AUTHORS
Christian Recher, Paresh Vyas, MD, PhD2, Hartmut Döhner3, Adriano Venditti, MD4, Sam Salek5, Samantha Nier6, Rebeca Rodriguez Veiga7, Thomas Cluzeau, MD, PhD8, Marie Anne Hospital9, Erika Borlenghi10, Koen Theunissen11, Mar Tormo Sr12, Antonio Curti Sr, MD13, Ioana Frinc14, David C de Leeuw15, Lalit Saini16, Emanuele Ammatuna, MD, Ph.D17, Panayiotis Panayiotidis, MD, PhD18, Andre C. Schuh Sr, BSc, MD, FRCPC19, Maria N. Pagoni20, Johan A. Maertens, MD21, Bogdan Ionescu22, Nina Orfali23, Vitaliy Mykytiv, MD24, Dilza Camanho25, Junxian Geng26, Vanessa Lacoste27, Mathilde Romagnoli28, Perrine Soret29, Benedicte Cognet30, Courtney DiNardo, MD, MSCE31, Susana Vives32
AFFILIATIONS
1 Université de Toulouse, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, Service d'Hématologie, Toulouse, France
2 Department of Haematology, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom, Medical Research Council Weatherall Institute of Molecular Medicine (MRC WIMM), University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom
3 Department of Internal Medicine III, Ulm University Hospital, Ulm, Germany
4 Hematology, Department of Biomedicine and Prevention, University Tor Vergata, Rome, Italy
5 School of Health, Medicine and Life Sciences, University of Hertfordshire, Hatfield, United Kingdom
6 Acute Leukemia Advocates Network, Bern, Switzerland
7 Hospital U.P. La Fe, Valencia, Spain
8 Centre Hospitalier Universitaire de Nice, Nice, France
9 Institute Paoli-Calmettes, Marseilles, France
10 ASST Spedali Civili di Brescia, Brescia, Italy
11 Jessa Hospital, Hasselt, Belgium
12 Hospital Clinico Universitario and INCLIVA Biomedical Research Institute, Valencia, Spain
13 IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia “Seràgnoli”, Bologna, Spain
14 The Oncology Institute “Prof. Dr. Ion Chiricuta” Cluj-Napoca, Cluj, Romania
15 Amsterdam UMC, Amsterdam, Netherlands, Cancer Center Amsterdam, Amsterdam, Netherlands
16 Division of Hematology, Department of Medicine, London Health Sciences Centre, London, Ontario, Canada
17 University Medical Center Groningen, Groningen, Netherlands
18 Hematology Clinic, National and Kapodistrian University of Athens Medical School, Laiko General Hospital, Athens, Greece
19 Princess Margaret Cancer Centre and University of Toronto, Toronto, Canada
20 Hematology-Lymphomas Department and BMT Unit, Athens, Greece
21 UZ Leuven, Leuven, Belgium
22 Clinical Institute Fundeni, Bucharest, Romania
23 St James’s Hospital, Dublin, Ireland
24 Cork University Hospital, Cork, Ireland
25 R&D Institute Servier Paris Saclay, Gif-sur Yvette, France
26 Servier BioInnovation, Boston, Massachusetts, United States
27 Servier Medical Affairs, Suresnes, France
28 R&D Institute Servier Paris Saclay, Gif-sur Yvette, France
29 R&D Institute Servier Paris Saclay, Gif-sur Yvette, France
30 Servier Medical Affairs, Suresnes, France
31 MD Andersen Cancer Center, Houston, Texas, United States
32 ICO Badalona-Hospital Germans Trias i Pujol, Institut de recerca Josep Carreras, Badalona, Spain
ABSTRACT
Introduction: Recurrent hotspot mutations in the gene encoding isocitrate dehydrogenase 1 (IDH1) occur in 6–10% of patients (pts) with acute myeloid leukemia (AML). Ivosidenib (IVO) is an oral first-in-class targeted inhibitor of mutant IDH1. In the pivotal AGILE trial (N=146), IVO + azacitidine (AZA) provided long-term clinical efficacy accompanied by a favorable safety profile in pts with newly diagnosed mutated (m) IDH1 (mIDH1) AML, ineligible for intensive chemotherapy (ICIE) (Montesinos et al. 2022, 2025). ALIDHE (NCT05907057) is assessing IVO+AZA in the same pt population but in a real-world setting. Here, we report updated safety, tolerability, and efficacy outcomes for ALIDHE.
