Azacitidine Triplet Yields MRD-Negative Responses in IDH1+ AML

Combining azacitidine (Vidaza) with venetoclax (Venclexta) and ivosidenib (Tibsovo) demonstrated positive minimal residual disease (MRD)–negative responses and enduring remissions among patients with acute myeloid leukemia (AML) harboring IDH1 mutations, according to a presentation on data from a phase 1b/2 trial (NCT03471260) at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting.¹

Among 40 evaluable patients with newly diagnosed AML, the overall response rate (ORR) was 95%, which included a composite complete response (CRc) rate of 93%. Best responses included morphologic leukemia-free state (MLFS) in 2.5%, CR with incomplete hematologic recovery (CRi) in 15%, CR with hematologic recovery (CRh) in 18%, and CRs in 60%. Based on flow cytometry among 34 evaluable patients, with a limit of detection lower than 0.1%, MRD negativity was achieved by 91%.

After a median follow-up of 35 months (95% CI, 19.3-40.5), data showed a median overall survival (OS) that was not reached (NR; 95% CI, 52.8-NR), with a 3-year OS rate of 79% (95% CI, 64%-96%). Additionally, the median duration of remission (DOR) was NR (95% CI, 43.4-NR); 83% (95% CI, 64%-100%) of responders sustained their response for at least 3 years. Investigators also noted a 3-year cumulative incidence of relapse (CIR) rate of 9% (95% CI, 0%-20%).

Of note, patients without co-occurring “signaling” pathway mutations appeared to experience improved responses with the triplet; the CRc rate was 100% vs 80% among patients without signaling mutations (n = 25) and those with signaling mutations (n = 15), respectively (P = .046). The median OS was NR in both groups, and the 3-year OS rates were 95% (95% CI, 86%-100%) in patients without signaling mutations vs 54% (95% CI, 30%-95%) in those with signaling mutations (P = .037). The 3-year DOR rates were 90% (95% CI, 78%-100%) vs 66% (95% CI, 40%-100%) in each respective group; the median DOR was NR across both populations (P = .29).

In patients with treated secondary AML (tsAML; n = 7), the CRc rate was 71% vs 97% in those with non-tsAML (n = 33; P = .162). Across each group, 43% vs 64% had CRs, 14% vs 15% had CRh, 14% vs 18% had CRi, and 14% vs 0% had MLFS.

“Despite 2 available doublet regimens for newly diagnosed intensive chemotherapy-ineligible IDH1-mutated AML, a significant proportion of patients either [do not] respond or eventually relapse,” lead study investigator Jennifer Marvin-Peek, MD, a medical oncology fellow at The University of Texas MD Anderson Cancer Center, stated in the presentation. “In this multicenter study, triplet therapy combining azacitidine, venetoclax, and ivosidenib demonstrated high MRD-negative response rates with durable remissions and comparable safety to doublet regimens.”

According to Marvin-Peek, patients with IDH1-mutated AML have 2 current standard-of-care hypomethylating agent (HMA)-based doublets: azacitidine plus venetoclax based on the phase 3 VIALE-A trial (NCT02993523), and ivosidenib plus azacitidine based on the phase 3 AGILE trial (NCT03173248).^2,3 Investigators of this phase 1b/2 trial aimed to assess whether combining all 3 agents into a triplet regimen could improve outcomes among those with newly diagnosed IDH1-mutated AML who are not eligible for standard induction chemotherapy.

Patients were assigned to receive azacitidine at 75 mg/m² on days 1 to 7, venetoclax at 400 mg on days 1 to 14, and ivonescimab at 500 mg continuously starting on day 14 of cycle 1. Investigators could attenuate doses to help minimize myelosuppression.

The trial’s primary end points included ORR, adverse effects (AEs), and dose-limiting toxicities.⁴ Secondary end points included DOR, event-free survival, and OS. Patients 18 years and older with an ECOG performance status of less than 2, relapsed/refractory AML or newly diagnosed disease not eligible for standard induction chemotherapy, and adequate hepatic function were eligible for enrollment.

The median age was 72 years (range, 51-80), and 35% of patients were female. Additionally, most patients had de novo AML (53%), received treatment at MD Anderson Cancer Center (48%), had adverse risk per ELN2022 criteria (70%), and had favorable risk per ELN2024 guidelines (83%).

Grade 3/4 non-hematologic AEs occurred in 30% of patients, which included infections (15%), tumor lysis syndrome (7.5%), QTc prolongation (5%), abdominal pain (2.5%), differentiation syndrome (2.5%), and myocardial infarction (2.5%). The 30- and 60-day mortality rates were 0%, and 55% of those not transplanted remained active on protocol at the time of analysis.

According to Marvin-Peek, investigators are also evaluating azacitidine plus ivosidenib with or without venetoclax among patients with newly diagnosed AML harboring IDH1 mutations as part of the ongoing phase 3 EVOLVE-1 trial (NCT07075016).

Disclosures: Marvin-Peek disclosed consulting or advisory roles with Rigel and Servier.

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). J Clin Oncol. 2026;44(suppl 16):6503. doi:10.1200/JCO.2026.44.16_suppl.6503
2. DiNardio CD, Jonas BA, Pullarkat V, et al. Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N Engl J Med. 2020;383(7):617-629. doi:10.1056/NEJMoa2012971
3. 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
4. Ivosidenib and venetoclax with or without azacitidine in treating patients with IDH1 mutated hematologic malignancies. ClinicalTrials.gov. Updated March 11, 2026. Accessed June 2, 2026. https://tinyurl.com/y73zkfsy