An accurate estimation of AML prognosis is complex since it depends on patient-related factors, AML manifestations at diagnosis, and disease genetics. Furthermore, the depth of response, evaluated using the level of MRD, has been established as a strong prognostic factor in several AML subgroups. In recent years, this rapidly evolving field has made the prognostic evaluation of AML more challenging. Traditional prognostic factors, established in cohorts of patients treated with standard intensive chemotherapy, are becoming less accurate as new effective therapies are emerging. The widespread availability of next-generation sequencing platforms has improved our knowledge of AML biology and, consequently, the recent ELN 2022 recommendations significantly expanded the role of new gene mutations. However, the impact of rare co-mutational patterns remains to be fully disclosed, and large international consortia such as the HARMONY project will hopefully be instrumental to this aim. Moreover, accumulating evidence suggests that clonal architecture plays a significant prognostic role. The integration of clinical, cytogenetic, and molecular factors is essential, but hierarchical methods are reaching their limit. Thus, innovative approaches are being extensively explored, including those based on “knowledge banks”. Indeed, more robust prognostic estimations can be obtained by matching each patient’s genomic and clinical data with the ones derived from very large cohorts, but further improvements are needed.

Acute myeloid leukemia (AML) in older patients is characterized by unfavorable prognosis due to adverse disease features and a high rate of treatment-related complications. Classical therapeutic options range from intensive chemotherapy in fit patients, potentially followed by allogeneic hematopoietic cell transplantation (allo-HCT), to hypomethylating agents or palliative care alone for unfit/frail ones. In the era of precision medicine, the treatment paradigm of AML is rapidly changing. On the one hand, a plethora of new targeted drugs with good tolerability profiles are becoming available, offering the possibility to achieve a prolonged remission to many patients not otherwise eligible for more intensive therapies. On the other hand, better tools to assess patients’ fitness and improvements in the selection and management of those undergoing allo-HCT will hopefully reduce treatment-related mortality and complications. Importantly, a detailed genetic characterization of AML has become of paramount importance to choose the best therapeutic option in both intensively treated and unfit patients. Finally, improving supportive care and quality of life is of major importance in this age group, especially for the minority of patients that are still candidates for palliative care because of very poor clinical conditions or unwillingness to receive active treatments. In the present review, we discuss the evolving approaches in the treatment of older AML patients, which is becoming increasingly challenging following the advent of new effective drugs for a very heterogeneous and complex population.