Engineering (Oct 2021)
Inhibition of FLT3: A Prototype for Molecular Targeted Therapy in Acute Myeloid Leukemia
Abstract
Modern therapy of acute myeloid leukemia (AML) began in 1973 with the first report of the successful combination of daunorubicin and cytarabine, which led to complete remission in approximately 45% of patients. Accurate AML diagnosis was dependent on morphology, aided initially only by cytochemistry. Unlike acute lymphoblastic leukemia (ALL), immunophenotyping offered little in the diagnosis of AML, at least during the 1970s and 1980s. The advent of reliable cytogenetics changed the entire prognostic outlook of AML. With karyotypic analysis, different groups of AML could be classified and stratified for various therapies. Unique mutational profiling was a major advance in further categorizing AML patients, aided by the immunophenotypic identification of antigenic markers on the cells. All these advances were occurring as the understanding of the importance of the tumor burden—known as minimal residual disease (MRD)—became crucial for the management of AML patients. The efficacy of MRD has rapidly progressed in the past decade, from a specificity of 10−3 with immunophenotyping to 10−4 with polymerase chain reaction (PCR), which is only appropriate for some patients with AML, and finally to 10−5 or even 10−6 cells with the extraordinary sensitivity of next-generation sequencing (NGS). All of these advances have promoted the concept of personalized medicine, which has led to the advent of targeted agents that can accurately be used for specific diagnostic subtypes. Responses can be predicted and measured accurately. Such targeted agents have now become a cornerstone in the management of AML, increasing efficacy and dramatically reducing toxicity. The focus of this review is on one of the most well-studied targeted agents in AML: the FMS-like tyrosine kinase 3 (FLT3) inhibitors, which have impacted the prognostication and therapeutics of AML. This review selectively discusses the FLT3 inhibitors in detail, as a model for the other burgeoning targeted agents that have already been approved, as well as those that are currently in development.
