Evolution of Therapy for Older Patients With Acute Myeloid Leukemia: How Should We Use Currently Available Agents?

Most patients with newly diagnosed acute myeloid leukemia (AML) are 65 years or older. The treatment of AML in older patients has been characterized by distinct patient- and disease-related challenges that have impeded the meaningful progress that has been observed in younger patients with AML. Higher rates of comorbidities and frailty contribute to higher rates of treatment-related complications, whereas adverse disease features such as poor-risk genomics and secondary AML are associated with therapeutic resistance and shortened survival. Intensive chemotherapy and allogeneic stem cell transplant, although still considered standard for many newly diagnosed patients with AML, may not be appropriate for a larger subset of older patients with AML. Lower-intensity approaches such as hypomethylating agents have been widely applied for newly diagnosed older and unfit patients with AML, improving tolerability among this subset, but providing more modest response rates. Numerous analyses have attempted to tackle the utility of higher- versus lower-intensity therapy in older AML and identify the factors that can help choose the approach that best optimizes tolerability and efficacy. Recently, a greater understanding of the genomic and biologic heterogeneity of AML has led to better risk stratification and has contributed to the development of specific targeted therapies that are starting to narrow the gap between safety and efficacy. Newly approved agents, such FLT3 (FMS-like tyrosine kinase 3) inhibitors, IDH1 and IDH2 inhibitors, and the BCL2 inhibitor venetoclax, as well postremission maintenance therapy with CC-486 (oral 5-azacitidine), are being systematically incorporated into the evolving treatment of older patients with newly diagnosed AML.