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

BACKGROUND: Mutations in isocitrate dehydrogenase (IDH)1 or IDH2 are seen in ~15-20% of patients with acute myeloid leukemia (AML). Mutant IDH (mIDH) reduces α-ketoglutarate to 2-hydroxyglutarate (2-HG), leading to histone hypermethylation and a block in myeloid differentiation, and may also exert leukemogenic effects by inducing dependence on BCL2 and inhibiting homologous recombination. Ivosidenib (AG-120) and enasidenib (AG-221) are oral inhibitors of mIDH1 and mIDH2, respectively, that as monotherapy are associated with robust overall response rates in patients with relapsed/refractory AML. We are assessing the safety and preliminary efficacy of ivosidenib or enasidenib in combination with standard induction chemotherapy.

METHODS: In this open-label, multicenter, phase 1 study (NCT02632708), eligible patients with newly diagnosed mIDH1 or mIDH2 AML are treated with standard induction chemotherapy (daunorubicin 60 mg/m²/day or idarubicin 12 mg/m²/day x 3 days with cytarabine 200 mg/m²/day x 7 days) in combination with either ivosidenib 500 mg once daily (for mIDH1) or enasidenib 100 mg once daily (for mIDH2). After induction, patients may receive ≤4 cycles of consolidation chemotherapy while continuing the mIDH inhibitor. Patients who either complete or are ineligible for consolidation may continue on maintenance ivosidenib or enasidenib for ≤2 years from the start of induction. Patients may be removed from the study at any point for an allogeneic hematopoietic stem cell transplant (HSCT); these patients do not receive maintenance therapy post-transplant.

RESULTS: As of Apr 18, 2017, 65 patients had been treated: 27 with ivosidenib (median age 60 years, range 24-76) and 38 with enasidenib (median age 63 years, range 32-76, Table 1). Of the 38 patients with mIDH2, 19 (50%) had secondary AML (sAML; arising after myelodysplastic syndrome or another antecedent hematologic disorder, or after exposure to genotoxic injury) compared with 9/27 (33%) with mIDH1. Ivosidenib or enasidenib combined with induction chemotherapy was generally well tolerated. One dose-limiting toxicity was observed (persistent grade 4 thrombocytopenia without leukemia on Day 42 in an enasidenib- and daunorubicin/cytarabine-treated patient). The most frequent grade ≥3 nonhematologic treatment-emergent adverse events during induction therapy, regardless of attribution, in ivosidenib-treated patients were febrile neutropenia (56%), alanine aminotransferase increased (11%), aspartate aminotransferase increased (11%), and colitis (11%); and in enasidenib-treated patients were febrile neutropenia (63%), hypertension (11%), colitis (8%), and maculopapular rash (8%; Table 2). Thirty- and 60-day mortality rates were both 7% in ivosidenib-treated patients, and were 5% and 8%, respectively, in enasidenib-treated patients. Median times for ANC recovery to ≥500/µL were 28 and 34 days for ivosidenib- and enasidenib-treated patients, respectively, and for platelet recovery to >50,000/µL were 28 and 33 days for ivosidenib- and enasidenib-treated patients, respectively. In enasidenib-treated patients with sAML there was an increased time to platelet count recovery (median 50 days). Among 23 efficacy-evaluable ivosidenib-treated patients, a response of CR, CRi, or CRp was achieved in 12/14 (86%) patients with de novo AML and 4/9 (44%) patients with sAML. Among 37 efficacy-evaluable enasidenib-treated patients, a response of CR, CRi, or CRp was achieved in 12/18 (67%) patients with de novo AML and 11/19 (58%) patients with sAML (Table 3). Seven ivosidenib-treated and 14 enasidenib-treated patients received ≥1 cycle of consolidation therapy; 6 ivosidenib-treated and 8 enasidenib-treated patients proceeded to HSCT.

CONCLUSION: Ivosidenib or enasidenib in combination with standard AML induction therapy is generally well tolerated. The slower platelet recovery observed in patients with mIDH2 sAML may reflect the reduced normal hematopoietic reserve in sAML patients; nevertheless, alternative dosing schedules for enasidenib with induction chemotherapy are being explored to see if delayed platelet recovery can be mitigated. Response rates thus far are encouraging, especially in patients with sAML, many of whom had received hypomethylating agent therapy. To further understand the quality of responses, analyses of minimal residual disease by mutational clearance are underway.

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