Ivosidenib and Azacitidine With or Without Venetoclax in Adult Patients With Newly Diagnosed IDH1-Mutated AML or MDS/AML Considered Ineligible for Intensive Chemotherapy

Inclusion Criteria: 1. Patient with newly diagnosed IDH1-mutated AML, or IDH1-mutated MDS/AML according to the 2022 International Consensus Classification (Appendix A). Patients with AML with both IDH1 and IDH2 mutation are eligible as well. Of note: in case both NPM1 and IDH1 are mutated and both EVOLVE-1 (HO173/AMLSG 3423/ACT-HOV-AML-001) and EVOLVE-2 (HO177/AMLSG 35-24/ACT-HOV-AML-002are open for inclusion at your site, then patients can only be included in the EVOLVE-1 trial (HO173) 2. Central confirmation of IDH1 mutation in one of the dedicated central genetic laboratories. 3. Age ≥ 18 years, no upper age limit. 4. Patient is ineligible for intensive induction chemotherapy by meeting at least 1 of the following criteria: * older than or equal to 75 years of age ineligible for intensive chemotherapy per physician's discretion (with an ECOG performance status 0-2; Appendix C). * 18-74 years: patient is not eligible for standard chemotherapy because of any of the following co-morbidities: o ECOG performance status 2 or 3 (Appendix C). o Cardiac history of chronic heart failure requiring treatment; or with an ejection fraction ≤50%; or chronic stable angina. * DLCO ≤ 65% or FEV1 ≤ 65%. * Creatinine clearance ≥ 30 mL/min to \<45 ml/min calculated by the Cockcroft Gault formula. * Moderate hepatic impairment with total bilirubin \> 1.5 to \< 3.0 x upper limit of normal (ULN). * Any other comorbidity that the local physician assesses to be incompatible with intensive chemotherapy. If a patient meets this criterion, sponsor must be informed via HO173@erasmusmc.nl 5. Patient must have a projected life expectancy of at least 12 weeks (as assessed by the treating physician). 6. Patient must have a white cell blood (WBC) count of \< 25 x 109/L. Hydroxyurea can be used prior to study enrollment to reduce the WBC count to meet this criterion. 7. Adequate renal function as evidenced by serum creatinine ≤ 2.0 × upper limit of normal (ULN) or creatinine clearance \>30 mL/min based on the Cockcroft-Gault glomerular filtration rate (GFR). 8. Adequate hepatic function as evidenced by: * Serum total bilirubin ≤ 3.0 × ULN unless considered due to Gilbert's disease, or leukemic involvement. If a patient meets this criterion, sponsor must be informed via HO173@erasmusmc.nl Page 30 of 117 HOVON 173 AML / AMLSG 34-23 / ACT-HOV-AML-001 Version 1.1, UK 11 FEB 2025 * Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) ≤ 3.0 × ULN, unless considered due to leukemic involvement. If a patient meets this criterion, sponsor must be informed via HO173@erasmusmc.nl 9. Female patients : * of nonchildbearing potential must be: o postmenopausal (defined as at least 1 year without any menses). o documented surgically sterile (e.g. documented hysterectomy, bilateral oophorectomy or bilateral salpingectomy) or status posthysterectomy (at least 1 month prior to screening). * of childbearing potential (not surgically sterile and not postmenopausal) must agree to avoid pregnancy during the study and for 6 months after the final study drug administration o and have a negative urine or serum pregnancy test at screening. o and, if heterosexually active, agree to consistently apply one highly effective\* method of birth control in combination to a barrier method for the duration of the study and for 6 months after the final study drug administration. * must agree not to breastfeed starting at screening and throughout the study period, and for 1 month after the final study drug administration. * must agree not to donate ova starting at screening and throughout the study period, and for 6 months after the final study drug administration. 10. Men must use a latex condom during any sexual contact with women of childbearing potential (WOCBP), even if they have undergone a successful vasectomy and must agree to avoid to father a child (while on therapy and for 6 months after the final study drug administration). In addition, their female partners of childbearing potential must use a highly effective method of birth control. 11. Male patient must not donate sperm starting at screening and throughout the study period and for 6 months after the final study drug administration. 12. Able to understand and willing to sign an informed consent form (ICF). 13. Institutional Review Board/Independent Ethics Committee-approved written informed consent and privacy language as per national regulations must be obtained from the participant prior to any study-related procedures (including consent for withdrawal of prohibited medication, if applicable). Exclusion Criteria: 1. Subject has previously been treated for AML; a treatment period with hydroxyurea to control WBC counts is allowed; prior treatment with a hypomethylating agent for MDS-EB is not allowed; prior treatment with erythropoiesis-stimulating agents or luspatercept for MDS is allowed. 2. Acute promyelocytic leukemia (APL) with t(15;17)(q24.1;q21.2); PML-RARA; or one of the other pathognomonic variant chromosomal translocations / fusion genes. 3. AML with BCR-ABL1; or myeloid blast crisis of CML 4. Significant active cardiac disease within 3 months prior to the start of study treatment, including: \- New York Heart Association (NYHA) class III or IV congestive heart failure (Appendix F) \- Myocardial infarction \- Unstable angina * Severe cardiac arrhythmias * Congenital long QT syndrome of family member with this condition * QTcF \>480 msec on screening electrogram (mean of triplicate recordings). 5. Familial history of sudden death or polymorphic ventricular arrhythmia. 6. Severe obstructive or restrictive ventilation disorder. 7. History of stroke or intracranial hemorrhage within 6 months prior to randomization. 8. Clinical symptoms suggestive of active central nervous system (CNS) leukemia or known CNS leukemia. Evaluation of cerebrospinal fluid (CSF) during scree