What have we learned about TP53-mutated acute myeloid leukemia?

Abstract

TP53 is a tumor suppressor gene frequently mutated in human cancers and is generally associated with poor outcomes. TP53 mutations are found in approximately 5% to 10% of patients with de novo acute myeloid leukemia (AML), more frequently observed in elderly patients and those with therapy-related AML. Despite recent advances in molecular profiling and the emergence of targeted therapies, TP53-mutated AML remains a challenge to treat. Current treatment strategies, including conventional chemotherapy, hypomethylating agents, and venetoclax-based therapies, have shown limited efficacy in TP53-mutated AML, with low response rates and poor overall survival. Allogeneic hematopoietic stem cell transplantation is a potentially curative option; however, its efficacy in TP53-mutated AML depends on comorbid conditions and disease status at transplantation. Novel therapeutic modalities, including immune-based therapies, did show promise in early-phase studies but did not translate into effective therapies in randomized controlled trials. This review provides a comprehensive overview of TP53 mutations in AML, outcomes based on allelic burden, clinical implications, and therapeutic challenges.

Fig. 1

Diagrammatic illustration of the mechanism of oncogenesis from TP53 loss and the spectrum of malignancies associated with such a lesion.

Fig. 2. Diagrammatic illustration of the mode of action of conventional and novel therapies used to manage TP53-mutated acute myeloid leukemia.

(ADC, antibody-drug conjugate; mAb; monoclonal antibody, DART; dual affinity retargeting antibody, MHC; major histocompatibility complex).