Clinical Characteristics And Prognosis Of Acute Myeloid Leukemia Patients With NPM1 Mutation

Objective:Acute myeloid leukemia?AML?is a clinical and molecular heterogeneous disease characterized by dysregulation of hematopoietic progenitor cell differentiation and proliferation.Abnormal genetic changes may indicate the prognosis etiology to a certain extent and provide guidance for treatment options and prognosis.With the rapid development and improvement of next generation sequencing technology,more and more gene mutations have been detected.The NPM1 gene mutation is considered to be one of the most common genetic mutations in AML.Reproducible co-mutation is a typical feature of NPM1 mutant AML,and the effect of co-mutation in NPM1 mutations on prognosis is also in the active research stage.We studied the NPM1 mutation positive AML patients in our hospital retrospectively to explore the clinical features and prognostic factors.Methods:Retrospective analysis of the clinical characteristics,genetics and molecular biology of 149 patients with non-acute promyelocytic leukemia who were diagnosed with NPM1 mutations by the next generation sequencing test from September 2010 to September 2018 in our hospital.A total of 69 patients who completed at least 2 high-dose cytarabine consolidation therapy were included in the long-term follow-up and prognosis analysis to determine the clinical features and prognostic factors of NPM1 mutant AML patients.Results:Among 149 newly diagnosed patients with NPM1 mutation AML,the FAB typing was mainly M5?39.60%?,M4?26.84%?and M2?22.15%?.91.60%of the patients who successfully analyzed their chromosome karyotypes were normal karyotypes.The main mutation type of NPM1 was type A?n=109,73.15%?.The median VAF of NPM1was 43%?2%⁷7%?.NPM1 VAF was correlated with leukocytes at first treatment?P=0.05?,but not with age and the number of bone marrow primordial cells?P=0.18,P=0.252?.NPM1 gene showed relatively low VAF compared with other co-mutation genes.38 co-mutated genes were detected.The most common co-mutation genes were DNMT3A?57.05%?,FLT3-ITD?51.01%?,IDH2?19.46%?,TET2?16.78%?,NRAS?16.78%?,PTPN11?10.74?.%),CEBPA?10.07%?,TPMT?8.05%?,WT1?6.71%?,RAD21?5.37%?,KRAS?4.03%?,SRSF2?4.03%?,IDH1?3.36%?,the most common types of co-mutation gene were demethylation-related genes?45.76%?and signaling pathway-related genes?34.19%?.The 2-year OS and RFS of NPM1 mutation AML patients with DNMT3A mutation were higher than those without DNMT3A mutation,but the difference was not statistically significant?63.4%vs 40.9%,p=0.581;64.8%vs 49.0%,P=0.803?.While the presence of DNMT3A R882 mutation were borderline associated with higher OS?P=0.097?and RFS?P=0.119?than DNMT3A non-R882 mutation.The 2-year OS and RFS of patients with NPM1 with FLT3-ITD mutation were lower than those without FLT3-ITD mutation,but the difference was not statistically significant?39.1%vs.63.1%,P=0.468;48.7%vs.70.8%,P=0.302?.The2-year OS and RFS of patients with NPM1 and IDH1/2 mutations were lower than those without IDH1/2 mutations,but the difference was not statistically significant?22.9%vs 63.5%,P=0.947;42.6%vs.65.3%,P=0.957?.The2-yearOSandRFSofthe NPM1^mut/DNMT3A^mut/FLT3-ITD^mut patients were lower than those of the NPM1^mut/DNMT3A^wt/FLT3-ITD^wt patients?57.7%vs 75.0%,P=0.200;62.7%vs.75%,P=0.225?;the 2-year OS and RFS of NPM1^mut/DNMT3A^wt/FLT3-ITD^wt patients were borderline associated with higher than those of with other mutations?75.0%vs 40.5%,P=0.130;75.0%vs.52.9%,P=0.147?.Conclusions:1.The newly diagnosed NPM1 mutant AML patients were mainly karyotypes,and most of them were found in M4 and M5 types in FAB typing.The mutation types were mainly type A mutations,and 13 new mutation sequences were found.2.NPM1 VAF was positively correlated with white blood cell count at initial treatment and was not associated with patient age and number of bone marrow blasts.NPM1 showed a relatively low VAF compared to other co-mutated genes.3.Multiple co-mutated genes are characteristic of NPM1 mutant AML patients.DNMT3A and FLT3-ITD are the most common co-mutation genes,followed by IDH2,TET2 and NRAS.Demethylation-related genes and signaling pathway-related genes are most commonly classified by functional classification.The number of co-mutated genes is the most common,and the most common combination of three mutations is NPM1/DNMT3A/FLT3-ITD.4.NPM1 mutations with DNMT3A non-R882 mutations may be a prognostic factor,and DNMT3A non-R882 mutations may attenuate the beneficial effects of NPM1 mutations on prognosis.FLT3-ITD has a poor prognosisinNPM1mutantAML.Patientswith NPM1^mut/DNMT3A^mut/FLT3-ITD^mut may have a poor prognosis.