Prognostic Impact of TP53 Mutation in Adult Acute Lymphoblastic Leukemia Treated with Pediatric-Inspired Regimen

Abstract

Background: TP53 is one of the most extensively studied genes in human cancer. However, the prognostic impact of TP53 mutations (TP53mut) in adult acute lymphoblastic leukemia (ALL) remained debatable, especially in those treated with pediatric-inspired regimen. Herein, we determined the characteristic of TP53mut in adult acute ALL patients and investigated the clinical significance of these TP53mut in newly diagnosed ALL.

Patients and Methods: We performed TP53 mutation analysis in 283 adult ALL patients (B-ALL n=227; T-ALL n=56) including 57 diagnose-relapse pairs using targeted next-generation sequencing (NGS). TP53 mutations were analyzed for their association with adult ALL enrolled in pediatric-inspired regimen evaluating clinical characteristics and treatment outcomes.

Results: A total of 35 TP53mut sites were detected in 31 diagnosed samples among 283 diagnosed patients and 17 among 57 paired diagnose-relapse samples, with a significant difference (11.0% vs 29.8%; c2=13.9, P<0.001). The major variant was missense mutation (n=32), followed by frameshift (n=11), nonsense mutation (n=4), in-frame (n=3), and splicing mutation (n=2). In paired diagnose-relapse samples, we identified acquired and/or loss of TP53mut in the samples at the time of relapse. In 283 newly diagnosed patients, patients with TP53mut had a higher proportion of the older population, complex karyotype, and MRD positivity before consolidation therapy (P=0.023, 0.002, 0.024). Survival analysis revealed that TP53mut was associated with inferior outcomes in the whole cohort of newly diagnosed ALL (4-year OS rates, 43.6% vs 63.6%, P=0.0086; 4-year EFS rates, 30.4% vs 52.2%, P=0.0056). Additional survival analysis showed that TP53mut did not confer poor outcomes in the AYA population (4-year OS rates, 60.6% vs 68.1%, P=0.55; 4-year EFS rates, 52.5% vs 55.5%, P=0.57). For the older patients, however, TP53mut predicted inferior OS and EFS in older patients (4-year OS rates, 18.2% vs 46.2%, P=0.0033; 4-year EFS rates, 0 vs 39.6%, P=0.00028).

Conclusion: Our data revealed that TP53mut was present at a low incidence at diagnosis and increase at relapse. TP53mut were potential biomarkers associated with poor prognosis in older patients with newly diagnosed ALL treated with pediatric-inspired regimen.

This research was supported by the National Natural Science Foundation of China(NFSC82170163, 81970147), Clinical Study of Nanfang Hospital(LC2016ZD009/2019CR012).

【 Key words 】TP53; Acute lymphoblastic leukemia; Pediatric-inspired regimen; Next-generation sequencing; Prognosis