AML-279 Molecularly-Defined and Secondary Acute Myeloid Leukemia Are Biologically and Clinically Different Entities

Abstract

Acute myeloid leukemia (AML) is a heterogeneous disease, which can be clinically classified in de novo AML or secondary AML (sAML) and separate from therapy-related AML. Secondary AML evolves from an antecedent hematological disorder, whereas de novo AML arises in absence of any prior hematological disease or leukemogenic treatment. A broad range of genetic and cytogenetic abnormalities that directly contribute to the development of AML has been identified. Nevertheless, the association of these markers with leukemia ontogeny and clinical response is not completely understood. The primary aim of this study was to discriminate de novo AML from secondary type AML (stAML) based on the occurrence of molecular and cytogenetic markers in a unique large cohort of AML patients (n=2,447) enrolled in the Dutch-Belgian Cooperative Trial Group for Hematology-Oncology (HOVON) or the Swiss Group for Clinical Cancer Research (SAKK) clinical trials. All patients received intensive treatment. We investigated the clinical and biological differences between de novo AML and sAML with the underlying hypothesis that (molecularly defined) de novo AML and stAML should be considered as two different entities. In our unique AML cohort, we demonstrated that RUNX1, EZH2, SRSF2, STAG2, ZRSR2, SF3B1, ASXL1 and U2AF1 significantly associated with clinically proven sAML (p<0.01). AML cases carrying these mutations were referred to as stAML. Mutations in NPM1, CEBPA (bi-allelic), FLT3-ITD, inv(16), t(8;21) and aberrations involving 11q23 were included as class-defining for de novo AML. AML patients with TP53 mutations were removed from all analyses since this genetically and clinically distinct subtype of AML should be considered as a separate entity. In comparison to de novo AML (n=1705), patients with stAML (n=742) were older (p<0.01), were more likely to be male (p<0.01), carried a higher number of driver mutations (p<0.01), had lower white blood cell counts (p<0.01), more frequently lower bone marrow blast and blood neutrophil counts (p<0.01). Importantly, patients with stAML had a significant inferior event-free (p<0.001) and overall survival (p<0.001). In conclusion, we revealed molecularly defined stAML as an AML subtype with a distinct genetic ontogeny that emphasizes a subgroup of patients with significantly worse clinical outcomes.