Prospective evaluation of response to treatment by analysis of measurable residual disease in younger adult patients (18-60 years) with acute myeloid leukemia (AML). The Backbone InterGroup (BIG)-2 umbrella trial from the Acute Leukemia French Intergroup (ALFA, FILO) - BIG2

Prior treatment

• Patients with secondary AML arising from a previously known myeloproliferative neoplasm (MPN) according to the 2022 WHO classification
• Sub-study 1: Prior treatment with quizartinib or other FLT3 inhibitors
• Sub-study 1: Treatment with any strong or moderate CYP3A inducers within 2 weeks or 5 half-lives of randomization whichever is longer
• Sub-study 2: Prior venetoclax exposure
• Patients with t(9;22)(q34.1;q11.2)/BCR::ABL1 or previous Ph1+ disorder (chronic myelogenous leukemia)

Other illness

• Sub-study 2: Uncontrolled infection such as sepsis, or multiple organ dysfunction syndrome, uncontrolled fever
• Sub-study 2: Documented uncontrolled fungal infection (positive blood test and cultures)
• Severe psychiatric or organic disorder, supposed to be independent from AML, that would contraindicate treatment, including allogeneic HSCT
• Prior cancer, if not stable for at least two years, except in-situ carcinoma and skin carcinoma
• Uncontrolled severe infection at study entry
• Patients with uncontroled HIV-1 and -2 infection, or active hepatitis virus B or C infection

Lab values

• Sub-study 1: Uncontrolled or significant cardiovascular disease, including any of the following: • Bradycardia < 50 beats per minute • QTcF interval >450 msec • Diagnosis of or suspicion of long QT syndrome (including family history of long QT syndrome) • Systolic blood pressure ≥180 mm Hg or diastolic blood pressure ≥110 mm Hg • History of clinically relevant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, or torsade de pointes) • History of second (Mobitz II) or third-degree heart block (patients with pacemakers were eligible if they had no history of fainting or clinically relevant arrhythmias while using the pacemaker) • History of uncontrolled angina pectoris or myocardial infarction within 6 months before screening • History of New York Heart Association class 3 or 4 heart failure • Left ventricular ejection fraction ≤45% or less than the institutional lower limit of normal per multigated acquisition scan or echocardiogram done within 30 days before randomization • Complete left bundle branch block

Other

• Pregnant or lactating women
• Sub-study 1: Patients with CBF-AML
• Sub-study 1: Uncorrected Grade 3 or 4 hypokalemia, hypomagnesemia or hypocalcemia. Subjects with Grade 1 or 2 electrolyte abnormalities can be enrolled while electrolytes are being corrected.
• Sub-study 2: Patients with AML with FLT3-ITD mutation without CBF
• Legal incapacity (patients under tutorship, curatorship or judicial protection)
• Sub-study 3: Patients with AML with FLT3-ITD mutation without CBF
• Patients with acute promyelocytic leukemia (APL), as confirmed either by t(15;17) or by the presence of PML::RARA fusion transcripts
• Any psychological, familial, social, or geographic reason that would compromise clinical follow up

• Age ≥ 18 years and < 61 years
• Health insurance coverage
• Sub-study 1 : Presence of FLT3-ITD activating mutation in bone marrow (allelic ratio ≥ 0.03)
• Sub-study 1 : Receiving standard 7+3 induction chemotherapy regimen as specified in the protocol
• Sub-study 1: Serum electrolytes within the institution’s normal limits: potassium, calcium (total calcium, calcium corrected for serum albumin in case of hypoalbuminemia, or ionized calcium), and magnesium.
• Sub-study 2: Refractory (no response) or CR/CRh/CRi with positive MRD by MFC in bone marrow (≥ 0.1%) after one cycle of 7+3 induction
• Sub-study 2: Eligible for a second cycle of intensive chemotherapy
• Sub-study 3: CR/CRh/CRi without MRD by MFC in bone marrow (< 0.1% OR < LOD) after one cycle of 7+3 induction.
• Signed written informed consent
• Newly diagnosed de novo AML, or secondary AML arising from a previously known myelodysplastic syndrome (MDS), or post cytotoxic therapy-related AML (AML-pCT), according to the 2022 WHO classification
• No prior treatment for AML (with the exception of hydroxyurea) or for MDS (with the exception of hematopoietic growth factors)
• ECOG performance status ≤ 3
• Eligible to induction chemotherapy
• No contraindication to anthracyclines: decompensated or uncontrolled heart failure, recent myocardial infarction, current signs of cardiac impairment, uncontrolled arrhythmias, or left ventricular ejection fraction (LVEF) < 50%
• Total bilirubin ≤ 2 x upper limit of normal (UNL), ASAT (SGOT) and ALAT (SGPT) ≤ 2.5 X UNL, creatinine < 150 µmol/l, unless AML-related values
• Women of childbearing potential should use appropriate methods of contraception