IDH1- and IDH2-mutated myeloid neoplasms: mutational pattern, clonal hierarchy, and the role in AML transformation

Mutations in the isocitrate dehydrogenase (IDH) genes, IDH1 and IDH2, are recurrently found in patients with myeloid neoplasms (MN) and clinically targeted by small-molecule inhibitors. We aimed to comprehensively study the genetic pattern and underlying clonal architecture in a large cohort of 12 071 patients (acute myeloid leukemia [AML], n = 4113; myelodysplastic neoplasms [MDS], n = 6316; or chronic myelomonocytic leukemia [CMML], n = 1642). IDH mutations were found in 28% of patients with AML (IDH1, 10%; IDH2, 18%), 6.3% of patients with MDS (IDH1, 1.8%; IDH2, 4.6%), and 5.2% of patients with CMML (IDH1, 0.8%; IDH2, 4.4%). IDH mutations were enriched in subgroups with increased blasts but almost absent within MDS with biallelic TP53 inactivation. The comutational pattern differed by age, between MN, and between mutation hot spots. The underlying clonal hierarchy suggested that IDH mutations were present in the founder clone in many, but not all, patients. Finally, the high frequencies of IDH1 mutations in secondary AML and myelodysplasia-related AML (both 9.5%), compared with MDS (1.8%) and CMML (0.8%), indicate a frequent acquisition of this mutation at the transition to AML, which was directly confirmed in a subset of patients analyzed before and after progression. Overall, our findings have potential implications for sequential molecular testing and targeted treatment decisions.