Clinical implications of RAS mutations in AML: Prognostic significance is based upon involved gene and mutation complexity

Acute myeloid leukemia (AML) is a heterogeneous disease with complex mutational profiles that lead to variable clinical outcomes. NRAS and KRAS are among the most frequently mutated genes in AML, but their clinical impact has not been well-characterized. In this cohort of over 2000 children and young adults with AML, we evaluated the role of mutations in RAS genes and mutation complexity in outcome determination. Given enrichment in KMT2A-rearranged AML (KMT2A-r), we specifically studied the significance of RAS mutations in KMT2A-r AML. Using variant calls from next generation sequencing (NGS) platforms, we identified RAS mutations in 35.1% (N=669) (NRAS, N=518; KRAS, N=216). We demonstrated that NRAS mutations were not associated with outcome in AML or in KMT2A-r AML. In contrast, KRAS mutations demonstrated inferior outcomes in AML, with enrichment of prevalence and enhancement of prognostic implications in KMT2A-r AML, including non-high risk KMT2A fusions. Additionally, we describe a complex RAS mutation cohort (Comp-RAS) characterized by two distinct RAS mutations or high variant allele frequency (VAF) RAS mutations that collectively account for 13.5% (n=90) of patients with RAS mutations. Patients with complex KRAS mutations, and those with complex RAS mutations in the KMT2A-r cohort, had a distinctly adverse outcome, and data demonstrates that Comp-RAS status drives adverse outcomes for those with KRAS mutations in the whole AML cohort.