Acute Myeloid Leukemia (AML) encompasses several subtypes defined by distinct cytogenetic and molecular characteristics, which complicates treatment and necessitates therapies that can target multiple pathways. Despite advancements, there remains a significant need for molecular treatments that can achieve long-term remissions and potentially cure this heterogeneous disease.

In the past 5 to 6 years, the FDA has approved several targeted therapies for both newly diagnosed and relapsed/refractory AML. These novel therapeutics, along with others currently being investigated, have shown promising activity against AML and have improved outcomes for many patients.

This presentation will explore various molecular mechanisms that contribute to the pathogenesis of AML and review current research into how these mechanisms are being targeted in treatment strategiesA

Since the 1970s, the classical therapy for AML has consisted of cytarabine combined with an anthracycline (daunorubicin or idarubicin), famously known as the “7 + 3” regimen. The small-molecule FDA-approved drugs for AML over the last decade include IDH inhibitors (olutasidenib, ivosidenib, enasidenib), FLT3 inhibitors (gilteritinib, midostaurin), BCL-2 inhibitor (venetoclax), hypomethylating agents (azacitidine, decitabine), and CPX-351 (liposomal cytarabine and daunorubicin).

Several FLT3 inhibitors, such as sorafenib and quizartinib, have undergone clinical trials for acute myeloid leukemia (AML). However, the FDA did not approve these drugs due to various concerns regarding the trial data. Recent reports from 2021 highlighted an oxoindoline-based selective FLT3 inhibitor as a potential candidate for treating FLT3-ITD-positive AML, a condition associated with a poor prognosis. Additionally, a first-in-class hydrazide-based HDAC inhibitor was reported in 2022, and a promising CDK9 inhibitor for AML treatment was identified in 2021. Rearrangements of the KMT2A (MLL1) gene occur in up to 10% of acute leukemias. Moreover, the TP53 tumor suppressor gene is often inactivated in cancers due to loss-of-function mutations or missense mutations in the DNA-binding domain, occurring in nearly 50% of cases. Targeting mutant p53 to restore its function could provide a promising avenue for new therapeutics. APR-246 is a compound designed to reactivate mutant p53.

While this presentation does not cover all targeted agents, many promising options are available. A continuous and dedicated focus on understanding the fundamentals of molecular genetics and epigenetics, along with ongoing monitoring of clonal evolution before and after treatment with these targeted therapies, could lead to innovative changes in treatment strategies. This may ultimately provide the most beneficial outcomes for patients of all ages.