Azacitidine Triplet Produces Durable MRD-Negative Remissions in IDH1+ AML

The combination of azacitidine (Vidaza), venetoclax (Venclexta), and ivosidenib (Tibsovo) produced composite complete remissions (CRc) in patients with newly diagnosed IDH1-mutated acute myeloid leukemia (AML), and most with measurable residual disease (MRD)–evaluable responses reached MRD negativity by flow cytometry. The findings came from a multicenter, investigator-initiated phase 1b/2 trial (NCT03471260) presented by Jennifer Marvin-Peek, MD, of The University of Texas MD Anderson Cancer Center, at the 2026 European Hematology Association (EHA) Congress.¹

Patients with IDH1-mutated AML who are ineligible for intensive induction chemotherapy currently have 2 hypomethylating agent (HMA)–based doublet standards of care—azacitidine plus venetoclax, supported by the phase 3 VIALE-A trial (NCT02993523), and ivosidenib plus azacitidine, supported by the phase 3 AGILE trial (NCT03173248)—yet a meaningful proportion of patients fail to respond or eventually relapse.^2-6 The triplet was designed to combine BCL-2 inhibition with targeted mutant-IDH1 inhibition on an HMA backbone in an effort to deepen and prolong responses.

Key Efficacy Data

Among the 40 patients in the newly diagnosed AML cohort treated at the recommended phase 2 dose (RP2D), the overall response rate was 95%, and the CRc rate was 93%. Best responses included complete remission (CR) in 60% of patients (n = 24), CR with partial hematologic recovery (CRh) in 18% (n = 7), CR with incomplete hematologic recovery (CRi) in 15% (n = 6), morphologic leukemia-free state in 2.5% (n = 1), and no response in 5% (n = 2).

Among 34 MRD-evaluable CRc responders, 91% (n = 31) achieved MRD negativity by flow cytometry at a detection limit below 0.1%. At a median follow-up of 35 months (95% CI, 19.3-40.5), the 3-year overall survival (OS) rate was 79% (95% CI, 64%-96%) and the 3-year duration of response (DOR) rate was 83% (95% CI, 64%-100%); both median OS and median DOR were not reached. The 3-year cumulative incidence of relapse was 9% (95% CI, 0%-20%).

A prespecified analysis examined co-occurring signaling pathway mutations (KRAS, NRAS, PTPN11, NF1, BRAF, FLT3-ITD, FLT3-TKD, KIT, JAK2, and CSF3R). Patients without a signaling mutation (n = 25) had a CRc rate of 100% and a 3-year OS rate of 95% (95% CI, 86%-100%), compared with a CRc rate of 80% and a 3-year OS rate of 54% (95% CI, 30%-95%) among those with a signaling mutation (n = 15; response P = .046; OS P = .037).

Trial Design and Patient Population

The phase 1b portion established the RP2D as ivosidenib at 500 mg orally once daily beginning on cycle 1, day 15; venetoclax at 400 mg orally on days 1 through 14; and azacitidine at 75 mg/m² intravenously or subcutaneously on days 1 through 7 of a 28-day cycle. Eligible patients were 18 years or older with IDH1 R132–mutant disease and included those with relapsed/refractory AML, newly diagnosed AML ineligible for standard induction, or high-risk myelodysplastic syndrome and/or myeloproliferative neoplasm; an ECOG performance status of 2 or lower was required. The phase 2 analysis was conducted after full enrollment of the newly diagnosed AML cohort (n = 40) across Cleveland Clinic, Dana-Farber Cancer Institute, MD Anderson, and Oregon Health & Science University.

