Next Generation Sequencing Study of clonal Evolution in AML Shows Mutations in RAS-MAPK Signaling Pathway as an Emergent Mechanism of Progression in Low-Intensity Treatments

Understanding the evolution patterns in patients diagnosed with acute myeloid leukemia (AML) after therapy is relevant due to the dismal outcome still present in refractory or relapsed AML patients. We performed a retrospective, single-center study to evaluate the mutation profile in paired samples obtained at the time of diagnosis and at the onset of progressive or refractory disease in patients diagnosed with AML through a commercial next-generation sequencing (NGS) panel. In total, 62 patients were analyzed. Of these, 28 patients received ICT, and 34 patients underwent low-intensity treatments. In LIT patients, there were emergent mutations at progressive disease in a 64% (22/34) of the patients. Emergent mutations in the RAS-MAPK signaling pathway were observed in 35.9% (12/34) , corresponding to 54.5% of all patients with emergent mutations (12/22). These were found in 12/22 patients that received venetoclax in combination with hypomethylating agents. Six presented mutations in genes related to the RAS-MAPK pathway. Emerging mutations are frequently observed at progressive AML disease after therapy. In patients treated with LIT, mutations in RAS-MAPK signaling pathway might have a key role on the secondary clinical resistance, not only if they are present at diagnosis, becoming a potential target for the development of new drugs.