Personalized Medicine for TP53 Mutated Myelodysplastic Syndromes and Acute Myeloid Leukemia.

Thomas Cluzeau,Thomas Cluzeau,Thomas Cluzeau,David A Sallman,Rami Komrokji,Pierre Fenaux,Pierre Fenaux,Pierre Fenaux,Michael Loschi

doi:10.3390/ijms221810105

Abstract

Targeting TP53 mutated myelodysplastic syndromes and acute myeloid leukemia remains a significant unmet need. Recently, new drugs have attempted to improve the outcomes of this poor molecular subgroup. The aim of this article is to review all the current knowledge using active agents including hypomethylating agents with venetoclax, eprenetapopt or magrolimab. We include comprehensive analysis of clinical trials to date evaluating these drugs in TP53 myeloid neoplasms as well as discuss future novel combinations for consideration. Additionally, further understanding of the unique clinicopathologic components of TP53 mutant myeloid neoplasms versus wild-type is critical to guide future study. Importantly, the clinical trajectory of patients is uniquely tied with the clonal burden of TP53, which enables serial TP53 variant allele frequency analysis to be a critical early biomarker in investigational studies. Together, significant optimism is now possible for improving outcomes in this patient population.

Highlights

We focus on outcomes of standard therapy in TP53 mutant myeloid neoplasms, evaluate investigational therapies which have shown promise in this molecular subset, as well as provide insight into future novel combinations that will ideally change the natural history of this challenging disease
The data to date strongly support that TP53 mutant patients require investigational therapy in order to improve outcomes
As additional myeloid specific therapies are showing robust response rates in myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML) patients, understanding how the TP53 mutant subgroup responds is of critical importance given clear differential outcomes in this patient subgroup

Summary

Introduction

Acute myeloid leukemia (AML), TP53 mutations are associated with the most inferior outcomes across independent studies, with a median OS of 6–12 months [1,2,3]. A high EAp53 was an independent negative prognostic covariate for outcomes in TP53 mutated MDS/AML. The TP53 variant allele frequency (VAF) or allelic state are tightly concordant with outcomes in this molecular subgroup [1,13,14,15]. In both MDS and AML patients, a VAF > 40% is a strong prediction of inferior overall survival (OS). The VAF of TP53 can be serially followed and is intimately correlated with the clinical trajectory of the patient [17]

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Conclusion