Clinical Significance of Mutant TP53 Alleles and Functions in Acute Myeloid Leukemia: HM-Screen-Japan 01/02 Study

[Introduction] TP53 mutations confer a dismal prognosis to patients with acute myeloid leukemia (AML). In addition to a simple model which have dichotomized AML patients into those with wild-type TP53 and mutant TP53 (mTP53), recent studies have shed light on allelic status of p53 abnormalities. One of the most important recent discovery is that multi-hit TP53 mutations more profoundly affect patients’ overall survival (OS) compared to single-hit mutations (Stengel et al. Blood Adv 2023;7:2952). In this study, we focused on the possible prognostic impact of the residual p53 function in AML patients with mTP53. We hypothesized that residual wild-type p53 function (functional or non-functional), gain of abnormal p53 function (GOF) of mTP53(GOF or non-GOF), or allelic status of mTP53 (single-hit or multi-hit) would all influence outcome of AML patients with mTP53. [Methods] Next-generation sequencing was performed in 330 AML patients enrolled in the Japanese multicenter study HM-SCREEN-JAPAN 01/02, to evaluate a possible association between qualitative and quantitative mTP53 abnormalities and overall survival (OS). Patients with treatment-naïve and relapsed AML were included. mTP53 function was assessed using the ClinVar and COSMIC databases. The TP53 mutations R175H, R248W, R248Q, R249S, R273H, R273L, and R282W were defined as GOF mTP53. Detection of ≥2 TP53 variants regardless of variant allele frequency, the presence of at least one TP53 gene variant coexisting with 17p13.1/TP53 deletion including 17p-, i(17q), and -17, and detection of TP53 mutations with a variant allele frequency >55% were defined as multi-hit mTP53, while others as single-hit mTP53. Results were considered statistically significant at P values <0.05. [Results] TP53 mutations were identified in 68 (20.5%) of the 330 AML patients, including 29 patients with single-hit mTP53 and 39 patients with multi-hit. Both patients with single-hit and multi-hit mTP53 had a significantly worse prognosis compared to patients with wild-type TP53 (median OS: 16.1 months versus 7.5 months versus 41.6 months). Median survival of patients with multi-hit mTP53 AML were significantly shorter than single-hit patients (P = 0.011). Patients having both mTP53 and complex karyotype had a worse prognosis than those with either mTP53 or complex karyotype (median OS: 7. 6 months versus 15.0 months versus 18.9 months; P = 0.03). Among patients with single-hit mTP53, presence of wild-type p53 function did not influence patients’ survival (P = 0.985). There was no difference in OS between patients with GOF mTP53 and those with non-GOF mTP53 (median OS: 9.5 months versus 9.8 months; P = 0.913). [Conclusion] Our data showed that although presence of a single-hit mTP53 already influences OS, multi-hit mTP53 further worsen OS in patients with AML. Unexpectedly, our study did not support the idea that qualitative mTP53 abnormalities affect patients’ survival. Since our study include heterogenous patient population with a wide variety of gene mutations, further studies with a large number of patients are required to draw a definitive conclusion.