Unraveling TP53-Mutated Acute Myeloid Leukemia : Clinical Insights and Genetic Profiles
Authors: Park Songyi , Kim Sang-A , Lee Ji Yun , Byun Ja Min , Lee Jeong-Ok , Koh Youngil , Hong Junshik , Lee Junglim , Bang Soo-Mee , Kim Inho , Yoon Sung-Soo , Shin Dongyeop 
Published: December 2024

Background
TP53 mutation in acute myeloid leukemia is known to poor outcomes and response to standard treatments. This study aimed to provide a detailed characterization of TP53- mutated AML focusing on its distinct clinical and molecular features.
Methods
A comprehensive analysis was conducted on 336 patients diagnosed with AML from March 2017 to April 2023 who were identified at Seoul National University Hospital and Seoul National University Bundang Hospital. The analysis included evaluation of baseline characteristics, next-generation sequencing (NGS) data, mutational details, immunophenotype profiles, and treatment results of the patient cohort.
Results
Out of 336 patients diagnosed with AML, a subset of 50 individuals exhibited TP53 mutations, representing approximately 14.9% of the total patient population. TP53-mutated AML showed a higher prevalence of secondary etiology compared to de novo cases. Among the patients analyzed, 226 (79.0%) had de novo AML with no TP53 mutation, while 60 (21.0%) had secondary AML with no TP53 mutation. In contrast, TP53 mutated AML comprised 30 (60.0%) de novo cases and 20 (40.0%) secondary etiology cases (p value = 0.039). Treatment related AML in TP53-mutated cases also showed a higher incidence than AML with no TP53 mutation (11.9 vs. 22.0%, p =0.053)
Immunophenotypic analysis, including cytoplasmic markers and surface markers, revealed no notable differences in the expression of cell lineage markers, including B-cell, T-cell, and NK-cell markers, among TP53-mutated and non-TP53-mutated AML patients.
NGS data focusing on 7 genes recurrently mutated in AML indicated that TP53-mutated AML patients had fewer concurrent mutations compared to those without TP53 mutation. For instance, ASXL1 mutations were present in 17.1% (49/286) without TP53 mutation and 5 patients 10.0% (5/50) with TP53 mutation. Similarly, NPM1, FLT3-ITD, BCOR, CEBPA, FLT3, IDH1 , and KRAS mutations showed less frequency in TP53-mutated AML patients.
Analysis of TP53 mutational details revealed a predominance of missense substitutions, accounting for 46 (92.0%) out of 50 TP53-mutated AML cases. Additionally, frameshift insertions were identified in 2 cases (4.0%), while 2 cases (4.0%) exhibited nonsense mutations
TP53 mutated AML demonstrated that treatment outcomes were similar to those reported in previous studies, with a composite complete response (CRc) rate of 65.1%(183/281) in non-TP53 mutated AML patients and 33.3%(16/48) in TP53 mutated AML patients (p &lt; 0.001). According to the treatment response based on intensiveness of regimens, in TP53-mutated AML patients, CR rates were 41.9%(13/31) with intensive regimens and 17.6%(3/17) with less intensive regimens (p &lt; 0.001). And in non-TP53-mutated AML patients, 75.0%(141/188) CRc with intensive regimens and 45.2%(42/93) with less intensive regimens (p &lt; 0.001).
TP53-mutated AML patients exhibited a median overall survival of 7.0 months (95% confidential index (CI): 2.52-11.48), whereas non-TP53-mutated AML patients showed a significantly longer median survival of 42.0 months (95% CI: 21.19-62.81, p &lt; 0.001), similar to previous studies. However, a comparison based on variant allele frequency (VAF) cutoff of 10% in TP53-mutated AML patients revealed similar median overall survival between patients with VAF &lt; 10 (7.0 months, 95% CI: 0.0-15.21) and VAF ≥ 10 (8.0 months, 95% CI: 2.14-13.86) (p = 0.364). The comparison based on a VAF cutoff of 20% also yielded no significant difference in median overall survival between the subgroups.
Conclusion
In conclusion, we observed a higher prevalence of secondary etiology in TP53-mutated AML compared to de novo cases, along with a predominance of missense substitutions in TP53 mutational details. Our findings suggest that TP53-mutated AML lacks specific characteristics in immunophenotype. Furthermore, TP53 mutations were observed to occur rarely alongside other genetic mutations, emphasizing the distinct genetic profile of TP53-mutated AML. Interestingly, our analysis revealed that TP53 VAF did not demonstrate a significant relationship with survival outcomes in TP53-mutated AML patients. These results underscore the unique genetic and clinical features of TP53-mutated AML and provide valuable insights into its prognosis and therapeutic considerations.