TP53-altered higher-risk myelodysplastic syndromes/neoplasms and acute myeloid leukemia: a distinct genetic entity with unique unmet needs

Abstract

Pathogenic alterations of TP53 are an independent poor prognostic factor in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Clinical course of TP53- altered myeloid neoplasms is dictated by genetic characteristics, such as TP53 allelic state and variant allele frequency (VAF), and not the blast count. Hence, it was recently proposed that MDS (with increased blasts) and AML with TP53 alterations may be best classified as a single molecular disease entity, TP53-mutated higher-risk (HR)-MDS/AML. TP53 mutations drive resistance to intensive chemotherapies and less intensive hypomethylating agents (HMA). Novel combinations incorporating BCL2 inhibitor venetoclax improve response rates for TP53-mutated subgroup, but the survival is not improved. Early clinical studies combining HMA with investigational agents demonstrated activity in TP53-mutated HR-MDS/AML, but updated results with larger samples, longer follow-up, or randomized trials were less impressive to date. Future research should focus on finding novel, potentially disease-modifying therapies to improve outcomes in patients with TP53-mutated HR-MDS/AML.

Keywords:

• p53
• AML
• MDS
• myeloid malignancy
• WHO 2022
• ICC 2022

Disclosure statement

Ball- Nothing to disclose. Loghavi- Advisory fees: Abbvie, BluePrint Medicine, Daiichi Sankyo, Guidepoint; Consultancy: Gerson Lehrman Group, Qual World, Guidepoint; Honoraria: Path Education Partners, Pathology Learning Center, Peer View; Stock Ownership: Abbvie; Research Support: Astellas, Amgen. Zeidan- Consultancy and Honoraria: Celgene, BMS, Abbvie, Pfizer, Boehringer-Ingelheim, Trovagene, Cardiff Oncology, Incyte, Takeda, Novartis, Aprea, Amgen, Otsuka, Jazz, Agios, Acceleron, Astellas, Daiichi-Sankyo, Cardinal Health, Taiho, Seattle Genetics, BeyondSpring, Gilead, Kura, Tyme, Janssen, Syndax, Geron, Ionis, Epizyme; Research Support: Celgene, BMS, Abbvie, Pfizer, Boehringer-Ingelheim, Trovagene, Cardiff Oncology, Incyte, Takeda, Novartis, Aprea, Amgen, Otsuka, Astex, Medimmune, Astrazeneca, ADC Therapeutics; Clinical Trial Committees: Celgene, BMS, Abbvie, Novartis, Gilead, Kura, Geron; Travel Support: Pfizer, Cardiff Oncology, Novartis.