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

Mutations in the isocitrate dehydrogenase 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=4 113), myelodysplastic neoplasms (MDS; n=6 316), or chronic myelomonocytic leukemia (CMML; n=1 642)). IDH mutations were found in 28% of AML (IDH1: 10%; IDH2: 18%), 6.3% of MDS (IDH1: 1.8%; IDH2: 4.6%), and 5.2% of CMML patients (IDH1: 0.8%; IDH2: 4.4%). IDH mutations were enriched in subgroups with increased blasts but almost absent within MDS-biTP53. The co-mutational pattern differed by age, between the MN, and also between mutation hotspots. The underlying clonal hierarchy suggested that IDH mutations were present in the founder clone in many, but not all cases. Finally, the high frequencies of IDH1 mutations in secondary AML and AML-MR (both 9.5%) compared to MDS (1.8%) and CMML (0.8%) indicated 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.