Impact of Allelic State on Overall Survival in TP53-mutant Acute Myeloid Leukemia (AML) and Higher Risk Myelodysplastic Syndromes (HR-MDS)

Introduction: Mutations in TP53 confer an adverse prognosis in patients (pts) with AML and HR-MDS. There are conflicting results regarding the prognostic impact of mono-allelic vs bi-allelic and mono-hit vs multi-hit TP53 mutation status on prognosis in AML and HR-MDS. Additionally, assessment of loss-of-heterozygosity (LOH) status is not routinely available in many settings limiting the clinical implementation of TP53 mutational status. Methods: We took advantage of a large, randomized study with extensive clinical and molecular annotation to analyze 61 patients (pts) with TP53-mutated (TP53-mut) disease and to compare them to 144 TP53 wild-type pts. All pts received azacitidine and half were randomized to receive the anti-PDL1 antibody durvalumab, which did not improve clinical outcomes (Zeidan et al. Blood Advances 2022). A 38 gene-targeted myeloid mutation analysis from screening bone marrow was performed at Munich Leukemia Laboratory. Only pathogenic TP53 variants with variant allele frequency (VAF) ≥2% were included. Pts with a common SNP or VUS in the TP53 gene were classified as TP53-WT in the analysis. Multi-hit TP53 mutations were defined as previously published by the International Consensus Conference (ICC; Arber et al. Blood 2022) as ≥2 distinct TP53 mutations (VAF ≥10%) or a single TP53 mutation associated with either: 1) cytogenetic deletion involving chromosome 17p (e.g., del(17p) or monosomy 17); 2) a VAF of >50%; or 3) with any complex karyotype. We also defined multi-hit TP53 mutations as proposed by Grob et al. (Blood 2022) as (I) ≥2 TP53 gene variants irrespective of VAF, (II) ≥1 TP53 gene variant co-occurred with a cytogenetic deletion involving chromosome 17p, or (III) TP53 mutations with VAF >55%. Based on multiple prior studies (Grob et al. Blood 2022, Weinberg et al. Blood Advances 2022) patients with AML and HR-MDS with TP53 mutations were analyzed as one disease entity. Results: 37 had TP53-mut AML, 89 were TP53-WT AML, 24 had TP53-mut HR-MDS, and 55 were TP53-WT HR-MDS pts. The average VAF for TP53 mutations was 37%, and 90% had ≥10% VAF. 93% of TP53 mutations occurred in the p53 DNA-binding domain. TP53-mut pts had fewer co-occurring mutations compared with TP53-WT pts (mean number of mutations: 1.8 [SD: 0.77] for TP53-mut pts (including TP53) vs 2.9 [SD: 1.4] for TP53-WT pts; Wilcoxon P <0.001) with distinct patterns in the distribution of co-occurring mutations. In terms of TP53 allelic status, 22 (11.0%) were mono-hit and 41 (20.5%) pts were multi-hit as defined by Grob et al, while 7 (3.4%) and 56 (28.0%) pts were classified as mono-hit and multi-hit per ICC definition, respectively. In the AML cohort, TP53-mut pts were more likely to have poor-risk cytogenetics (59.5% vs 11.2%; p<0.001), therapy-related myeloid neoplasm (10.8% vs 1.1%; p=0.042), and lower bone marrow blast percentage (27.5% vs 35.5%; p=0.001) compared to TP53-WT. Among MDS pts, TP53-mut pts were more likely to have secondary MDS (20.8% vs 1.8%; p=0.013), very poor risk cytogenetics by IPSS-R (75% vs 14.6%; p<0.001), and very high risk IPSS-R score (62.5% vs 34.6%; p=0.039). There were no statistically significant differences in terms of baseline demographics and other clinical characteristics. There was no difference in overall response rate (ORR) between TP53-mut and TP53-WT pts (AML: ORR: 35.1% [95% CI: 20.7% - 52.6%] vs. 33.7% [95% CI: 24.2% - 44.6%]; p=1.000; MDS: ORR: 41.7% [95% CI: 22.8% - 63.1%] vs. 60.0% [95% CI: 45.9% - 72.7%]; p=0.208). TP53 allelic status did not influence OS using either definition (Grob et al: mono-hit: median OS 7.6 months [95% CI:5.4-10.6 months]; multi-hit 10.6 months [95% CI: 9.1-13.0 months] (Figure A); ICC definition: 8.0 months (95% CI: 6.1-20+ months) and 9.5 months [95% CI: 7.7-10.9 months], (Figure B)) and was inferior to TP53-WT (median OS: 18.9 months; 95% CI: 15.5-22.9 months). Conclusion: Outcomes of AML and MDS pts with TP53 mutations are worse compared to TP53-WT without differences between mono-hit vs multi-hit status as defined by the ICC and Grob et al. This suggests that either the negative prognostic impact of a multi-hit TP53 allelic status can be overcome by treatment with azacitidine or that a distinction by TP53 allelic status in newly diagnosed AML/HR-MDS pts treated with azacitidine does not provide additional prognostic information. Whether incorporating TP53 LOH status is necessary to further refine risk assessment warrants additional studies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal