TP53-Mutated Myeloid Neoplasms: 2024 Update on Diagnosis, Risk-Stratification, and Management

Alterations in the tumor suppressor gene TP53 are common in human cancers and are associated with an aggressive nature. Approximately 8%–12% of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) harbor TP53 mutations (TP53^mut) and present immense challenges due to inherent chemoresistance and poor outcomes. As TP53^mut are more common in older individuals and those with secondary/therapy-related myeloid neoplasms (MN), their incidence is expected to increase with an aging population and rising proportion of cancer survivors. Treatments used for other MN—intensive chemotherapy, hypomethylating agents, and the BCL-2 inhibitor venetoclax—do not improve the survival of TP53^mut MN patients meaningfully. Additionally, further development of many promising agents has been discontinued, highlighting the challenges. Widespread acknowledgment of these problems led to the recognition of TP53^mut MN as a distinct entity in the 5th edition of the World Health Organization and International Consensus Classifications. However, critical discrepancies between the two classifications may lead to under- or overestimation of the prognostic risk. Here, we review recent advances in the biology, diagnosis, and treatment of TP53^mut MN. The development of TP53^mut MN is positioned at the intersection of age, hereditary predisposition, and anti-cancer therapies. Precursor TP53^mut clones can be detected years prior to the eventual leukemic transformation—raising the possibility of early intervention. We discuss the two classification systems and the bearing of the discrepancies between the two on timely and effective management. We provide novel evidence in the areas of discrepancies. Finally, we review the current therapeutic landscape and the obvious limitations of the currently used therapies.