How I treat children with relapsed/refractory FLT3-mutated AML

Abstract

Mutations of the gene encoding fms-related tyrosine kinase 3 (FLT3), a type III receptor tyrosine kinase, are observed in approximately 30% of adults and 10% of children with acute myeloid leukemia (AML). There are two types of FLT3 mutation in AML, namely, FLT3 internal tandem duplication (FLT3-ITD) and tyrosine kinase domain mutation (FLT3-TKD); the former is the major type and strongly correlates with poor prognosis. The outcome of children with FLT3-ITD-positive AML is poor with a low rate of remission and a high rate of relapse. Currently in the Japanese pediatric AML studies, all the patients with FLT3-ITD are considered at a high risk of relapse and allocated to hematopoietic cell transplantation in the first remission. However, their prognoses have not improved. Recently, the development of tyrosine kinase inhibitors targeting FLT3 has been in progress, and two products have been approved to date for use in adults with relapsed or refractory FLT3-mutated AML: gilteritinib and quizartinib. There are no agents indicated for pediatric use, use for a combination therapy, or use for cases with the initial diagnosis of AML, but FLT3 inhibitors are becoming a promising treatment choice for relapsed or refractory cases. The current state of FLT3 inhibitors, development of novel therapeutics, and overview of FLT3-mutated AML therapy are discussed.