Enasidenib, a targeted inhibitor of mutant IDH2 proteins for treatment of relapsed or refractory acute myeloid leukemia

Future Oncol. 2018 Jan;14(1):23-40. doi: 10.2217/fon-2017-0392. Epub 2017 Sep 18.

Abstract

Mutations in IDH2 genes (mIDH2) occur in approximately 12% of patients with acute myeloid leukemia. Enasidenib is an oral, small-molecule inhibitor of mIDH2 proteins. Enasidenib is shown to suppress the oncometabolite, 2-hydroxyglutarate, and promote differentiation of leukemic bone marrow blasts. In a Phase I dose-escalation and expansion study, 40.3% of patients with relapsed/refractory acute myeloid leukemia responded to enasidenib monotherapy, including 19.3% who achieved complete remission and 11% who proceeded to transplant. Median overall survival was 9.3 months. 2-hydroxyglutarate suppression did not predict response and mIDH2 clearance was possible, but not required for response. Patients with ≥6 co-mutations or NRAS co-mutations were less likely to attain a response. Enasidenib was safe and well tolerated with low rates of treatment-related adverse events. [Formula: see text].

Keywords: 2-HG; 2-hydroxyglutarate; AG-221; IDH2; acute myeloid leukemia; enasidenib; hematologic malignancy; isocitrate dehydrogenase 2; refractory; relapsed.

Publication types

  • Clinical Trial, Phase III
  • Randomized Controlled Trial

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Aminopyridines / administration & dosage*
  • Aminopyridines / adverse effects
  • Aminopyridines / pharmacokinetics
  • Bone Marrow Cells / drug effects
  • Cell Differentiation / drug effects
  • Disease-Free Survival
  • Female
  • GTP Phosphohydrolases / genetics
  • Humans
  • Isocitrate Dehydrogenase / antagonists & inhibitors
  • Isocitrate Dehydrogenase / genetics*
  • Leukemia, Myeloid, Acute / drug therapy*
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / pathology
  • Male
  • Membrane Proteins / genetics
  • Middle Aged
  • Mutant Proteins / antagonists & inhibitors
  • Mutant Proteins / genetics*
  • Mutation
  • Recurrence
  • Triazines / administration & dosage*
  • Triazines / adverse effects
  • Triazines / pharmacokinetics

Substances

  • Aminopyridines
  • Membrane Proteins
  • Mutant Proteins
  • Triazines
  • enasidenib
  • IDH2, human
  • Isocitrate Dehydrogenase
  • GTP Phosphohydrolases
  • NRAS protein, human