A multicenter phase Ib/II trial of azacitidine, venetoclax, and ivosidenib in <i>IDH1</i> -mutated acute myeloid leukemia (AML).

Abstract

6503 Background: Outcomes for patients with IDH1 mut AML have improved with the advent of targeted therapies. Two doublet regimens are approved for IDH1 mut AML: venetoclax (VEN) with a hypomethylating agent (HMA), and azacitidine (AZA) plus ivosidenib (IVO). Both regimens are effective, yet a substantial proportion of patients fail to respond or eventually relapse. Combining all three agents into a “triplet” regimen may improve outcomes. Herein, we report results from the fully enrolled newly diagnosed (ND) cohort of the multicenter phase Ib/II study of AZA+VEN+IVO for IDH1 mut AML (NCT03471260). Methods: Adults ≥18 years with ND IDH1 mut AML not eligible for standard induction chemotherapy and treated at the RP2D in the phase Ib or II cohorts were included. Patients received AZA 75 mg/m 2 days 1-7, VEN 400mg days 1-14, and IVO 500mg continuously starting C1D14. Dose attenuations in remission were permitted to minimize myelosuppression. The primary objectives were to determine the safety and overall response rate (ORR: CR + CRh + CRi + MLFS). Results: From November 2019 to October 2025, 40 patients with ND AML at four U.S. academic centers initiated treatment (Phase Ib: 9, Phase II: 31). The median age was 72 years (range, 51-80), and 26 patients (65%) were male. AML was classified as de novo in 21 (53%), therapy-related in 4 (10%), and secondary to antecedent myeloid neoplasm in 15 (38%). Six (15%) had received a prior HMA. The ORR was 95% (38/40) with 93% (37/40) achieving a composite CR (CRc; CR+CRh+CRi). The median number of cycles to best response was two (range, 1-7). Measurable residual disease (MRD) negativity by flow cytometry (sensitivity &lt;0.1%) was achieved in 92% (34/37) of CRc responders. With a median follow up of 35 months, median overall survival (OS) and duration of remission (DOR) were not reached. The 3-year OS was 79% (95% CI 64-96%). Three patients relapsed during follow-up with IDH1 -negative clones, and 18 patients (45%) transitioned to SCT. The 3-year DOR censored and not-censored at SCT was 82% (95% CI 68-98%) and 83% (95% CI 64-100%), respectively. Among the 22 patients who did not undergo SCT, the median number of cycles received is 14, with 10 patients (45%) remaining on study. Reasons for discontinuation included lack of response/relapse (n=5), development of another malignancy (n=2), adverse events (AEs; n=2), and patient preference (n=1). Non-hematologic AEs occurred in 32 patients (80%), with 12 (30%) experiencing grade ≥3 AEs. Most grade ≥3 AEs were infectious (n=7, 23%), although two patients each experienced grade ≥3 QTc prolongation, tumor lysis syndrome, and differentiation syndrome, all successfully managed with supportive care and/or with dose modifications. Conclusions: Triplet therapy with AZA+VEN+IVO demonstrates high MRD negative response rates, durable remissions, and comparable safety to doublet regimens in this multicenter study for patients with ND IDH1 mut AML. Clinical trial information: NCT03471260 .