About 10% of individuals with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) have TP53 mutations, constituting a distinct subgroup with an extremely poor prognosis. On chromosome 17p13, TP53 is critical in regulating the cell cycle and DNA damage response.  The presence of complicated karyotypes (CK) and massive structural and complex chromosomal abnormalities shows that mutant TP53 is closely related to these conditions. CK is linked to worse overall survival rates in myeloid malignancies, just like mutant TP53. The 2017 European LeukemiaNet (ELN) risk categorization places mutant TP53 AML in the unfavorable risk group. Allogeneic hematopoietic stem cell transplantation (HSCT) is typically given to mutant TP53 AML patients in complete remission (CR), although recurrence rates are still quite high. Recent discoveries in the myelodysplastic syndrome (MDS) give the molecular traits of mutant TP53, such as TP53 mutant allelic status (mono-allelic or bi-allelic) and TP53 clone size, significant prognostic relevance. Furthermore, it was unknown at this time whether mutant TP53 high-risk MDS with an excess of blast (EB) and AML differ in their molecular make-up, responses to therapy, and deserving distinct considerations.

On 2,200 AML/MDS-EB specimens, researchers used next-generation sequencing (NGS) to examine the TP53 mutant allelic status (mono or bi-allelic), the number of TP53 mutations, the size of the mutant TP53 clone, concurrent mutations, cytogenetics, and mutant TP53 molecular minimal residual disease, as well as the associations between these factors and outcome.

About 230 (10.5%) AML/MDS-EB patients had TP53 mutations, with a median variable allele frequency (VAF) of 47%. Around 174 (76%) individuals had bi-allelic mutant TP53 status, which was observed. In addition, 49 (21%) individuals had multiple TP53 mutations.

About 113 individuals (49%) had concurrent mutations found. Between AML and MDS-EB, there was no discernible change in any of the aforementioned molecular traits of mutant TP53. Patients with mutant TP53 had extremely poor outcomes (2-year OS, 12.8%), although there is no survival difference between AML and MDS-EB. In the context of the ELN 2017 unfavorable risk category, mutant TP53 was significantly related to decreased survival (2-year OS, 12.8% TP53 mutant vs. 42.5% TP53 wild type; P<0.001). They looked at whether the presence of MDS-EB or AML was associated with survival due to the molecular homogeneity of mutant TP53 AML and MDS-EB. The mutant TP53 AML and MDS-EB subgroups did not vary in their outcomes (P=0.549). TP53 mutant AML or mutant TP53 MDS-EB was subsequently treated as a single entity (AML/MDS-EB). There were no appreciable variations in outcome between mono- and bi-allelic, numerous and single TP53 mutations, or mutant TP53 clone size within AML/MDS-EB. Regardless of the kind of consolidation treatment, they were able to confirm that CK is associated with decreased survival in TP53 mutant AML/MDS-EB (2-year OS, 9% CK vs. 34% non-CK; P=0.002). The overall survival of TP53 mutant AML/MDS-EB that lacks CK was still very low. About 73% of AML/MDS-EB patients had TP53 mutations that could still be found by deep sequencing in complete remission (CR).

The correct assessment of the prognostic significance for individual AML/MDS-EB patients was not possible due to significant clinical and molecular variability within the mutant TP53 AML/MDS EB subgroup. Between AML and MDS-EB patients, there were no discernible variations in the distribution of TP53 molecular features and outcomes. In reality, the 5-year overall survival of patients with mutant TP53 AML and MDS-EB in the research was comparable to that of prior studies. A molecularly homogenous population with unique clinicopathologic traits and prognosis was represented by mutant TP53 AML/MDS-EB. Therefore, regardless of the required blast proportion upon diagnosis, they suggested that mutant TP53 MDS-EB and AML be treated as a single entity. Recent research found significant correlations between the size of the mutant TP53 clone and the TP53 mutant allelic status and better outcomes for MDS and AML patients. The investigations demonstrated important relationships with TP53 mutant allelic status, mutant TP53 clone size, and CK. The findings suggested that additional categorization based on mutant TP53’s molecular features may be less important when patients have advanced to MDS-EB or AML. They did not see this connection in mutant TP53 AML/MDS-EB, despite the fact that molecular MRD has prognostic significance for predicting oncoming relapse in AML/MDS-EB17–19. Molecular MRD discovery in mutant TP53 AML/MDS-EB did not provide predictive value, even though they utilized deep sequencing, revealing MRD in most patients. It was plausible that all mutant TP53 AML/MDS-EB patients who achieve CR also have MRD, albeit seldom and at levels that were currently undetected by NGS.

In a small percentage of AML/MDS-EB patients with non-CK mutant TP53, overall survival was shown to be improved, albeit still being very low.

The enrichment of single TP53 mutations with low VAFs and greater frequencies of concurrent mutations in the group may contribute to the improved prognosis in certain instances, suggesting that mutant TP53, in some cases, may reflect clonal hematopoiesis rather than subclonal illness.

In conclusion, there were no differences between mutant TP53 AML and MDS-EB in clinical traits, molecular traits, or survival. As a result, AML/MDS-EB with mutant TP53 should be regarded as a separate molecular disease entity.

 

Reference: SOHO