Mutant Isocitrate Dehydrogenase 1 Inhibitor Ivosidenib in Combination With Azacitidine for Newly Diagnosed Acute Myeloid Leukemia

Abstract

PURPOSE Ivosidenib is an oral inhibitor of the mutant isocitrate dehydrogenase 1 (IDH1) enzyme, approved for treatment of IDH1-mutant (m IDH1) acute myeloid leukemia (AML). Preclinical work suggested that addition of azacitidine to ivosidenib enhances mIDH1 inhibition–related differentiation and apoptosis. PATIENTS AND METHODS This was an open-label, multicenter, phase Ib trial comprising dose-finding and expansion stages to evaluate safety and efficacy of combining oral ivosidenib 500 mg once daily continuously with subcutaneous azacitidine 75 mg/m2 on days 1-7 in 28-day cycles in patients with newly diagnosed m IDH1 AML ineligible for intensive induction chemotherapy (ClinicalTrials.gov identifier: NCT02677922 ). RESULTS Twenty-three patients received ivosidenib plus azacitidine (median age, 76 years; range, 61-88 years). Treatment-related grade ≥ 3 adverse events occurring in > 10% of patients were neutropenia (22%), anemia (13%), thrombocytopenia (13%), and electrocardiogram QT prolongation (13%). Adverse events of special interest included all-grade IDH differentiation syndrome (17%), all-grade electrocardiogram QT prolongation (26%), and grade ≥ 3 leukocytosis (9%). Median treatment duration was 15.1 months (range, 0.3-32.2 months); 10 patients remained on treatment as of February 19, 2019. The overall response rate was 78.3% (18/23 patients; 95% CI, 56.3% to 92.5%), and the complete remission rate was 60.9% (14/23 patients; 95% CI, 38.5% to 80.3%). With median follow-up of 16 months, median duration of response in responders had not been reached. The 12-month survival estimate was 82.0% (95% CI, 58.8% to 92.8%). m IDH1 clearance in bone marrow mononuclear cells by BEAMing (beads, emulsion, amplification, magnetics) digital polymerase chain reaction was seen in 10/14 patients (71.4%) achieving complete remission. CONCLUSION Ivosidenib plus azacitidine was well tolerated, with an expected safety profile consistent with monotherapy with each agent. Responses were deep and durable, with most complete responders achieving m IDH1 mutation clearance.

IDH1/IDH2 Inhibition in Acute Myeloid Leukemia

“…Although the ivosidenib/azacitidine combination could be safely administered in an outpatient setting, more than half of the patients required hospitalizations related to AEs. However, the number of hospitalization days per patient-year of drug exposure owing to AEs in this study was encouragingly lower than that previously reported for azacitidine monotherapy (43).…”

“…Median OS has not been reached with a 12-month survival estimate of 82.0% (95% CI, 58.8% to 92.8%). mIDH1 clearance in bone marrow mononuclear cells by BEAMing (beads, emulsion, amplification, magnetics) digital polymerase chain reaction with a sensitivity of 10 -4 (60) was seen in 10/14 patients (71.4%) achieving CR (43).…”

Targeting IDH1 and IDH2 Mutations in Acute Myeloid Leukemia: Emerging Options and Pending Questions

“…A small phase 1/2 study of ivosidenib in combination with azacitidine in newly diagnosed AML showed a response rate of 78.3% that was durable. 19 Patients who achieved a CR had a high clearance rate of IDH1 mutation (71.4%). In the same trial, IDH2 -mutated AML patients were enrolled and treated with the combination of enasidenib and azacitidine.…”

Acute myeloid leukemia with IDH1 and IDH2 mutations: 2021 treatment algorithm

“…Pre-clinical investigation of mutant IDH1 transformed cell lines demonstrated enhanced differentiation and apoptosis with the combination of azacytidine and ivosidenib (Yen, Cancer Res 78;2018 suppl; abstr 4956). This led to a Phase 1b clinical trial which enrolled 23 patients to the combination of azacytidine and ivosidenib, demonstrating a CR rate of 61%, CR/CRh rate of 70%, and a 12-month OS of 82% (median duration of response or DOR has not been reached, with median follow-up of 16 months) 30 . The follow-up confirmatory Phase 3 AGILE study of ivosidenib vs placebo in combination with azacytidine in untreated AML is now ongoing (NCT 03173248) with a primary endpoint of relapse-free survival.…”