Persistence of IDH2 mutations in remission predicts relapse in patients with wildtype NPM1 acute myeloid leukemia.
Mutations in IDH1 and IDH2 are among the most frequent acquired mutations in acute myeloid leukemia (AML) patients, accounting for approximately 20% of all cases. With the emergence of small molecule inhibitors targeting mutant IDH1 or IDH2, therapeutic interest in this subtype of AML has sparked in recent years. Molecular measurable residual disease (MRD) assessment has been established for only a few specific markers, including mutant NPM1 and FLT3-ITD. Validation of other molecular MRD markers, including IDH1/2, has been hampered by cohort size as well as the availability of adequate and sensitive assays. Here, we comprehensively investigate the influence of persisting IDH1/2 mutations in complete remission (CR) in a large cohort of newly diagnosed AML patients using a sensitive next generation sequencing (NGS) approach.
In a cohort of 163 newly diagnosed IDH-mutant AML patients enrolled in HOVON-SAKK clinical trials, deep sequencing targeting hotspot mutations of IDH1 (R132) and IDH2 (R140, R172) was performed on DNA samples of patients in CR after two cycles of induction chemotherapy. The sensitivity of 10-4 as well as the levels of mutant IDH1 and IDH2 by NGS were confirmed by an independent technology based on SuperRCA (Rarity Bioscience, Uppsala, Sweden).
Persistence of IDH mutations was not related to increased relapse incidence or inferior overall survival. However, stratification into IDH1 and IDH2 mutant AML, revealed that relapse risk was significantly increased in AML patients with persisting IDH2 mutations, but not in patients with persisting mutant IDH1. Interestingly, the increased risk of relapse in IDH2 mutant AML patients was only present in the patients without concomitant mutant NPM1.
We revealed mutant IDH2 as a potential novel prognostically relevant MRD marker in a subset of AML patients who were not subject to molecular MRD assessment before.