32.22%)had both new and reduced mutations(mixed group),and 17 patients(stable group)had no change in mutation type(18.89%).The new mutations were mainly in the genes of signal transduction pathway,chromatin modification,DNA methylation,myeloid transcription factor,etc.;the reduced mutations were mainly in the genes of signal transduction pathway,myeloid transcription factor,DNA methylation,chromatin modification,nucleophilin protein,etc.In the stable group,10 patients showed reduced VAF,1 patient showed increased VAF,and 2 patients had both with increased and decreased VAF in different genes.Statistical analysis for genes with more mutations gained and lost,revealed statistically significant differences in changes for FLT3-ITD(P=0.006),NRAS(P<0.001),GATA2(P<0.001),KIT(P=0.004),and PTPN11(P=0.012).4.For the comparative analysis of gene mutation patterns with or without the application of demethylation therapy before relapse,it was found that in patients under 60 years of age,the application of demethylation therapy had a statistically significant effect on gene mutation patterns and was less likely to result in gain genes(P=0.026).The differences in the time between when patients first achieved remission and relapse,the time between relapse and the end of the last chemotherapy treatment had no statistically significant effect on gene patterns.5.84 patients received retreatment after relapse in 90 patients,including chemotherapy induction in 44 patients treated,with single demethylation in 5 cases,demethylation combined with chemotherapy in14 cases,demethylation combined with Venetoclax in 15 cases,and salvage transplantation in 6 cases,with an overall CR rate of 47.62 %(40/84).There was no statistically significant difference between different treatment regimens in comparing the CR rates of patients with different gene mutation patterns.There was no statistically significant difference in survival comparing patients with different mutation patterns.Patients with NPM1(P=0.004),NRAS(P<0.001),and PTPN11(P=0.0107)mutations had a significant decrease in survival after relapse.There was a trend of decrease in survival in FLT3-ITD positive patients,but the difference was not statistically significant.No significant effect on survival was seen for GATA2 mutation positivity.Patients receiving transplantation had significantly longer survival than non-transplantation patients.Conclusion:1.The gene mutations after relapse of AML had significant changes compared with the initial diagnosis,and the new mutations were mainly in the genes of signal transduction kinesis,chromatin modification,DNA methylation,oncogene,and myeloid transcription factor;the reduced mutations were mainly in the genes of signal transduction kinesis,myeloid transcription factor,DNA methylation,chromatin modification,and nucleophilin protein.NPM1,FLT3-ITD,NRAS,GATA2,KIT,and PTPN11 genes varied greatly after relapse.2.Four mutation pattern changes in the gene mutation(acquisition group,loss group,stable group and mixed group)did not show any significant effect on the remission rate and overall survival rate with retreatment.3.The presence of NRAS,NPM1 and PTPN11 mutations after relapse decreased survival rate,and the presence of FLT3-ITD mutations had a trend to decrease survival rate.Patients who received transplantation after relapse had an increased survival rate compared to those who did not. |
PDF Full Text Request