Methods: ALIDHE is an international, single-arm, post-approval, phase 3b study enrolling ICIE pts aged ≥18 years with newly diagnosed AML and a documented IDH1 R132 mutation. Treatment (tx) comprises IVO (500 mg) once daily and AZA (75 mg/m2/day) for 7 days in 28-day cycles. The primary aim is to assess the safety of this combination. Efficacy outcomes, including complete remission (CR), CR with partial hematologic recovery (CRh), CR with incomplete hematologic recovery (CRi), their composite measure (CRc: CR + CRh + CRi), and overall survival (OS), were also assessed. Correlation of response with mIDH1 variant allele frequency (VAF) and co-mutations, and measurable residual disease (MRD, optional consent) are exploratory endpoints. ALIDHE has been designed with the Acute Leukemia Advocates Network, putting pt needs, experiences, and perspectives at the forefront.
Results: As of 3 May 2026 (data cut-off date), recruitment had been closed for 2 months (mos); 156 pts from 10 countries (Europe and Canada) had been enrolled and treated (77 pts remained on tx). Median age was 76.0 years (range: 51–87) and 37.2% of pts had secondary AML. Median mIDH1 VAF was 20% (IQR: 7.3–36). The most common co-mutations were DNMT3A (43.3% of pts), RUNX1 (29.9%), SRSF2 (27.8%), and ASXL1 (26.8%).
The safety profile was consistent with that reported in AGILE. In the safety analysis set (N=156), 145 (92.9%) pts experienced ≥1 tx-emergent adverse event (TEAE) and 114 (73.1%) experienced TEAEs related to IVO and/or AZA. Grade ≥3 TEAEs occurred in 128 (82.1%) pts and serious TEAEs in 85 (54.5%) pts. Grade ≥2 differentiation syndrome was reported in 18 (11.5%) pts and grade ≥3 QT prolongation in 14 (9.0%) pts, none of whom discontinued tx. Twelve (7.7%) TEAEs leading to death were reported; none were considered related to IVO and/or AZA. Over the study period, hematology parameters (neutrophils, platelets, hemoglobin, transfusion independence) improved and bone marrow blasts decreased in responding patients.
With a median tx duration of 7.2 mos (range: 0.1–26.2), clinical activity with IVO+AZA was observed across a molecularly diverse pt population. Rates of CR and CRc were 53.8% and 62.8%, respectively, in the full analysis set (N=156); 70.8% and 75.0% in pts with mNPM1 (n=24); 54.5% and 63.6% in mNPM1 with ≥1 receptor tyrosine kinase (RTK) pathway co-mutation (PTPN11, NRAS, KRAS, FLT3-ITD, other FLT3, KIT, NF1, JAK2; n=11); 33.3% and 50.0% in pts with mTP53 (n=12); and 32.5% and 45.0% in pts with any RTK pathway co-mutation (n=40). Baseline mIDH1 VAF was not associated with tx response (CR or CRc), even when the mIDH1 clone appeared subclonal relative to co-mutations, including those in DNMT3A, SRSF2, RUNX1, and ASXL1. Of the 36 MRD-evaluable pts in CR, 15 (41.7%) were MRD-negative by flow cytometry, including 14 pts by cycle 6. Among pts in CRc, six (6/96, 6.3%) were confirmed to have subsequently undergone allogeneic stem cell transplant. Median time to CR was 3.7 mos (range: 0.4–10.8) and median duration of CR (mos) was not reached (NR) (95% CI: 13.8–NR). Median OS follow-up was 10.6 mos (range: 9.0–12.9) and the 6-mo OS rate was 91.2% (95% CI: 85.0–95.0). OS data remain immature at data cut off.
Summary/conclusion: These updated data from ALIDHE confirm consistent clinical benefit and a manageable safety profile with IVO+AZA in pts with AML in a real-world setting. Responses were observed across molecularly diverse pt subgroups regardless of baseline mIDH1 VAF, with particularly favorable response rates in pts with NPM1 co-mutations. Collectively, these findings prospectively confirm and extend the efficacy and safety outcomes reported in the pivotal AGILE study. Longer follow-up will further characterize survival outcomes.
DISCLOSURES
Christian Recher: AbbVie, BMS, IQVIA - Research Funding; AbbVie, Amgen, Astellas, BMS, Johnson & Johnson, and Servier - Consultancy (Includes expert testimony)