Laboratory And Clinical Studies Of RUNX1 Mutation-Positive Acute Myeloid Leukemia Based On ELN Stratification

More than 90%of acute myeloid leukemia（AML）patients can be detected at least one gene mutation by second-generation sequencing（NGS）technology.In the domestic and foreign guidelines,NPM1,FLT3,RUNX1 and other gene mutations have been included in the diagnostic classification and prognostic stratification system of AML.In the 4th edition World Health Organization（WHO）Classification of Haematolymphoid Tumours pubulished in 2016,AML with RUNX1 mutation(AML-RUNX1^mut)was recognized as a provisional distinct AML entity.However,this subtype was canceled due to lack of sufficient specificity according to the 5th edition WHO Classification of Haematolymphoid Tumours pubulished in 2022.Meanwhile,AML with RUNX1 and other myelodysplasia-related gene mutations were classified as adverse prognosis in the 2022 European LeukemiaNet（ELN）recommendations for the diagnosis and management of AML.After the update of the new guidelines,there were no relevant clinical studies to verify the above updated points of the new guidelines in China.Objectives:1.To investigate the clinical and prognostic characteristics of AML-RUNX1^mut and verify the updated WHO and ELN guidelines for the diagnosis and prognostic stratification of AML-RUNX1^mut.2.To analyze the effects of RUNX1 mutation on long term survival for AML patients of favorable,intermediate and adverse prognosis based on the prognostic risk stratification criteria of 2017 ELN and analyze the factors affecting the therapeutic effect and survival outcome of AML-RUNX1^mut patients.3.To compare the clinical and prognostic characteristics between AML-RUNX1^mut and AML with myelodysplasia-related gene mutation（AML-MRmut）patients.Methods:Retrospectively collected the laboratory examination and clinical data of newly diagnosed AML patients in the First Affiliated Hospital of Soochow University from January 2017 to December 2021.Targeted NGS panel covering 172 genes was used to detect gene mutations in bone marrow cells at diagnosis.The 1136 patients were divided into RUNX1 mutated and RUNX1 wild type group based on RUNX1 mutation state.The effect of clinical factors and gene mutations on objective remission rate（ORR）,overall survival（OS）and events-free survival（EFS）were analyzed by Logistic regression model,Kaplan-Meier method and Cox regression model.Results:1136 AML patients were enrolled in this study.RUNX1 mutations were detected in 120 patients.There were 71（59.2%）male and 49（40.8%）female,with a median age of 49（16-75）years old.1.The overall incidence of RUNX1 gene mutation was 10.6%（120/1136）,with a median variant allele frequency of 40%（3%～93%）.Eight patients only had RUNX1 mutations and 112 patients were concomitant with other gene mutations.The common co-mutation of RUNX1 were FLT3-ITD（22.5%）,DNMT3A（19.2%）,BCOR（16.7%）and WT1（15.0%）.The detection rates of RUNX1 mutation were extremely low in CEBPA b-zip,NPM1,t（8;21）and inv（16）/t（16;16）patients,which were 3.7%（6/163）,1.8%（4/220）,2.6%（3/117）and 0%（0/48）respectively.2.Compared with RUNX1 wild type AML（AML-RUNX1wt）,AML-RUNX1^mut had a lower ORR（62.7%vs 72.9%,P=0.025）,lower 5-year OS rate（35%vs 43%,HR=1.643,P=0.019）.There was no significant difference in 5-year EFS rate（40%vs 37.3%,HR=1.427,P=0.091）.In the ELN prognostic category of favorable,intermediate and adverse group,there were no significant differences in OS and EFS between RUNX1^mut and RUNX1wt patients.Multivariate Cox regression analysis showed that among the total 1136 AML patients,RUNX1 mutated patients had a trend of death and disease progression,but the differences were not statistically significant（OS:HR=1.352,P=0.129;EFS:HR=1.394,P=0.078）.Forty-two AML-RUNX1^mut patients received allogeneic hematopoietic stem cell transplantation（allo-HSCT）.Allo-HSCT could improve the OS（HR=0.277,P=0.003）,EFS（HR=0.426,P=0.031）for patients of intermediate prognosis and OS（HR=0.079,P=0.0013）for patients of adverse prognosis.Patients of favorable prognosis benefited less through allo-HSCT（OS:HR=0.190,P=0.160;EFS:HR=0.567,P=0.214）.3.Compared AML-RUNXlmut with AML-MRmut patients,the two group patients had similar laboratory examination,cytogenetic,molecular biological characteristics,and there were no significant differences in 5-year OS and EFS rates between the two groups（OS:40.3%vs 46.4%,P=0.318;EFS:41.5%vs 25.8%,P=0.220）.Conclusions:1.Compared with RUNX1 wild type,RUNX1 mutated AML patients had a lower induction remission rate and worse prognosis.2.Based on the ELN prognosis risk stratification,RUNX1 mutation had no impact on the clinical outcomes of AML patients in favorable,intermediate and adverse group.AML-RUNX1^mut could not be recognized as a distinct AML entity.3.Compared AML-RUNX1^mut with AML-MRmut patients,the two group patients had similar clinical and prognostic characteristics and could be treated uniformly in clinical work.