Most Risk-Stratification Molecular Markers in Acute Myeloid Leukemia (AML) Are Rarely Found in Early Childhood AML in the Middle Eastern Population

Acute myeloid leukemia (AML) is biologically heterogeneous with significant molecular and clinical variation. Most of the recent studies suggest that AML in pediatric population differs significantly clinically and biologically from adult AML. Numerous newly described molecular abnormalities in AML have been described in adult patients, but except for rare publications, a little is known about the molecular abnormalities and their clinical relevance in pediatric AML, especially in early childhood and when the patients are treated with intensive chemotherapy followed by hematopoietic stem cell transplant (HSCT). The Saudi Arabian population is known to be genetically homogenous due to high consanguinity. Higher incidence of inherited diseases including certain types of cancer has been reported in Saudi Arabia. We attempted to compare the molecular abnormalities and their clinical relevance in pediatric AML patients from Saudi Arabia with adult AML from the same population.

Samples from 87 adult patients with AML and samples from 40 pediatric AML patients were analyzed for FLT3-ITD and FLT3-D835, IDH1, IDH2, NPM1, and DNMT3A mutations by direct sequencing and by fragment length analysis (FLT3 and NPM1). The prevalence of mutations was compared between the adult and pediatric groups. They included patients with intermediate-risk cytogenetics (N=66 adults, N=26 pediatrics) and adverse cytogenetics (N=21 adults, N=14 pediatrics). The median age of the pediatric patients is 7 years, with a range from less than one year to 14 years. All patients were treated with intensive chemotherapy, followed by HSCT in first remission.

FLT3-ITD mutation was detected in 18 patients (21%) of the adult group, but detected only in 3 patients of the pediatric group (7.5%). Two of the 3 patients in the pediatric group carrying the FLT3 mutation died within the first year after the transplant. The FLT3-D835 mutation was detected in 6 patients (7%) of the adult group, while none of the pediatric patients showed this mutation. In addition, the pediatric patients showed no mutations in IDH1 or IDH2, while the adult patients showed IDH1 and IDH2 mutations in 6 (7%) and 7 (8%), respectively. Mutations in the DNMT3A gene were detected in three patients (3%) in the adult group, but were not detected in any of the pediatric AML. NPM1 mutations were detected in 9 (10%) of the adult AML patients, but none of the pediatric patients showed NPM1 mutation.

This data suggests that the biology of AML in pediatric patients is significantly different from that in the adult patients. Mutations in FLT3, IDH1, IDH2, NPM1, and DNMT3A genes are very rare in pediatric patients. However, our data involves early childhood (90% younger than 13 years of age) and there is a possibility that older children may have higher incidence of mutations. Most of the currently used molecular markers in risk-stratifying adult AML patients are difficult to use in stratifying pediatric AML patients.

No relevant conflicts of interest to declare.