High Throughput Molecular Characterization of Normal Karyotype Acute Myeloid Leukemia in the Context of the Prospective Trial 02/06 of the Northern Italy Leukemia Group (NILG)

Abstract

By way of a Next-Generation Sequencing NGS high throughput approach, we defined the mutational profile in a cohort of 221 normal karyotype acute myeloid leukemia (NK-AML) enrolled into a prospective randomized clinical trial, designed to evaluate an intensified chemotherapy program for remission induction. NPM1, DNMT3A, and FLT3-ITD were the most frequently mutated genes while DNMT3A, FLT3, IDH1, PTPN11, and RAD21 mutations were more common in the NPM1 mutated patients (p < 0.05). IDH1 R132H mutation was strictly associated with NPM1 mutation and mutually exclusive with RUNX1 and ASXL1. In the whole cohort of NK-AML, no matter the induction chemotherapy used, by multivariate analysis, the achievement of complete remission was negatively affected by the SRSF2 mutation. Alterations of FLT3 (FLT3-ITD) and U2AF1 were associated with a worse overall and disease-free survival (p < 0.05). FLT3-ITD positive patients who proceeded to alloHSCT had a survival probability similar to FLT3-ITD negative patients and the transplant outcome was no different when comparing high and low-AR-FLT3-ITD subgroups in terms of both OS and DFS. In conclusion, a comprehensive molecular profile for NK-AML allows for the identification of genetic lesions associated to different clinical outcomes and the selection of the most appropriate and effective treatment strategies, including stem cell transplantation and targeted therapies.

Features and impacts on the prognosis of gene mutations in patients with acute myeloid leukemia

“…There was a significantly positive correlation between SRSF2 mutations and adverse risk genes including RUNX1 and ASXL1, which is consistent with other studies [12]. Although mechanisms remain unknown, SRSF2 mutations have been reported to have negative impacts on outcomes of MDS patients [13][14][15][16]. In AML, SRSF2 mutations were found to associate with longer time to hematologic recovery [17].…”

Clinical significance of chromatin-spliceosome acute myeloid leukemia: a report from the Northern Italy Leukemia Group (NILG) randomized trial 02/06

“…Targeted next-generation sequencing (NGS) was performed on 196 normal karyotype patients using an amplicon-based method (Trusight Myeloid, Illumina, San Diego, California, USA) (n=161) amplifying 54 gene regions and a capture-based method (Sophia Myeloid Solution, Sophia Genetics SA, Saint Sulpice, Switzerland) (n=35) selecting 30 gene regions ( Online Supplementary Tables S1 and S2 ). 18 …”

Downregulation of GNA15 Inhibits Cell Proliferation via P38 MAPK Pathway and Correlates with Prognosis of Adult Acute Myeloid Leukemia With Normal Karyotype

“…Advances in the therapy of AML, such as risk stratification, concurrent chemotherapy, novel drugs and hematopoietic stem cell transplantation, have improved the treatment outcomes of patients ( 3 ). Cytogenetic analysis has proved to be crucial for the risk stratification of AML patients ( 4 ). However, nearly half of AML patients have a normal karyotype (NK) ( 4 ).…”

“…Cytogenetic analysis has proved to be crucial for the risk stratification of AML patients ( 4 ). However, nearly half of AML patients have a normal karyotype (NK) ( 4 ). Identification of the changes in genetic profiles such as mutations of NPM1 , FLT3-ITD and CEBPA has further improved the risk stratification of NK-AML.…”

“…Identification of the changes in genetic profiles such as mutations of NPM1 , FLT3-ITD and CEBPA has further improved the risk stratification of NK-AML. However, most NK-AML still belongs to the intermediate prognostic subgroup in which the most appropriate treatment remains to be defined ( 4 ). It is urgent to identify novel prognostic biomarkers and update the risk stratification for NK-AML.…”