Are We Moving the Needle for Patients with TP53-Mutated Acute Myeloid Leukemia?

Simple Summary TP53-mutated acute myeloid leukemia (AML) represents one of the most informative examples of adverse risk AML. As the currently available therapies have not translated to meaningful advances in the survival of these patients, a clinical trial should be the recommendation for all newly diagnosed patients. CD47/SIRP alpha axis and TIM-3 inhibition appear to be some of the more promising strategies, but other agents with novel mechanisms of action are in development. We review the pathobiology of TP53-mutated AML, the possible heterogeneity among patients with this disease and how some of the novel and emerging therapies may fit into the treatment landscape in the hopefully not-so-distant future. The currently available therapeutic options for patients with TP53-mutated acute myeloid leukemia (AML) are insufficient, as they translate to a median overall of only 6-9 months, and less than 10% of patients undergoing the most aggressive treatments, such as intensive induction therapy and allogeneic hematopoietic stem cell transplantation, will be cured. The lack of clear differences in outcomes with different treatments precludes the designation of a standard of care. Recently, there has been growing attention on this critical area of need by way of better understanding the biology of TP53 alterations and the disparities in outcomes among patients in this molecular subgroup, reflected in the development and testing of agents with novel mechanisms of action. Promising preclinical and efficacy data exist for therapies that are directed at the p53 protein rendered dysfunctional via mutation or that inhibit the CD47/SIRP alpha axis or other immune checkpoints such as TIM-3. In this review, we discuss recently attractive and emerging therapeutic agents, their preclinical rationale and the available clinical data as a monotherapy or in combination with the currently accepted backbones in frontline and relapsed/refractory settings for patients with TP53-mutated AML.