IDH1/2

IDH mutations in AML - Educational session at the 2017 ASCO Annual Meeting

During the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting, an Educational Session took place discussing emerging treatment options for Acute Myeloid Leukemia (AML) subsets. The session was chaired by Richard M. Stone, MD, from the Dana-Farber Cancer Institute, USA.

Courtney Denton Dinardo, M.D., from The University Texas MD Anderson Cancer Center gave a talk during this session and discussed the role of Isocitrate Dehydrogenase (IDH) mutations in AML and their validity as therapeutic targets.

IDH mutations occur in approximately 20% of AML patients, with the prevalence increasing with patient age. However, the prognostic significance of IDH mutations in AML is controversial and not very clear.

IDH enzymes catalyze the conversion of isocitrate to α-Ketoglutarate (αKG). However, mutations in IDH1/2 lead to a reverse reaction of αKG to the oncometabolite D-2-Hydroxyglutarate (D-2HG). The accumulation of 2HG competitively inhibits αKG, thus leading to alterations in TET2-dependent hydroxymethylation, chromatin modification, activation of the hypoxic response, and increased dependence on BCL2.

Courtney Denton Dinardo then discussed results of on-going clinical studies with the new class of agents targeting IDH1 and IDH2 mutations in AML. The new class of targeted IDH inhibitors binds with the mutant IDH1 or IDH2 catalytic active site thus preventing the oncogenic reduction of αKG to D-2HG. These agents include enasidenib (AG-221), a mutant IDH2 inhibitor, and IDH1 mutant inhibitors including AG-120, IDH305, and FT-2102, and the pan IDH1/IDH2 inhibitor AG-881.

Interim results from the phase I/II study of enasidenib monotherapy in patients with R/R AML showed that enasidenib was well tolerated with an ORR of 41% and a CR rate of 18% in 128 evaluable R/R AML patients. Ongoing studies with enasidenib are listed in the table below

Trial Status Population Treatment 

Phase III IDHentify 

NCT02577406

Enrolling AML patients 60 years or older with IDH2 mutation enasidenib vs investigator's choice 

Phase I/II

NCT02632708

Enrolling Newly diagnosed AML enasidenib plus 7+3 induction chemotherapy

Phase I/II 

NCT02677922

Enrolling  Newly diagnosed AML enasidenib plus azacitidine vs azacitidine alone

AG-120, an IDH1 inhibitor, has also shown promising results in patients with R/R AML patients. In a phase I dose-escalation study, AG-120 was shown to be effective at suppressing D-2HG. Additionally, 36% of patients that achieved CR attained IDH1 mutational clearance as detected by Next Generation Sequencing (NGS). There are other ongoing studies with AG-120 in IDH1 mutated AML patients, including a phase I/II study of AG-120 in combination with 7+3 for newly diagnosed AML patients (NCT02632708) and also a phase I/II study (NCT02677922) of AG-120 in combination with azacitidine for newly diagnosed AML patients.

Clinical trials with other IDH inhibitors including AG-881, IDH305, FT-2102, and BAY 1436032 are ongoing.

The speaker concluded by stating that IDH1/2 mutations represent valid therapeutic targets. Additionally, targeted mutant IDH inhibitors demonstrate encouraging activities as single agents in R/R AML. Combination of IDH inhibitors with other therapies are currently underway.

References
  1. DiNardo C. D. Role of IDH Mutations in Acute Myeloid Leukemia: A Valid Therapeutic Target?. 2017 American Society of Clinical Oncology (ASCO) Annual Meeting; 2017 June 2–6; Chicago, IL, USA.