Findings from a phase Ib study of the combination of the mutant IDH1 inhibitor ivosidenib plus azacitidine for patients with IDH1-mutated, newly diagnosed acute myeloid leukemia (AML) ineligible for intensive treatment showed that the combination was well tolerated and produced more responses than those achieved with azacitidine treatment alone. These findings were presented at the 2019 Society of Hematologic Oncology (SOHO) Annual Meeting and published by Courtney D. DiNardo, MD, and colleagues in Clinical Lymphoma, Myeloma & Leukemia.
Courtney D. DiNardo, MD
Methods
The trial included 23 patients (48% male, with a median age of 76). Patients received 500 mg of ivosidenib orally daily plus 75 mg/m2 of azacitidine subcutaneously on days 1–7 in 28-day cycles. Exploratory analysis included digital polymerase chain reaction assessment of mutant-IDH1 allele frequency in bone marrow mononuclear cells (≤ 0.04% sensitivity). Primary outcome measures included dose-limiting toxicities, adverse events, pharmacokinetics, and overall response rate.
Findings
Ten patients remained on treatment at data cutoff, and the median duration of treatment was 15.1 months.
The overall response rate was 78%; 61% of patients experienced a complete remission, 9% experienced morphologic complete remission with incomplete neutrophil recovery/morphologic complete remission with incomplete platelet recovery, 9% achieved a morphologic leukemia-free state. Median time to response was 1.8 months, and median time to complete remission was 3.7 months; the median response duration was not reached. Mutant IDH1 clearance was seen in 63% of patients with complete remission/complete remission with partial hematologic recovery and in 64% of patients with complete remission.
Adverse Events
All-grade adverse events regardless of cause in at least 30% of patients were thrombocytopenia (in 65% of patients), nausea (61%), diarrhea (57%), anemia (52%), constipation (52%), febrile neutropenia (44%), pyrexia (44%), vomiting (35%), fatigue (35%), hypokalemia (35%), dizziness (35%), insomnia (35%), neutropenia (35%), and back pain (30%). Grade 3 or 4 adverse events in at least 10% of patients were thrombocytopenia (61%), anemia (44%), febrile neutropenia (44%), neutropenia (30%), sepsis (22%), and QT prolongation (13%).
The authors concluded, “Ivosidenib/azacitidine was well tolerated with a safety profile consistent with ivosidenib or azacitidine monotherapy, including prevalence of cytopenias. Complete remission and overall response rates exceeded those of azacitidine alone and most responders achieved IDH1 mutation clearance. Based on these findings, a phase III, double-blind, placebo-controlled study of ivosidenib/azacitidine (AGILE) is actively enrolling patients.”
Disclosure: For full disclosures of the study authors, visit clinical-lymphoma-myeloma-leukemia.com.
