Abstract
Baseline mutations are associated with response (
JAK2
) or resistance (
NRAS
,
PTPN11
) to ivosidenib monotherapy in m
IDH1
R/R AML.
2-HG restoration via novel
IDH1
second-site and
IDH2
mutations, and non-
IDH
–related pathways, are identified at relapse.
Isocitrate dehydrogenase (
IDH
) 1 and 2 mutations result in overproduction of D-2-hydroxyglutarate (2-HG) and impaired cellular differentiation. Ivosidenib, a targeted mutant IDH1 (mIDH1) enzyme inhibitor, can restore normal differentiation and results in clinical responses in a subset of patients with m
IDH1
relapsed/refractory (R/R) acute myeloid leukemia (AML). We explored mechanisms of ivosidenib resistance in 174 patients with confirmed m
IDH1
R/R AML from a phase 1 trial. Receptor tyrosine kinase (RTK) pathway mutations were associated with primary resistance to ivosidenib. Multiple mechanisms contributed to acquired resistance, particularly outgrowth of RTK pathway mutations and 2-HG–restoring mutations (second-site
IDH1
mutations,
IDH2
mutations). Observation of multiple concurrent mechanisms in individual patients underscores the complex biology of resistance and has important implications for rational combination therapy design. This trial was registered at
www.clinicaltrials.gov
as #NCT02074839
