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ASH 2017 | IDH inhibitors in mIDH1 and mIDH2 AML – Enasidenib monotherapy in previously untreated IDH2 mutated AML and Ivosidenib and enasidenib in combination with azacitidine in newly diagnosed IDH mutated AML 

Dec 15, 2017

Recurrent mutations in the Isocitrate Dehydrogenase (IDH) gene occur in approximately 20% of Acute Myeloid Leukemia (AML) patients. Isocitrate Dehydrogenase (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 2-Hydroxyglutarate (2HG), which can induce hematopoietic differentiation block. Enasidenib and ivosidenib, are selective, oral, potent inhibitors of mIDH2 and mIDH1 respectively. In August 2017, enasidenib (Idhifa®) was approved by the U.S. Food and Drug Administration (FDA) for adult patients with relapsed or refractory AML with an IDH2 mutation.

At the 59th American Society of Hematology (ASH) Annual Meeting, there was an oral abstract session on Monday 11th December 2017. At this session, there were two talks focused on the use of IDH inhibitors in patients with mID1 and mIDH2 AML.

Abstract 638

Daniel A. Pollyea, from the University of Colorado School of Medicine, Aurora, CO, presented at this session, the clinical outcomes of older patients with previously untreated mIDH2 AML who were treated with enasidenib monotherapy in the AG221-C-001 study (NCT01915498). This phase I/II dose escalation study is evaluating efficacy and safety of enasidenib monotherapy in patients with advanced hematologic malignancies with mIDH2.

In the AG221-C-100 study, 38 patients (median age = 77 years) with previously untreated mIDH2 AML who were unfit for standard treatment were enrolled. Patients on the dose escalation phase were administered 50–650 mg/day enasidenib, and all patients in the expansion phase received enasidenib 100 mg/day, continuous 28-Day treatment cycles. The data cut-off was 1st September 2017.

Key highlights:


  • Median number of enasidenib treatment cycle: 6.5 (range, 1–35)
  • Median follow-up time: 8.6 months (0.5– 4.3)
  • Overall Response Rate (ORR): 32% (12/38)
    • Complete Remission (CR) rate: 18% (7/38)
    • Time to CR: 5.6 months (3.4–12.9)
    • Duration of CR: Not Reached (NR)
  • Median OS: 11.3 months (95% CI, 5.7-17.0)
  • Median OS in responding patients: NR (95% CI, 10.4-NR)


  • Most frequent treatment-related Treatment-Emergent Adverse Events (TEAEs) any grade were hyperbilirubinemia (32%) and nausea (24%)
  • Two patients discontinued treatment due to treatment-related TEAE of cardiac tamponade and thrombocytopenia respectively
  • Serious treatment-related TEAEs was reported > 1 patient including IDH differentiation syndrome (n = 4) and tumor lysis syndrome (n = 2)

Daniel Pollyea summarized his talk by stating that “enasidenib monotherapy was generally well tolerated by older patients with previously untreated mIDH2 AML”. Additionally, enasidenib monotherapy was associated with encouraging response rate in older AML patients with mIDH2. The presenter further concluded that the use of enasidenib for older patients with newly diagnosed mIDH2 AML who are unfit to receive standard therapy is a “promising strategy”.

Abstract 639

The next talk on IDH inhibitors was given by Courtney D. DiNardo, from the University of Texas MD Anderson Cancer Center, Houston, TX.

Dr DiNardo presented preliminary results from the phase Ib portion of an ongoing phase Ib/II study (NCT02677922) of mIDH inhibitors (enasidenib or ivosidenib) in combination with azacitidine (AZA) in patients with newly diagnosed AML.

Overall, 17 newly diagnosed patients with mIDH were treated with enasidenib (n = 6, median age = 68 years) or ivosidenib (n = 11, median age = 76 years) in combination with AZA. mIDH2 patients received enasidenib in dose-escalation cohorts of 100 (n = 3) or 200 mg (n = 3) and mIDH1 patients received ivosidenib 500 mg QD, each in continuous 28-Day cycle. All patient were administered subcutaneous AZA (75 mg/m2/day x 7 Days/cycle). At data cut-off of 1st September 2017, 11 patients in the enasidenib (n = 3) and ivosidenib (n = 8) arm remained on the study.

Key highlights:

Enasidenib + AZA

  • Safety
    • Most common TEAEs any grade were nausea (n = 4) and hyperbilirubinemia (n = 4)
    • Enasidenib-related TEAEs any grade in > 1 patient were nausea (n = 3), vomiting (n = 2) and hyperbilirubinemia (n = 2)
    • IDH- differentiation syndrome occurred in one patient in the enasidenib 200 mg cohort
  • Response
    • ORR: 4/6
    • Two patients achieved CR in enasidenib 100 mg cohort
    • In the enasidenib 200 mg cohort, Partial Remission (PR) and Morphologic Leukemia –Free State (MLFS) was achieved in one patient each
    • One patient in the 200 mg cohort maintained Stable Disease (SD) on study

Ivosidenib + AZA

  • Safety
    • Most common TEAEs any grade were nausea (n = 8), constipation (n = 6), fatigue (n = 5) and diarrhea (n = 4)
    • Ivosidenib-related TEAEs any grade in > 1 patient were nausea (n = 6) and fatigue
    • IDH- differentiation syndrome occurred in one patient
    • One patient died as result of pneumonia which was not considered to e treatment-related
  • Response
    • ORR: 8/11
    • CR: 4/11
    • PR: 1/11
    • MLFS: 2/11
    • Three patients maintained SD

Courtney D. DiNardo concluded the presentation by highlighting that enasidenib or ivosidenib plus AZA combination regimens were “well tolerated” and the preliminary efficacy is “encouraging”.

Based on the clinical activity and tolerability observed in this study, the 100 mg enasidenib dose and 500 mg ivosidenib dose will be further investigated in combination regimens. Moreover, the expansion of this study and the phase III AGILE study of ivosidenib + AZA (NCT03173248) is ongoing, in order to further evaluate the toleration and efficacy of these promising drugs.

  1. Pollyea D.A. et al. Enasidenib Monotherapy Is Effective and Well-Tolerated in Patients with Previously Untreated Mutant-IDH2 (mIDH2) Acute Myeloid Leukemia (AML). Oral Abstract #638. 59th ASH Annual Meeting and Exposition, December 2017, Atlanta, GA.
  2. DiNardo C.D. et al. Mutant Isocitrate Dehydrogenase (mIDH) Inhibitors, Enasidenib or Ivosidenib, in Combination with Azacitidine (AZA): Preliminary Results of a Phase 1b/2 Study in Patients with Newly Diagnosed Acute Myeloid Leukemia (AML). Oral Abstract #639. 59th ASH Annual Meeting and Exposition, December 2017, Atlanta, GA.