Clonal architecture predicts clinical outcomes and drug sensitivity in acute myeloid leukemia

Individual studies have been underpowered to draw clear associations between clonal heterogeneity and response to therapy in acute myeloid leukemia (AML). Here, the authors aggregate multiple AML cohorts and are able to correlate the clonal abundance of somatic mutations with clinical outcomes and drug sensitivity. The impact of clonal heterogeneity on disease behavior or drug response in acute myeloid leukemia remains poorly understood. Using a cohort of 2,829 patients, we identify features of clonality associated with clinical features and drug sensitivities. High variant allele frequency for 7 mutations (including NRAS and TET2) associate with dismal prognosis; elevated GATA2 variant allele frequency correlates with better outcomes. Clinical features such as white blood cell count and blast percentage correlate with the subclonal abundance of mutations such as TP53 and IDH1. Furthermore, patients with cohesin mutations occurring before NPM1, or transcription factor mutations occurring before splicing factor mutations, show shorter survival. Surprisingly, a branched pattern of clonal evolution is associated with superior clinical outcomes. Finally, several mutations (including NRAS and IDH1) predict drug sensitivity based on their subclonal abundance. Together, these results demonstrate the importance of assessing clonal heterogeneity with implications for prognosis and actionable biomarkers for therapy.

Automated summary

This study aggregates multiple AML cohorts to explore the correlation between clonal abundance of somatic mutations and clinical outcomes. High variant allele frequency for certain mutations is associated with poor prognosis, while increased GATA2 variant allele frequency correlates with better outcomes. Clinical features such as white blood cell count and blast percentage are related to the subclonal abundance of mutations like TP53 and IDH1.