The Landscape Of Gene Mutations In Acute Myeloid Leukemia(AML)patients With Intermediate-risk-cytogenetic-group

Backgrounds Acute myeloid leukemia(AML)is a heterogeneous hematopoietic malignancy characterized by chromosomal translocations and somatic mutations.This study investigated the clinical implications of gene mutations(focusing on FLT3-ITD、NPM1 and DNMT3 A mutations)at diagnosis and post-induction in AML patients with intermediate-risk-cytogenetic-group,using a next-generation sequencing(NGS)42-gene panel,aims to improve the risk stratification of AML and provide relevant information for clinical management.Methods A total of 132 de novo AML patients were enrolled from the Affiliated Hospital of Oregon Health and Science University from 2010 to 2016,and they were classified into favorable-risk-cytogenetic-group,intermediate-risk-cytogenetic-group and adverse-risk-cytogenetic-group(27 cases).There were 2 cases with unknown cytogenetic information.Totally,42 genes being relevant to hematopoietic malignancies were determined by NGS at diagnosis and post-induction in AML patients with intermediate-risk-cytogenetic-group.Results There were 91%(120/132)of AML cases with at least one mutation,the pattern of co-mutations(≥2)accounted for 79% of intermediate-risk-cytogenetic-group.The most mutated gene include NPM1、FLT3-ITD and DNMT3 A.Kaplan-Meier analysis demonstrated that FLT3-ITD is an adverse prognostic indicator only in the presence of a DNMT3 A co-mutation,regardless of NPM1 mutation status.In the absence of a concomitant DNMT3 A mutation,there was no significant difference in overall survival between FLT3-ITD positive and FLT3-ITD negative patients(P>0.05).Furthermore,mutation analysis on post-induction specimens showed that residual FLT3-ITD and/or DNMT3 A mutations were associated with a high frequency of therapy resistance or relapse in AML.Conclusions Incorporating DNMT3 A mutation with FLT3-ITD status may be needed to refine prognostication and guide clinical management in AML patients with intermediate-risk-cytogenetic-group.Moreover,follow up mutation analysis in post therapy specimens may provide additional clinically relevant prognostic information.Multi-gene mutation analysis at diagnosis and during therapy is important in the clinical management of AML allowing for an improved biological understanding of pathogenesis,better predictions of AML outcomes,and identification of clonal biomarkers for monitoring therapeutic responses.Multi-gene mutation testing is essential to provide novel insights related to diagnostic and prognostic information.