TP53‐Mutated Acute Myeloid Leukemia: Unanswered Questions

: TP53-mutated acute myeloid leukemia (AML) remains one of the most treatment-resistant hematologic malignancies, with poor overall survival despite advancements in therapeutic strategies. The loss of functional p53 compromises DNA repair, apoptosis, and genomic stability, rendering both conventional and novel therapies largely ineffective. This review evaluates the efficacy of various treatment approaches, including intensive chemotherapy (IC), hypomethylating agents (HMAs), venetoclax-based regimens, and immune checkpoint inhibitors. Additionally, we discuss emerging strategies such as p53 reactivation, multi-targeted inhibition, and novel immunotherapies, including bispecific T-cell engagers (BiTEs) and CAR-T cell therapy. Current treatment options provide limited benefits in TP53-mutated AML, with complete remission rates ranging from 13% to 46% and median overall survival of only 6.1-6.5 months. Allogeneic stem cell transplantation (allo-SCT) offers minimal survival advantage due to high relapse rates. Despite promising preclinical data, checkpoint inhibitors and TIM-3 blockade have failed to demonstrate significant clinical efficacy, likely due to the immunosuppressive tumor microenvironment. Novel approaches, such as APR-246 (eprenetapopt) and MCL-1/CHK1 inhibitors, are under investigation, but their therapeutic impact remains uncertain. The failure of single-agent therapies underscores the need for combination strategies targeting multiple resistance mechanisms. Future research should focus on integrating targeted inhibitors with immunotherapy and bone marrow microenvironment modifiers. While TP53-mutated AML remains a formidable challenge, ongoing advances in precision medicine and immunotherapy hold the potential to improve patient outcomes.