Interaction between myelodysplasia-related gene mutations and ontogeny in acute myeloid leukemia: an appraisal of the new WHO and IC classifications and ELN risk stratification

Accurate classification and risk stratification is critical for clinical decision making in AML patients. In the newly proposed World Health Organization (WHO) and International Consensus classifications (ICC) of hematolymphoid neoplasms, the presence of myelodysplasia-related (MR) gene mutations is included as one of the diagnostic criteria of AML, myelodysplasia-related (AML-MR), largely based on the assumption that these mutations are specific for AML with an antecedent myelodysplastic syndrome. ICC also prioritizes MR gene mutations over ontogeny (as defined by clinical history). Furthermore, European LeukemiaNet (ELN) 2022 stratifies these MR gene mutations to the adverse-risk group. By thoroughly annotating a cohort of 344 newly diagnosed AML patients treated at Memorial Sloan Kettering Cancer Center (MSKCC), we show that ontogeny assignment based on database registry lacks accuracy. MR gene mutations are frequently seen in de novo AML. Among MR gene mutations, only EZH2 and SF3B1 were associated with an inferior outcome in a univariate analysis. In a multivariate analysis, AML ontogeny had independent prognostic values even after adjusting for age, treatment, allo-transplant and genomic classes or ELN risks. Ontogeny also stratified the outcome of AML with MR gene mutations. Finally, de novo AML with MR gene mutations did not show an adverse outcome. In summary, our study emphasizes the importance of accurate ontogeny designation in clinical studies, demonstrates the independent prognostic value of AML ontogeny and questions the current classification and risk stratification of AML with MR gene mutations. Key pointsO_LIBoth ontogeny and genomics show independent prognostic values in AML. C_LIO_LIThe newly proposed myelodysplasia-related gene mutations are neither specific to AML-MRCWHO2016 nor predictive for adverse outcomes. C_LIO_LIOntogeny stratifies the outcome of AML with myelodysplasia-related gene mutations. C_LI