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Phase 1b/2 Study of Ivosidenib with Venetoclax ± Azacitidine in IDH1-Mutated Hematologic Malignancies

2020 Year in Review - AML - Leukemia

Mutations in the isocitrate dyehydrogenase-1 (IDH1) gene promote leukogenesis due to the resulting myeloid differentiation arrest and accumulation of 2-hydroxyglutarate. In this study, the IDH2 inhibitor ivosidenib (Tibsovo) combined with venetoclax (Venclexta) with and without azacitidine (Onureg) is assessed for efficacy and safety. This open-label, nonrandomized trial enrolled 19 patients with IDH1-mutated myeloid malignancies (high-risk myelodysplastic syndromes [MDS] and acute myeloid leukemia [AML]) into 1 of 3 successive cohorts (cohort 1: ivosidenib plus venetoclax 400 mg; cohort 2: ivosidenib plus venetoclax 800 mg; cohort 3: ivosidenib plus venetoclax 400 mg plus azacitidine) and assessed the primary end points of safety, tolerability, and overall response rate. Survival end points and pharmacokinetic correlates were key secondary end points. Patients received medications corresponding to their cohort according to the following schedule: ivosidenib 500 mg by mouth daily from day 15 onward; venetoclax on days 1 to 14 per 28-day cycle; and azacitidine 75 mg/m2 on days 1 to 7.

Seventeen of the 19 enrolled patients had AML: 9 with relapsed/refractory AML (median, 1 line of previous therapy), 5 with treatment-naïve AML, and 3 hypomethylating agent–failure MDS with progression to secondary AML. The remaining 2 patients had high-risk MDS. European LeukemiaNet risk was favorable for 37% of patients, intermediate for 15%, and adverse for 47%. Co-mutations were present in some members of the study population and included NPM1, chromatin spliceosome genes, RAS pathway genes, and methylation pathway enzyme genes at 37%, 32%, 21%, and 16%, respectively. The evaluable population was comprised of 18 patients.

Regarding adverse events, IDH differentiation syndrome occurred in 4 patients (grade >3 in 1) and tumor lysis syndrome occurred in 2 patients (1 being a grade 3 event in an NPM1-positive co-mutated patient who was successfully managed without hemodialysis). For the evaluable population, the composite complete remission (CRc; complete remission [CR] plus CR with incomplete hematologic recovery plus CR with partial hematologic recovery) rate was 78%. For the treatment-naïve subpopulation, CRc was 100%, and for the relapsed/refractory subpopulation it was 75%. CRc was 67%, 100%, and 67% for cohorts 1, 2, and 3, respectively. Median time to best response was 2 months. Using flow cytometry, it was determined that 50% of patients achieving CRc had also achieved minimal residual disease–negative status. One patient experienced a morphologic leukemia-free state and 1 had hematologic improvement without achieving CR.

Currently 9 patients remain on study, 3 proceeded to stem-cell transplant while in CR, 2 were considered nonresponders, and 5 experienced progressive disease occurring at a median of 3 months following CRc. Current median follow-up time is 3.5 months, median overall survival was 9.7 months in patients with relapsed/refractory disease but has not been reached in treatment-naïve patients.

Based on this study, ivosidenib plus venetoclax ± azacitidine therapy is well-tolerated, effective, and warrants additional studies to better define efficacy, safety, and biomarkers of response in patients with IDH2-mutated AML.


DiNardo C, Lachowiez C, Borthakur G, et al. Phase IB/II Study of the IDH1-Mutant Inhibitor Ivosidenib with the BCL2 Inhibitor Venetoclax +/- Azacitidine in IDH1-Mutated Hematologic Malignancies. Presented at: 25th European Hematology Association Congress Virtual; June 11-21, 2020. Abstract S143.

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