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Context: IDH1-mutated (IDH1+) myeloid malignancies depend on the anti-apoptotic protein BCL-2 for survival. Combining the IDH1 inhibitor ivosidenib (IVO) with the BCL-2 inhibitor venetoclax (VEN) may improve outcomes. We report the completed P1b portion of a P1b/II study investigating IVO (500 mg PO daily D15-continuous) with VEN (D1–14), with or without azacitidine (AZA; 75 mg/m2 D1–7) every 28 days. Objectives: Primary P1b objectives included safety, tolerability, and IWG-defined overall response (ORR: CR+CRi+CRh+PR+MLFS). Design: A dose-escalation/-de-escalation study evaluating cohorts of 6 patients enrolled within 4 dose levels: DL1 (IVO+VEN 400 mg), DL2 (IVO+VEN 800 mg), DL3 (IVO+VEN 400 mg+AZA), DL4 (IVO+VEN 800 mg+AZA). Participants: Eligible patients were ≥ age 18 with IDH1+ MDS, newly diagnosed (ND) or relapsed/refractory (R/R) AML. Results: Thirty-one patients enrolled with a median follow-up of 26 months. The median age was 67 years (range: 44–84), 71% had AML (ND: N=14, R/R: N=8), and 29% had MDS. ELN risk was intermediate or adverse in 19% and 55%, respectively (N=17). The ORR was 94% (DL1: 67%, DL2–DL4: 100%); composite CR (CRc: CR+CRi+CRh) was 87% (DL1: 67%, DL2: 100%, DL3: 85%, DL4: 100%). Of the AML patients, 60% attained measurable residual disease–negative CRc by multiparameter flow cytometry. IDH1+ mutation clearance by digital droplet PCR (sensitivity: 0.1%–0.25%) occurred in 64% of patients following cycle 5. Grade 3–5 adverse events (AEs) in ≥ 10% of patients included febrile neutropenia (29%) and pneumonia (23%). AEs of special interest (AESI) included grade 3 tumor lysis syndrome in 2 (dose-limiting toxicity in 1), and differentiation syndrome in 4 (G2: N=2, G3: N=2) patients. All AESIs were transient and reversible. Median EFS and OS were 36 and 42 months, respectively, and 24-month OS was 71% (95% CI: 55–91; ND-AML: 67%, R/R-AML: 50%, MDS: 100%). MRD-negative CRc improved OS (median NR vs. 8 months, P: 0.002) in ND- and R/R-AML. Based on efficacy and toxicity, DL3 (IVO+VEN400+AZA) was the recommended phase 2 dose. Conclusions: IVO+VEN±AZA is an effective treatment for IDH1+ myeloid malignancies with an expected toxicity profile and notable activity across disease groups. Single-cell sequencing and CyTOF correlatives will also be presented.

Original publication




Journal article


Clinical Lymphoma, Myeloma and Leukemia

Publication Date





S240 - S241