Polyclonal relapse mechanisms. Single-cell analysis showing clonal evolution in individual patients. (A) mIDH2 acquired in the same clone as mIDH1, with elevation of 2-HG at relapse. Two distinct mIDH1 clones were present at baseline: 1 harboring NPM1/NRAS and the other harboring NPM1/FLT3-TKD comutations. After ivosidenib treatment, the IDH1/NPM1/NRAS clone was no longer detected. Reduction in the IDH1/NPM1/FLT3-TKD clone was observed at cycle 2 day 1, but it ultimately expanded at relapse with the acquisition of mIDH2. (B) mIDH2 was not detected at baseline, but emergence of mIDH2 in a separate clone than mIDH1 was observed at cycle 12 day 1, with elevation of 2-HG. (C) mIDH2 was present at baseline (though not detected by bulk NGS) in a distinct clone to mIDH1, with clinical relapse associated with detection of an NRAS clone. In this case of NRAS-driven clinical relapse, the 2-HG levels remained low at relapse. Additional details on these cases shown in supplemental Figure 7. NS, not specified.