TP53 in Acute Myeloid Leukemia: Evolving from Just Another Prognostic Marker to an Actionable Biomarker Informing Treatment

Introduction

Acute Myeloid Leukemia (AML) is a devastating disease with poor overall survival. Access to Precision Medicines is revolutionizing AML care and is driving an increase in Next Generation Sequencing (NGS) utilization to determine the genomic profile of patients with AML. Collaborative efforts to identify and promote emerging and established actionable biomarkers benefits all stakeholders in the patient diagnostic pathway and, ultimately, leads to more patients getting the right test for the right treatment. TP53 plays a central role in key cellular processes such as oncogenesis, cellular proliferation, and DNA repair.¹ TP53 is commonly mutated in most cancers. However, a vast majority of AML patients harbor intact, wild-type TP53 in which TP53 pathway dysregulation is promoted by mechanisms such as FLT3 mutations and chromosomal translocations. TP53 mutations lead to clonal propagation and promotes leukemogenesis, and are associated with altered drug sensitivity, chemoresistance, and high risk of relapse.Thus, mutated TP53 is a powerful independent prognostic indicator of poor outcome in AML. TP53 mutations are common in AML cases characterized by increased genomic instability, relapse, and the elderly. Therefore, treating AML patients by directly targeting TP53 mutant AMLs, or leveraging wild-type TP53 AMLs with therapeutic strategies in combination with standard AML chemotherapy or other targeted therapies requires that all AML patients have their TP53 status tested.¹

Methods

We assessed the testing landscape for determining TP53 status in AML cancer using a data set of 7758 newly diagnosed and relapsed/refractory (R/R) AML patients in the US from Q1-2017 through Q2-2019 identified from Diaceutics' proprietary Global Diagnostic Index (GDI). An analysis of real-world TP53 and Next Generation Sequencing (NGS)-associated testing data and a laboratory profile mapping exercise of 806 US labs was carried out using Diaceutics' proprietary methods and data sources to evaluate TP53 testing rates, test availability, and testing methodology. AML biomarker testing rates were determined from 1176 patients and results available for 437 of them were used to obtain positivity rates.

Results

Overall, 95 labs performed in-house AML molecular biomarker testing. Of these, 50 performed TP53 testing, 65 performed IDH testing, and 84 performed FLT3 testing. Testing rates on bone marrow aspirates for TP53, IDH1/2, and FLT3 were 59%, 63% and 68%, respectively, with corresponding positivity rates of 15%, 9% (IDH1), 13% (IDH2), 17%, respectively. Simultaneous testing with cytogenetic markers occurred 77% of the time vs 23% of the time following the results from cytogenetic testing. A total of 43 labs included TP53 as part of comprehensive NGS panels, with 3 labs exclusively using Sanger Sequencing and 4 labs testing TP53 via single gene (Sanger and/or NGS) and comprehensive NGS panels. Co-mutation rates between mutated TP53 and FLT3 or IDH1 were 1.3% and 4.2%, respectively. Co-mutation rates between unmutated TP53 and FLT3 or IDH1 were 17.5% and 9.3%, respectively.

Conclusion

TP53 status is evolving from simply a poor prognostic indicator to an attractive actionable biomarker in newly diagnosed and R/R AML patients. Thus, TP53 status should always be properly tested in parallel with other actionable AML biomarkers. Stakeholder awareness should be increased and recommendations for TP53 clinical utility, preferred testing methods, gene regions to test, and results reporting should be updated, to advance standardization and harmonization that ultimately improves treatment outcomes for AML patients.

Reference

1. Barbosa K, Li S, Adams PD, Deshpande AJ. The role of TP53 in acute myeloid leukemia: Challenges and opportunities. Genes Chromosomes Cancer. 2019;58:875-888. https://doi.org/10.1002/gcc.2279