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Interim phase II results from the ongoing AG221-AML-005 study on enasidenib plus azacitidine in patients with newly diagnosed acute myeloid leukemia with IDH2 mutations

Feb 4, 2020

Isocitrate dehydrogenase 2 (IDH2) mutations are one of the most common mutations in AML, occurring in 8–19% of patients.1 Enasidenib (ENA) is an oral, small-molecule inhibitor of mutant (m) IDH2 protein approved in the United States (US) for use in adult patients with relapsed/refractory mIDH2 AML. In a large phase I/II study, a cohort of newly diagnosed (ND) AML patients receiving ENA monotherapy showed a complete remission (CR) rate of 18%, an overall response rate (ORR) of 30.8% and a median overall survival (mOS) of 11.3 months.2

Similarly, azacitidine (AZA), a hypomethylating agent, is approved for the treatment of newly diagnosed patients with AML not eligible for intensive chemotherapy, inducing ORRs of 19–30% with a mOS of about 10 months.3

Given the enhanced effect on cell differentiation obtained in vitro with the combination of ENA + AZA, a phase I/II study (AG221-AML-005) was initiated to evaluate the combination of ENA + AZA in patients with mIDH2 ND-AML who are not candidates for intensive chemotherapy (NCT02677922).

The results from the phase Ib portion of the study were presented at the 23rd Congress of the European Hematology Association, at the 61st American Society of Hematology Meeting & Exposition,  Courtney DiNardo from the University of Texas, MD Anderson Cancer Center, Houston, US, reported the interim results from the randomized, phase II portion of the study.4

Study design4

  • Adult patients (age ≥ 18 years) with mIDH2 ND-AML who were ineligible for intensive chemotherapy and with no prior hypomethylating agent treatment were randomized (N= 101) in a 2:1 ratio to receive ENA + AZA (n= 68) or AZA only (n= 33) in repeated 28-day cycles
  • All patients received subcutaneous AZA 75 mg/m2/day from Day one to Day seven of each treatment cycle; patients randomized to ENA + AZA also received continuous ENA 100 mg/day
  • The primary endpoint was ORR
  • The secondary endpoints include CR, overall survival (OS), event-free survival (EFS) and safety

Patient characteristics

  • Median ages were 74 years (range, 62–85) in the ENA + AZA arm and 75 years (range, 57–85) in the AZA-only arm
  • About three quarters of the patients presented the IDH2-R140 mutation (75% in the ENA + AZA arm and 73% in the AZA-only arm). The most common co-occurring mutations were DNMT3A and ASXL1
  • The majority of patients had intermediate-risk cytogenetics (80% in the ENA + AZA arm and 90% in the AZA-only arm)



  • At data cut-off (August 2019), 22 patients were still receiving their randomized treatment
  • Response rates were significantly higher in the ENA + AZA arm vsAZA-only arm:
    • ORR 71% (95% confidence interval [CI], 58─81) vs 42% (95% CI, 26─61) (p= 0.0064)
    • CR 53% (95% CI, 41─65) vs 12% (95% CI, 3─28) (p=0.0001)
  • The median number of treatment cycles was 10 (range, 1–26) in the ENA + AZA arm and six (range, 1–28) in the AZA-only arm
  • The time to first response was approximately two months. In responding patients, the median duration of response was 24.1 months (95% CI, 11.1─not reached) vs 12 months (95% CI, 2.8─14.6) in the ENA + AZA arm vs  AZA-only arm
  • The most common reason for study discontinuation was progression of disease (31% in the ENA + AZA arm and 52% in the AZA-only arm). Discontinuation due to adverse events (AEs) was rare in both arms (6%)
  • At a median follow-up of 14 months:
    • Median OS was 22 months in the ENA + AZA arm vs 22.3 months in the AZA-only arm (hazard ratio [HR]= 0.99 [95% CI, 0.52─1.87], p= 0.9686)
      • Median OS was not reached in the ENA + AZA arm who achieved CR
      • Median EFS was 17.2 months in the ENA + AZA arm vs 10.8 months in the AZA-only arm (HR= 0.59 [95% CI, 0.3─1.17], p= 0.1278)
    • Maximal mIDH2 variant allelic frequency (VAF) reduction from baseline was stronger in the ENA + AZA arm (-83.4%) compared to the AZA-only arm (-17.7%, p= 0.0008), with more than 20% of patients in CR in the ENA + AZA arm having complete mIDH2 VAF clearance
    • Median maximal 2-hydroxyglutarate reduction, as a marker for inhibition of IDH2 enzyme activity, was significantly higher in the ENA + AZA arm vs the AZA-only arm (-97.8% vs -54.3%, p= 0.0004)


  • The most common treatment-emergent AEs (TEAEs) in the ENA + AZA arm vs AZA-only arm were:
    • Thrombocytopenia: 62% vs 44%
    • Nausea: 69% vs 38%
    • Anemia: 53% vs 44%
    • Vomiting: 49% vs 47%
  • Treatment-related Grade 3–4 TEAEs in the ENA + AZA arm vs AZA-only arm were similar, except for the occurrence of IDH differentiation syndrome (IDH-DS) in the combination arm:
    • Thrombocytopenia: 37% vs 19%
    • Neutropenia: 35% vs 22%
    • Anemia: 19% vs 22%
    • Febrile neutropenia: 15% vs 16%
    • IDH-DS: 10% vs 0%
    • Infections: 18% vs 31%
  • In the first 60 days, five (7%) patients died in the ENA + AZA arm and one died (3%) in the AZA-only arm


  • The combination of ENA and AZA was effective, with a significant improvement in ORR and CR rates
  • Although the median OS was similar between treatment arms, for ENA + AZA patients who achieved CR median OS was not reached
  • The combination treatment was well tolerated:
    • Patients should be monitored for infections and anti-infective prophylactic treatments should be considered; in case of suspected IDH-DS, corticosteroids should be initiated
  1. Döhner H. et al., Acute Myeloid Leukemia. N Engl J Med. 2015 Sep 17;373(12):1136-52. DOI: 10.1056/NEJMra1406184
  2. Pollyea D.A. et al., Enasidenib, an inhibitor of mutant IDH2 proteins, induces durable remissions in older patients with newly diagnosed acute myeloid leukemia. 2019 Nov;33(11):2575-2584. DOI: 10.1038/s41375-019-0472-2
  3. Pleyer L. et al., Azacitidine for Front-Line Therapy of Patients with AML: Reproducible Efficacy Established by Direct Comparison of International Phase 3 Trial Data with Registry Data from the Austrian Azacitidine Registry of the AGMT Study Group. Int J Mol Sci. 2017 Feb 15;18(2). DOI: 10.3390/ijms18020415
  4. DiNardo C. et al., Enasidenib Plus Azacitidine Significantly Improves Complete Remission and Overall Response Compared with Azacitidine Alone in Patients with Newly Diagnosed Acute Myeloid Leukemia (AML) with Isocitrate Dehydrogenase 2 (IDH2) Mutations: Interim Phase II Results from an Ongoing, Randomized Study. Oral Abstracts #643. 2019 Dec 9. 61st American Society of Hematology Annual Meeting & Exposition, Orlando, FL