AML-156: The Clinical Implications and Outcomes of RAS Mutatome in Core-Binding Factor Acute Myeloid Leukemia

Abstract

<h3>Context</h3> The clonal architecture of <i>KRAS/NRAS</i> mutations (<i>RAS</i>^MT) in Core-Binding Factor AML (CBF-AML). <h3>Objective</h3> To dissect the impact of <i>RAS</i>^MT on CBF-AML. <h3>Design/Setting</h3> Clinical and molecular data and survival outcomes (OS) of the patients were collected at The Cleveland Clinic Foundation and Munich Leukemia Laboratory. <h3>Patients</h3> A cohort of 368 CBF-AML patients was identified, in whom inv(16) and t(8;21) represented 64% (n=237) and 36% (n=131) of the cases. Thirty-eight percent (141/368) carried <i>RAS</i>^MT (<i>KRAS</i>=22; <i>NRAS</i>=105) with 14 patients harboring both <i>KRAS/NRAS.</i> <h3>Main outcome measures</h3> Clinical and molecular characteristics and OS of <i>RAS</i>^MT CBF-AML. <h3>Results</h3> Leukopenia and anemia were significantly higher in <i>RAS</i>^MT and <i>RAS</i>^WT. <i>RAS</i>^MT had more +8 (14 <i>vs.</i> 7%) but less -Y (7 <i>vs.</i> 15%; <i>P</i>=0.02) and -X (2 <i>vs.</i> 7%; <i>P</i>=0.03) abnormalities. <i>RAS</i>^MT were less associated with <i>TET2</i>^MT (6 <i>vs.</i> 12%; <i>P</i>=0.02) and <i>KIT</i>^MT (9 <i>vs.</i> 31%; <i>P</i> < 0.0001). <i>DNMT3A</i>^MT was the most common dominant lesion, <i>KIT</i>^MT was the most frequent co-dominant mutation while <i>NPM1</i>^MT and <i>FLT3</i>^MT were the most subclonal hits in <i>RAS</i>^MT. <i>RAS</i>^MT associated with a neutral impact on OS (HR: 0.7; <i>P</i>=0.06) compared to <i>RAS</i>^WT. <i>KRAS/NRAS</i> were dominant in 35%, co-dominant in 5%, and secondary hits in 60% of <i>RAS</i>^MT cases. No effect on OS was observed per <i>RAS</i>^MT hierarchy (HR: 0.8; <i>P</i>=0.6). However, IDH2^MT (90% R140Q,10% R172K) and <i>RUNX1</i>^MT predicted worse OS in <i>RAS</i>^MT compared to <i>RAS</i>^WT (31 <i>vs.</i> 3 mo., <i>P</i>=0.007 and 30.7 <i>vs.</i> 9.7 mo.; <i>P</i>=0.04, respectively). <h3>Conclusions</h3> <i>RAS</i> ^MT account for one-third of CBF-AML and their prognostic relevance is still a matter of debate. Similar to previous studies, our analysis demonstrated no impact on OS for <i>RAS</i>^MT CBF-AML. However, the dissection of clonal succession and mutational ranking concluded that the acquisition of multiple hits in epigenetic regulators (<i>e.g., IDH2, RUNX1</i>) determined poorer OS in the <i>RAS</i>^MT CBF-AML.