Genetic alterations in Thai adult patients with acute myeloid leukemia and myelodysplastic syndrome—excess blasts detected by next-generation sequencing technique

Abstract

Several molecular aberrations affect the prognosis of patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) with excess blasts (EB). This study aimed to determine the incidence and clinical impact of molecular genetic aberrations in Thai patients with AML and MDS-EB, detected by the next-generation sequencing (NGS) technique. This prospective, observational study was conducted between 2018 and 2020 on newly diagnosed Thai AML or MDS-EB patients aged above 15 years. NGS was performed using a custom amplicon-based targeted enrichment assay for 42 genes recurrently mutated in myeloid neoplasms. The molecular results were correlated with baseline patient and disease characteristics as well as outcomes. Forty-nine patients were enrolled in this study. The median age was 56 years (interquartile range [IQR], 44–64), with nearly equal proportions of males and females. The median number of mutations was 3 (IQR, 2–4). The most frequent alterations were FLT3 internal tandem duplications (ITD) (28.6%), DNMT3A (24.5%), and WT1 (22.4%) mutations. FLT3-ITD was more frequent in the de novo AML group than in the MDS/secondary AML group, whereas in the MDS/secondary AML group, ASXL1, ETV6, and SRSF2 mutations were more frequent. Patients aged greater than 65 years and patients with mutated TP53 were more likely to have inferior overall survival from multivariate analysis. FLT3-ITD was the most common mutation among newly diagnosed Thai AML patients. TP53 mutation and advanced age were independent adverse factors for survival outcome. The genetic landscapes of AML patients vary between national populations. Thai Clinical Trials Registry identifier: TCTR20190227003.

Secondary Acute Myeloid Leukemia in Myelodysplastic Syndrome Patients Aged Over 60 Years

“…In addition to the distinct statistics seen in terms of the decline in the overall survival (OS) rate of the patients with this mutation, it also increases the chances of MDS patients getting secondary AML [ 15 ]. TP53 mutation has also been positive in older patients (above 65 years old) more commonly in comparison with their younger counterparts, which adds to the statistics of poor prognosis and diminished relapse-free survival (RFS) rates in MDS-AML patients above 65 years of age [ 6 ]. There are also some protective genes that prevent the transformation of MDS into full-blown AML.…”

“…Hence, hypomethylating agents (HMAs) in combination with other drugs are being used, as the remission and cure rates of HMAs alone are still not optimal [ 17 ]. For instance, "Decitabine," a pyrimidine nucleoside analog, was considered a potential treatment for TP53 mutation-based MDS and secondary AML [ 6 ]. It is a DNA HMA that induces erythroid differentiation and increases levels of fetal hemoglobin [ 18 ].…”

“…The monoclonal anti-CD47 antibody "Magrolimab" is currently being used to target MDS and AML neoplasms. It works by targeting "cluster of differentiation (CD) 47," enhances phagocytosis, and causes tumor growth inhibition [ 6 , 17 ]. Another novel drug "APR-246," which works as a TP53 reactivator, has been recently approved for use.…”

“…Overlapping mutations occur in AML, and hence, both disorders seem to share a similar natural course. However, the genetics of some MDS and AML patients show no cytogenic abnormalities, indicating that other molecular pathologies may also be causal to these disorders [ 6 ]. Secondary AML due to MDS tends to have the same genetic mutations as MDS.…”

“…Secondary AML due to MDS tends to have the same genetic mutations as MDS. For example, FLT3-ITD mutation is more commonly seen in primary AML, whereas ASXL1, ETV6, and SRSF2 mutations are more commonly seen in MDS/secondary leukemia patients [ 5 , 6 ]. At the same time, though primary AML and MDS do share similar gene aberrations, there are also plenty of differences, such as MDS cells needing additional genetic mutations in order to develop into AML blasts (mutations in RUNX1, NRAS, and NTRK3) [ 7 ].…”