Abstract
Acute myeloid leukemia (AML) is the second most common leukemia of childhood and is associated with high rates of chemotherapy resistance and relapse. Clinical outcomes for children with AML treated with maximally intensive multi-agent chemotherapy lag far behind those of children with the more common acute lymphoblastic leukemia, demonstrating continued need for new therapeutic approaches to decrease relapse risk and improve long-term survival. Mutations in the FMS-like tyrosine kinase-3 receptor gene (FLT3) occur in approximately 25% of children and adults with AML and are associated with particularly poor prognoses. Identification and development of targeted FLT3 inhibitors represents a major precision medicine paradigm shift in the treatment of patients with AML. While further development of many first-generation FLT3 inhibitors was hampered by limited potency and significant toxicity due to effects upon other kinases, the more selective second- and third-generation FLT3 inhibitors have demonstrated excellent tolerability and remarkable efficacy in the relapsed/refractory and now de novo FLT3-mutated AML settings. While these newest and most promising inhibitors have largely been studied in the adult population, pediatric investigation of FLT3 inhibitors with chemotherapy is relatively recently ongoing or planned. Successful development of FLT3 inhibitor-based therapies will be essential to improve outcomes in children with this high-risk subtype of AML.
Highlights
Acute myeloid leukemia (AML) is a group of biologically heterogeneous diseases that comprise 20% of pediatric and 80% of adult acute leukemias [1, 2]
It is estimated that 21,380 people in the United States will be diagnosed with AML in 2017, and 10,590 of these patients will die from leukemia [3]
While outcomes for children with de novo AML have improved over the past several decades, event-free survival (EFS) and overall survival (OS) remain suboptimal at approximately 60 and 70%, respectively [4]
Summary
Acute myeloid leukemia (AML) is a group of biologically heterogeneous diseases that comprise 20% of pediatric and 80% of adult acute leukemias [1, 2]. In a recent subgroup analysis, the COG phase 3 trial AAML0531 reported decreased relapse rates in children with FLT3–ITD AML with addition of the CD33-targeting antibody-drug conjugate gemtuzumab ozogamicin to standard chemotherapy [16, 34], demonstrating potential for improved clinical outcomes in this high-risk patient population with inclusion of targeted therapies. Subsequent trials, combined midostaurin with induction chemotherapy and reported improved CR rates in patients with FLT3–ITD AML [42]. These studies were followed by the Cancer and Leukemia Group B 10603 RATIFY trial, an international double-blind randomized controlled study comparing standard chemotherapy without or with midostaurin in adults (18–59 years) with de novo FLT3–ITD or FLT3–TKD AML.
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