The Clinical Characteristics And Prognosis Of Acute Myeloid Leukemia Patients With RUNX1 And DAT Mutations:a Single-center Retrospective Study

Part Ⅰ The clinical characteristics and prognosis of acute myeloid leukemia patients with RUNX1 and DAT mutationsObjectiveTo analyze the clinical characteristics of RUNX1 with DAT mutations(DNMT3A,ASXL1 and TET2 mutation)in patients with acute myeloid leukemia(AML)and explore possible prognostic factors.MethodsWe retrospectively analyzed the clinical and gene mutations characteristics of 122 AML patients with RUNX1 mutation treated in the First Affiliated Hospital of Soochow University from June 2016 to December 2020.Based on different DAT mutations,patients were divided into DAT positive group and DAT negative group.The differences between these two groups were analyzed in clinical features,gene mutation characteristics,treatment response and prognosis.Based on the different VAF of RUNX1 at diagnosis,patients were divided into high VAF RUNX1 group and low VAF RUNX1 group,the difference in prognosis between the two groups was analyzed.Risk factors that affect the prognosis in AML patients with RUNX1 mutations were also explored.Results1.A total of 122 AML patients with RUNX1 mutations from June 2016 to December 2020 were enrolled in this study,including 79 males and 43 females.The median age was 48.5(18-79)years.Among 47 AML patients with DAT mutations,34 patients were males and 13 patients were females.The median age was 55(26-79)years.Among 75 AML patients without DAT mutations,including 45 males and 30 females,median age was 42(18-77)years.Comparing the differences in clinical features between the two groups,patients with DAT mutations were older than those without DAT mutations(P<0.001).2.Based on the NGS approach,a total of 143 RUNX1 mutations were detected in 122 AML patients with RUNX1 mutations.41.2%(59/143)of RUNX1 mutations were missense mutations,43%(62/143)of RUNX1 mutations were frameshift mutations,and 14%(20/143)of RUNX1 mutations were stop gain.1.4%(2/143)of RUNX1 mutations were in-frame mutations.The RUNT domain was dominated by missense mutation,while the TAD domain was dominated by frameshift mutation.The most frequently comutated genes in RUNX1mut AML patients were FLT3-ITD,DNMT3A,BCOR,WT1,and ASXL1.According to signaling pathways,mutations involved in activated signaling,DNA methylation and other epigenetic modifiers were found frequently in RUNX1mut AML patients.3.47(38.5%,47/122)AML patients with DAT mutations,including 24(20%,24/122)DNMT3A mutations,21(17%,21/122)ASXL1 mutations,and 8(7%,8/122)TET2 mutations.There was no statistical difference in the distribution of comutations between DAT positive and DAT negative patients.4.AML patients with RUNX1 and DAT mutations had poor response to induction chemotherapy,with a CR rate of only 36%after one course of induction chemotherapy.For 105 patients with complete follow-up information,2-year overall survival(OS)was 39.46%and 2-year relapse-free survival(RFS)was 37.92%.After 1:1 propensity score matching(PSM)eliminated the effects of age and transplantation on prognosis,2-year RFS of patients with DAT mutations were lower than those in the DAT negative group(20.83%vs.40.74%,P=0.041),while there was no statistically significant difference in OS(P=0.218).In addition,patients were grouped according to the VAF of RUNX1 at diagnosis,the 2-year OS and RFS in the high VAF RUNX1 group were lower than those in the low VAF RUNX1 group(OS:29.00%vs.50.54%,P=0.033;RFS:28.71%vs.48.34%,P=0.027).Moreover,if patients with high VAF of RUNX1 and DAT mutations,their 2-year OS and RFS were worse(OS:13.46%vs.39.33%,P=0.004;RFS:6.67%vs.43.04%,P=0.003).Multivariate analysis showed WBC≥30×109/L at initial diagnosis[HR=1.803,95%CI(1.057-3.076),P=0.030],≥2 additional mutations[HR=2.434,95%CI(1.147-5.165),P=0.020]and RUNX1 VAF value≥37.6%[HR=1.807,95%CI(1.090-2.996),P=0.022]were independent risk factors affecting OS.FLT3-ITD mutation[HR=2.012,95%CI(1.066-3.798),P=0.031]and DAT mutation[HR=2.324,95%CI(1.254-4.307),P=0.007]were independent risk factors for RFS at initial diagnosis.ConclusionRUNX1 mutations clustered within the RUNT and TAD domains of the gene.The RUNT domain was dominated by missense mutation,while the TAD domain was dominated by frameshift mutation.DAT mutations occurred in 38.5%of the RUNX1mut patients in this study.Patients with AML with high RUNX1 VAF and DAT mutations had poor prognosis.WBC≥30× 109/L,≥2 additional mutations and RUNX1 VAF value≥37.6%at initial diagnosis were independent risk factors for OS.FLT3-ITD mutation and DAT mutation at initial diagnosis were independent risk factors for RFS.Part Ⅱ The prognostic values of allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia patients with RUNX1 and DAT mutationsObjectiveTo evaluate the efficacy of allogeneic hematopoietic stem cell transplantation(allo-HSCT)in patients with RUNX1 with DAT mutation and RUNX1 high VAF during first complete response(CR1).MethodsWe retrospectively analyzed 97 AML patients with RUNX1 mutation who acquired CR1 after induction chemotherapy from June 2016 to December 2020,to explore the prognostic value of patients with DAT mutations and high RUNX1 VAF who underwent allo-HSCT in CR1.Results1.Of 97 RUNX1 mutated AML patients who acquired CR1 after induction chemotherapy.34 patients received allo-HSCT at CR1,and 63 patients received chemotherapy as consolidation.Patients in the chemotherapy group were older(P=0.003),with more DAT mutations(P=0.028),and had higher RUNX1 VAF at first diagnosis than those in the transplantation group(P=0.042).Patients with RUNX1 mutation who underwent allo-HSCT in CR1 had better 2-year OS(67.1%vs.29.9%,P=0.002)and RFS(62.1%vs.20.63%,P<0.001)than patients who received chemotherapy as consolidation.2.Of 34 AML patients with RUNX1 mutations with DAT mutations,7 patients chose to underwent allo-HSCT at CR1,and 27 patients continued chemotherapy after achieved CR1.Survival analysis showed that 2-year OS(71.43%vs.17.79%,P=0.021)and 2-year RFS(57.14%vs.5.56%,P=0.015)were better in patients receiving allo-HSCT during CR1 than patients receiving chemotherapy.3.Among 47 AML patients with high RUNX1 VAF,12 patients received allo-HSCT at CR1,and 35 patients continued chemotherapy.Survival analysis showed that 2-year OS(57.14%vs.25.14%,P=0.017)and RFS(60%vs.17.86%,P=0.006)of patients receiving allo-HSCT at CRI were higher than those receiving chemotherapy.4.17 patients had RUNX1 high VAF with DAT mutation,two of whom underwent allo-HSCT at CR1.At subsequent follow-up,one patient developed extramedullary recurrence and died 6 months after transplantation,and another patient was still alive with 64 months.The median survival time was only 8 months of patients who chose chemotherapy as consolidation.Conclusion Patients with DAT mutations and high RUNX1 VAF who received chemotherapy as consolidation therapy had poor 2-year OS and RFS,while allo-HSCT at CR1 significantly improved the clinical outcomes of these patients.