Prognostic heterogeneity and clonal dynamics within distinct subgroups of myelodysplastic syndrome and acute myeloid leukemia with <i>TP53</i> disruptions

Abstract

<i>TP53</i> aberrations constitute the highest risk subset of myelodysplastic neoplasms (MDS) and acute myeloid leukemia (AML). The International Consensus Classification questions the blast threshold between MDS and AML. In this study, we assess the distinction between MDS and AML for 76 patients with <i>TP53</i> aberrations. We observed no significant differences between MDS and AML regarding <i>TP53</i> genomics. Median overall survival (OS) was 223 days for the entire group, but prognostic discrimination within subgroups showed the most inferior OS (46 days) for AML with multihit allelic state plus <i>TP53</i> variant allele frequency (VAF) > 50%. In multivariate analysis, unadjusted Cox models revealed the following variables as independent risk factors for mortality: AML (vs. MDS) (hazard ratio [HR]: 2.50, confidence interval [CI]: 1.4-4.4, <i>p</i> = 0.001), complex karyotype (HR: 3.00, CI: 1.4-6.1, <i>p</i> = 0.003), multihit status (HR: 2.30, CI 1.3-4.2, <i>p</i> = 0.005), and absence of hematopoietic cell transplant (HCT) (HR: 3.90, CI: 1.8-8.9, <i>p</i> = 0.0009). Clonal dynamic modeling showed a significant reduction in <i>TP53</i> VAF with front-line hypomethylating agents. These findings clarify the impact of specific covariates on outcomes of <i>TP53</i>-aberrant myeloid neoplasms, irrespective of the diagnosis of MDS versus AML, and may influence HCT decisions.