ASH 2017 | Emerging molecularly targeted therapies in AML: focus on IDH inhibitors 

At present, there has been more and more interest in studying gene mutations in order to develop a more targeted therapy for Acute Myeloid Leukemia (AML). Particular attention has been focused on driver mutations in the Isocitrate Dehydrogenase (IDH) gene.

IDH mutations occur in approximately 20% of AML patients, with the prevalence increasing with patient age. 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. IDH inhibitors bind with the mutant IDH1 or IDH2 catalytic active site thus preventing the oncogenic reduction of αKG to D-2HG.1

At the 59th American Society of Hematology (ASH) Annual Meeting, Atlanta, GA, on Monday 11th December 2017, there was an oral abstract session focused on emerging molecularly targeted therapies for Acute Myeloid Leukemia (AML),co-chaired by Mark J. Levis, from John Hopkins University and Amir T. Fathi, from the Massachusetts General Hospital, Harvard Medical School. At this session, results from two on-going clinical studies with agents targeting IDH1 and IDH2 mutations in AML including ivosidenib and enasidenib respectively were discussed.

Abstract 725

Courtney D. DiNardo, from The University Texas MD Anderson Cancer Center, Houston, TX, presented results from the phase I dose-escalation and expansion study (NCT02074839), which aimed to assess the safety and efficacy of ivosidenib in patients with IDH1 mutated (mIDH1) advanced hematologic maligancies.2

Overall, 258 patients were enrolled in the dose escalation (n = 78) and expansion phase (n = 180) of this trial. During dose-escalation, patients with mIDH1+ advanced hematologic malignancies were administered ivosidenib as a single agent orally once daily (QD) or twice daily (BID) in a 28-day cycle. The MTD was not reached, however 500 mg QD was the recommended dose used in the expansion phase of this study.

The expansion cohort consisted of four arms including Arm 1 (R/R AML patients, n = 126), Arm 2 (patients with untreated AML not eligible for standard of care, n = 25), Arm 3 (mIDH1 patients with other advanced hematological malignancies, n = 11) and Arm 4 (patients with R/R AML but not eligible for Arm 1, n = 18).

The speaker reported the key results at data cut-off (12 May  2017) of the safety analysis of all treated patients (n = 258) and the primary analysis in R/R AML patients (n = 125) treated in the dose-escalation phase (n = 33) and patients treated in Arm 1 expansion cohort (n = 92):

  • Safety in all treated patients (n = 258)
    • Most common Adverse Events (AEs) of any grade occurring in ≥ 15% of patients regardless of causality were diarrhea (33%), leukocytosis (30%), nausea (30%), fatigue (29%), febrile neutropenia (25%), dyspnea (24%), anemia (23%) and QT prolongation (23%)
    • IDH- Differentiation Syndrome (IDH-DS) occurred in 11.2% (29/258) of patients with 5.4% (14/29) experiencing grade ≥ 3
  • Among patients in the  R/R AML patient set (n = 125)
    • Safety
      • Grade ≥ 3 leukocytosis was reported in 8% (10/125) of patients
      • Grade 3 QT prolongation occurred in 8% (10/125) of patients
      • IDH-DS all grade were reported in 9.6% (12/125) of patients
    • Efficacy
      • Complete Remission (CR) plus CR with partial hematologic recovery (CRh) rate: 30.4% (38/125)
        • CR rate: 21.6% (27/125)
        • CRh rate: 8.8% (11/125)
      • Overall Response Rate (ORR): 41.6% (52/125)
      • Median duration of CR/CRh in responders (n = 52):8.2 months
      • Median Overall Survival (OS) at a median follow-up of 14.8 months
        • CR/CRh: NR
        • Non CR/CRh responders: 9.3 months
        • Non responders: 3.9 months

In an interview with the AML Global Portal, Courtney DiNardo stated that ivosidenib monotherapy was “well tolerated” in patients with mutated IDH1 AML. Additionally, in R/R AML patients with unmet medical needs, ivosidenib induced durable responses and improved patient outcomes. She concluded by noting that the findings of this phase I study support the role of ivosidenib as an “effective, oral targeted treatment for patients with mIDH1 AML”.

Abstract 726

Eytan M. Stein, from the Memorial Sloan Kettering Cancer Center, NY, presented results from the ongoing phase I multi-center study (NCT02632708), which evaluated the safety and efficacy of ivosidenib or enasidenib combined with standard chemotherapy in newly diagnosed AML patients with mIDH1 or IDH2 mutation (mIDH2).

In this phase I study, patients with previously untreated AML (de novo or Secondary AML [sAML]) with documented mIDH1 or mIDH2 were administered ivosidenib (500 mg once daily for patients with mIDH1) or enasidenib (100 mg once daily for patients with mIDH2) respectively in combination with standard chemotherapy (daunorubicin 60 mg/m2/day or idarubicin 12 mg/m2/day for 3 Days with cytarabine 200 mg/m2/day for 7 days).

As of August 2017, a total of 88 AML patients have been treated in the ivosidenib (n = 32, median age = 60 years) and enasidenib (n = 56, median age = 63 years) cohort.

Key findings:
  • Safety
    • DLT of persistent grade 4 thrombocytopenia without leukemia on Day 42 occurred in one patient treated with enasidenib and chemotherapy
    • Most frequent grade ≥3 non-hematologic treatment-emergent AEs
      • Ivosidenib-treated patients; febrile neutropenia (56%), alanine aminotransferase increased (11%), aspartate aminotransferase increased (11%), and colitis (11%)
      • Enasidenib-treated patients; febrile neutropenia (63%), hypertension (11%), colitis (8%), and maculopapular rash (8%)
    • 60-day mortality rate
      • Ivosidenib cohort: 6%
      • Enasidenib cohort: 7%
    • Median time to platelet recovery > 50,000/ µL
      • Ivosidenib cohort: 28 days
      • Enasidenib cohort: 33 days
    • Efficacy in evaluable patients
      • Ivosidenib treatment arm (n = 30)
        • ORR: 77% (23/30)
        • ORR in de novo AML patients (n = 21): 91% (19/21)
        • ORR in sAML patients (n = 9): 44% (4/9)
      • Enasidenib treatment arm (n = 50)
        • ORR: 62% (31/50)
        • ORR in de novo AML patients (n = 18):67% (18/27)
        • ORR in sAML patients (n = 23): 57% (13/23)

The speaker, Eytan Stein, stated that ivosidenib or enasidenib in combination with standard AML induction therapy was “well tolerated”. Additionally, the response rates observed so far from this phase I study were “encouraging”, particularly in patients with sAML.

The speaker further emphasized that it would be important to understand the quality of response observed in this study and thus noted that analyses of minimal residual disease by mutational clearance are currently ongoing.

  1. DiNardo C. et al. Characteristics, clinical outcome, and prognostic significance of IDH mutations in AML. Am J Hematol. 2015 Aug; 90(8): 732–736. DOI: 10.1002/ajh.24072
  2. DiNardo C. et al. Ivosidenib (AG-120) in Mutant IDH1 AML and Advanced Hematologic Malignancies: Results of a Phase 1 Dose Escalation and Expansion Study. Oral Abstract #725: 59th ASH Annual Meeting and Exposition, Atlanta, GA.
  3. Stein E. M. et al. Ivosidenib or Enasidenib Combined with Standard Induction Chemotherapy Is Well Tolerated and Active in Patients with Newly Diagnosed AML with an IDH1 or IDH2 Mutation: Initial Results from a Phase 1 Trial. Oral Abstract #725: 59th ASH Annual Meeting and Exposition, Atlanta, GA.
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