Utility of IDH1/2 mutations as biomarkers for detection of measurable residual disease in acute myeloid leukemia

Molecular measurable residual disease (MRD) assessment in acute myeloid leukemia (AML) patients has been established for only a few specific markers, i.e. mutant NPM1 and FLT3-ITD. Mutations in IDH1/2 are present in approximately 20% of AML patients. However, validation of mutant IDH1/2 MRD has been hampered by cohort size as well as the availability of highly sensitive and specific MRD detection assays. Here, we comprehensively investigate the impact of persisting IDH1/2 mutations in complete remission (CR) after intensive chemotherapy in a cohort of 163 newly diagnosed IDH-mutant AML patients enrolled in HOVON-SAKK clinical trials using a next-generation sequencing (NGS)-based approach, targeting all hotspot mutations in IDH1 (R132) and IDH2 (R140, R172). The high sensitivity (10-4) as well as the levels of persisting IDH1/2 mutations detected by the NGS-based approach were confirmed by an independent rolling circle amplification (superRCA) assay. We demonstrate that relapse risk was significantly increased in AML patients with measurable persisting IDH2 mutations (p=0.027, SHR:2.34), but not in patients with persisting mutant IDH1 (p=0.591, SHR:0.80). Moreover, the association of persistence of mutant IDH2 and increased risk of relapse was most pronounced in mutant IDH2 AML patients without concomitant NPM1 mutations or FLT3-ITD (p=0.011, SHR:5.29). Thus, mutant IDH2 appears a potentially useful novel molecular MRD marker with prognostic significance in AML.