Introduction

Mutations in IDH1 occur in 6–10% of patients (pts) with AML. Ivosidenib (IVO), an oral, targeted, small-molecule inhibitor of mIDH1, has been approved in combination with azacitidine (AZA) for pts with mIDH1 AML who are ineligible for IC, on the basis of results from the phase 3 AGILE study. AGILE demonstrated the long-term clinical benefit of IVO+AZA, with a median overall survival (OS) of 29 months. Here, we report preliminary results from ALIDHE (NCT05907057), an ongoing postapproval study designed in collaboration with the Acute Leukemia Advocates Network to evaluate safety and efficacy of IVO+AZA in a real-world setting inclusive of all pts with mIDH1 AML ineligible for IC managed as per local clinical practice. A pt steering committee ensures that pt needs, experiences, and perspectives are at the forefront of the study.

Methods This international, single-arm, open-label phase 3b study enrolls adult pts (≥18 years) with newly diagnosed mIDH1 AML ineligible for IC and ECOG PS ≤2. Pts are treated with 500 mg oral IVO once daily and 75 mg/m2 SC or IV AZA for 7 days in 28-day cycles. Data are collected every 4 weeks while pts are on treatment for ≥112 weeks, and then every 12 weeks for OS. Primary endpoints include treatment-emergent adverse events (TEAEs), serious AEs (SAEs), AEs of special interest (AESIs), and AEs leading to IVO and/or AZA discontinuation, interruption, dose reduction, or death. Secondary endpoints include event-free survival, disease response, and time to response. Measurable residual disease (MRD) and biomarker correlations with clinical outcomes are exploratory endpoints under optional consent. MRD is assessed centrally by flow cytometry on fresh bone marrow (BM) aspirates. mIDH1 allele subtype and co-mutations are analyzed centrally on baseline peripheral blood samples using NGS.

Results As of 5 May 2025 data cutoff, 92 pts from 7 countries (Europe + Canada) were enrolled; 89 were included in safety and efficacy analyses. Median age was 75 years (min-max: 51–84; Q1-Q3: 72–80); 66.3% of pts had ECOG PS 0–1 and 58.4% had de novo AML. Median baseline BM blast level was 39.8% (min-max: 0–100; Q1-Q3: 23.8–56.3; n=76). Median turnaround time for mIDH1 local testing was 7 days and median time from testing to study drug start was 20 days. Locally, direct molecular profiling methods were used in 73.0% of pts, including NGS (56.2%). In central assessment by NGS, distribution of the 5 most common mIDH1 variants (R132C, G, H, L, and S) was 51.1%, 7.6%, 18.5%, 3.3%, and 8.7%, respectively. Most frequent co-mutated genes included DNMT3A (40.7%), ASXL1 (28.8%), RUNX1 (28.8%), SRSF2 (27.1%), U2AF1 (20.3%), TET2 (15.3%), STAG2 (15.3%), CEBPA (10.2%), and NPM1 (10.2%). TP53 and JAK2 mutations occurred in 8.5% and 6.8% of pts, respectively; 25.4% of pts had mutations in the RTK/RAS pathway.

At the cutoff date, 68 pts (76.4%) were still on treatment; median treatment duration was 5.1 months (min-max: 0.2–14.9; Q1-Q3: 2.9–7.8). Any-grade (G) TEAEs were reported in 93.3% of pts, G≥3 TEAEs in 80.9%, and SAEs in 57.3%. TEAEs occurring in >20% of pts were neutropenia (32.6%), nausea (29.2%), QT prolongation (23.6%), and anemia (20.2%). AESIs occurred in 22.5% of pts, including G≥3 QT prolongation in 9% and G≥2 differentiation syndrome in 13.5%. TEAEs led to any study drug discontinuation in 11.2% of pts, any dose reduction in 7.9%, and any study drug interruption in 75.2%. In total, 6 (6.7%) pts had TEAEs leading to death, none of which were considered treatment related. Preliminary efficacy showed CR in 37 (42%) pts, CR/CRh in 40 (45%), and an ORR of 52/89 (58%). As of 7 April 2025, MRD was assessed in 16 pts in CR/CRh/CRi after ≥6 cycles of IVO+AZA; 5 (31.3%) reached MRD negativity per flow cytometry, all (45.5%) among the 11 pts in CR at the time of assessment.

Conclusions Outcomes in clinical practice can differ from those reported in pivotal trials. However, preliminary findings from ALIDHE are consistent with the AGILE pivotal trial. IVO+AZA had similar safety results in ALIDHE as in AGILE and efficacy outcomes were promising. The data will enrich knowledge on the IVO+AZA safety profile and help translate efficacy to effectiveness, bridging the gap between clinical trials and clinical practice, fulfilling the objectives of this real-world postapproval study. The study is still enrolling; future analyses will focus on effectiveness and QOL.

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2025
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