The cohort had a median age of 72 years (range, 51-80). De novo AML accounted for 53% of cases, secondary AML for 38% (including treated secondary AML in 18%), and therapy-related AML for 10%. By ELN 2022 criteria, 70% of patients had adverse-risk disease; the median IDH1 variant allele frequency was 24% (range, 6%-46%).¹

Safety Data

Grade 3/4 nonhematologic adverse events occurred in 30% of patients (n = 12/40). The most frequent were infections (15%; n = 6/40), tumor lysis syndrome (7.5%; n= 3/40), and QTc prolongation (5%; n = 2/40); differentiation syndrome, myocardial infarction, and abdominal pain were each reported in 2.5% of patients (n = 1/40). Both 30-day and 60-day mortality rates were 0%. Two patients (5%) discontinued because of adverse events (a fall with hip fracture and diverticulitis). Venetoclax dosing was reduced in later cycles and adjusted for concomitant azole antifungals, while azacitidine and ivosidenib required no dose modifications for azole coadministration.

Allogeneic hematopoietic stem cell transplantation (HSCT) was the most common reason for coming off protocol, which was undertaken in 45% of patients (n = 18/40); 30% (n = 12) remained on study at the time of the analysis. Among responding patients, outcomes did not differ significantly by receipt of HSCT (3-year OS, 90% without HSCT vs 82% with HSCT; P = .70). Only 3 patients (7.5%) relapsed, each with IDH1–wild-type clones, suggesting that disease recurrence was driven by IDH1-independent mechanisms rather than on-target resistance.

The data position the triplet as an active frontline option that produced deep molecular responses across high-risk subgroups, including treated secondary AML.

Limitations and Next Steps

The analysis was limited by a single-arm design, a cohort of 40 patients, and small biomarker-defined subgroups that constrain comparative interpretation. The triplet is now being evaluated against a doublet control in the randomized phase 3 EVOLVE-1 trial (NCT07075016) of azacitidine plus ivosidenib with or without venetoclax in newly diagnosed IDH1-mutated AML or MDS/AML.⁷

Disclosures: Marvin-Peek noted consultancy/advisory board roles with Servier, Rigel Pharmaceuticals, and Blueprint.

References

1. Marvin-Peek J, Garcia JS, Borthakur G, et al. A multicenter phase Ib/II trial of azacitidine, venetoclax, and ivosidenib in IDH1-mutated acute myeloid leukemia (AML). Presented at: 2026 European Hematology Association Congress; June 11-14, 2026; Stockholm, Sweden. Abstract S127.
2. Pratz KW, Jonas BA, Pullarkat V, et al. Long-term follow-up of VIALE-A: venetoclax and azacitidine in chemotherapy-ineligible untreated acute myeloid leukemia. Am J Hematol. 2024;99(4):615-624. doi:10.1002/ajh.27246
3. Pollyea DA, DiNardo CD, Arellano ML, et al. Impact of venetoclax and azacitidine in treatment-naïve patients with acute myeloid leukemia and IDH1/2 mutations. Clin Cancer Res. 2022;28(13):2753-2761. doi:10.1158/1078-0432.CCR-21-3467
4. Montesinos P, Recher C, Vives S, et al. Ivosidenib and azacitidine in IDH1-mutated acute myeloid leukemia. N Engl J Med. 2022;386(16):1519-1531. doi:10.1056/NEJMoa2117344
5. Montesinos P, Marchione DM, Recher C, et al. Long-term results from the AGILE study of azacitidine plus ivosidenib vs placebo in newly diagnosed IDH1-mutated AML. Blood Adv. 2025;9(20):5177-5189. doi:10.1182/bloodadvances.2025016399
6. DiNardo CD, Stein EM, de Botton S, et al. Durable remissions with ivosidenib in IDH1-mutated relapsed or refractory AML. N Engl J Med. 2018;378(25):2386-2398. doi:10.1056/NEJMoa1716984
7. Study of ivosidenib and azacitidine with or without venetoclax in newly diagnosed IDH1-mutated AML or MDS/AML (EVOLVE-1). ClinicalTrials.gov. Updated August 19, 2025. Accessed June 11, 2026. https://tinyurl.com/3k29tc9u