Ivosidenib or Enasidenib plus Standard Induction Chemotherapy Is Active in Patients with mIDH, Newly Diagnosed AML
Ivosidenib and enasidenib are inhibitors of mutated IDH (mIDH)1 and mIDH2, respectively, that have demonstrated robust single-agent activity in patients with relapsed/refractory acute myeloid leukemia (AML). The current open-label, multicenter, phase 1 study is evaluating the safety and preliminary efficacy of ivosidenib or enasidenib plus standard induction chemotherapy in newly diagnosed patients with mIDH1 or mIDH2 AML.
In this study, previously untreated patients with AML (de novo or secondary), documented mIDH1, and no prior chemotherapy for AML were enrolled. Patients with mIDH1 were treated with ivosidenib 500 mg once daily plus standard induction chemotherapy, and patients with mIDH2 AML were treated with enasidenib 100 mg once daily plus standard induction chemotherapy; standard induction chemotherapy consisted of daunorubicin 60 mg/m2 daily or idarubicin 12 mg/m2 daily for 3 days with cytarabine 200 mg/m2 daily for 7 days. Following induction, patients may continue maintenance ivosidenib or enasidenib alone for ≤2 years from the start of induction, with or without ≤4 cycles of consolidation chemotherapy.
As of April 18, 2017, 88 patients had been treated on the study (ivosidenib, 32; enasidenib, 56). The median age of the enasidenib-treated cohort was 63 years (range, 32-76 years), 24 (50%) patients had secondary AML (sAML), 25 (45%) and 20 (36%) patients had intermediate and poor risk, respectively, based on cytogenetics and molecular abnormalities. The median age of the ivosidenib-treated cohort was 60 years (range, 24-76 years), 10 (31%) patients had sAML, and 13 (41%) and 11 (34%) patients had intermediate and poor risk, respectively.
One dose-limiting toxicity (DLT) of grade 4 thrombocytopenia without leukemia was reported in an enasidenib- and daunorubicin/cytarabine-treated patient; no DLTs were reported in the ivosidenib cohort. In the ivosidenib-treated cohort, the most common grade ≥3 nonhematologic treatment-emergent adverse events during induction therapy, regardless of causality, were febrile neutropenia (60%), hypertension (9%), increased ALT (9%), increased AST (9%), and colitis (9%); in the enasidenib-treated cohort, febrile neutropenia (63%), hypertension (9%), and colitis (5%) were commonly reported. The 30-day and 60-day mortality rates were 6% each in ivosidenib-treated patients, and were 5% and 7%, respectively, in enasidenib-treated patients. Median times for absolute neutrophil count recovery to ≥500/µL were 20 days for ivosidenib-treated patients and 29 days for enasidenib-treated patients. Median times for platelet recovery to >50,000/µL were 20 days for ivosidenib-treated patients and 29 days for enasidenib-treated patients.
In the ivosidenib-treated cohort (n = 30), 23 evaluable patients achieved a response, including 19 complete responses (CRs), and 4 CRs with incomplete hematologic recovery (CRi) or CRs with incomplete platelet recovery (CRp); of the 23 responses, 19/21 (91%) patients had de novo AML and 4/9 (44%) patients had sAML. In the enasidenib-treated cohort (n = 50), 31 responses were achieved, including 25 CRs and 6 CRi/CRp; of these, 18/27 (67%) patients had de novo AML and 9/23 (39%) patients had sAML.
These preliminary results suggest that combination therapy with ivosidenib or enasidenib plus standard AML induction therapy is safe and generally well-tolerated in patients with mIDH, newly diagnosed AML, and showed encouraging response rates.
Stein EM, et al. 2017 ASH. Abstract 726.