Clinico-genomic profiling and clonal dynamic modeling of <i>TP53</i>-aberrant myelodysplastic syndrome and acute myeloid leukemia

Abstract

<i>TP53</i>-aberrant myelodysplastic syndrome and acute myeloid leukemia have dismal outcomes. Here, we define the clinico-genomic landscape of <i>TP53</i> disruptions in 40 patients and employ clonal dynamic modeling to map the mutational hierarchy against clinical outcomes. Most <i>TP53</i> mutations (45.2%) localized to the L3 loop or LSH motif of the DNA-binding domain. <i>TP53</i> disruptions had high co-occurrence with mutations in epigenetic regulators, spliceosome machinery, and cohesin complex and low co-occurrence with mutations in proliferative signaling genes. Ancestral and descendant <i>TP53</i> mutations constituted measurable residual disease and fueled relapse. High mutant <i>TP53</i> gene dosage predicted low durability of remission. The median overall survival (OS) was 280 days. Hypomethylating agent-based therapy served as an effective bridge to transplant, leading to improved median OS compared to patients who did not receive a transplant (14.7 <i>vs.</i> 5.1 months). OS was independent of the genomic location of <i>TP53</i> disruption, which has implications for rational therapeutic design.