Cytogenetic and genomic profiling of acute myeloid leukemia (AML) guides personalized treatment according to ELN2022 recommendations. However, marked outcome variability persists among cytogenetically normal (CN-) patients, representing an unmet clinical need. We used long-read whole-genome sequencing to interrogate the prognostic significance of structural variations (SVs) in a prospective cohort of 162 intensively treated CN-AML patients. After stringent filtering, we identified 5 somatic SVs associated with shorter overall survival (OS) (HR:4.18, p ITD and NPM1mut. Among the latter patients, HRVs independently predicted shorter OS (8.2 months versus not-reached; p < 0.001), EFS (3.5 versus 25.7 months; p < 0.001), and lower complete response rates (66.7% versus 90.1%; p < 0.005). Finally, we provided evidence of transcriptional deregulation of SV-related genes in primary samples and engineered cell models. Current findings support the value of SVs for refining risk stratification in CN-AML, by identifying patients at exceedingly dismal outcome who might benefit from personalized approaches.
Bartalucci et al. (Fri,) studied this question.