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

Abstract

ABSTRACT: Molecular measurable residual disease (MRD) assessment in patients with acute myeloid leukemia (AML) has been established for only a few specific markers: mutant NPM1 and FLT3 internal tandem duplication (ITD). Mutations in isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) are present in ∼20% of patients with AML. 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 persistent IDH1/2 mutations in complete remission after intensive chemotherapy in a cohort of 163 newly diagnosed patients with IDH-mutant AML, enrolled in Dutch-Belgian Cooperative Trial Group for Hematology-Oncology and Swiss Group for Clinical Cancer Research clinical trials, using a next-generation sequencing (NGS)-based approach, targeting all hot spot mutations in IDH1 (R132) and IDH2 (R140 and R172). The high sensitivity (10-4) as well as the levels of persistent IDH1/2 mutations detected by the NGS-based approach were confirmed by an independent super rolling circle amplification assay. We demonstrate that the risk of relapse was significantly increased in patients with AML with measurable persistent IDH2 mutations (P = .027; subdistribution hazard ratio (SHR), 2.34) but not in patients with persistent mutant IDH1 (P = .591; SHR, 0.80). Moreover, the association of persistence of mutant IDH2 and increased risk of relapse was most pronounced in patients with mutant IDH2 AML without concomitant NPM1 mutations or FLT3-ITD (P = .011; SHR, 5.29). Thus, mutant IDH2 appears as a potentially useful novel molecular MRD marker with prognostic significance in AML.

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