Continuation therapy
Bradycardia, non-melanoma skin cancer.- Severe neurologic or, acute myeloid leukemia, HAM, AML, bifascicular block.-, Arrhythmias, ventilation disorder.-, Hyperleukocytosis, psychiatric, Severe neurologic or, hypersensitivity, hyperleukocytosis)-, bleeding diathesis
AML, CEREBROVASCULAR ACCIDENT, LEFT BRANCH BUNDLE BLOCK, SECOND MALIGNANCY, DISEASE CHARACTERISTIC, BLEEDING DIATHESIS, POSITIVE, HYPERLEUKOCYTOSIS, HEPATITIS A INFECTION, SINUSOIDAL OBSTRUCTION SYNDROME, CONGENITAL LONG QT SYNDROME, HYPERSENSITIVITY, DISORDER, ACUTE MYELOID LEUKEMIA, UNCONTROLLED HYPERTENSION, TRANSIENT ISCHEMIC ATTACK, ARRHYTHMIAS, MUTANT, MYOCARDIAL INFARCTION
All patients achieving CR are allocated according to randomization to either (a) the MRD-triggered arm or (b) the prophylactic arm receiving treatment with quizartinib. During consolidation therapy, patients allocated to the MRD-triggered arm (a) receive one cycle of HAM and are further allocated based on the MRD results assessed by flow cytometry with a cut of level of 0.1%: if the MRD is negative they remain in the MRD-triggered arm for another HAM cycle, whereas MRD-positive patients move to the prophylactic arm. All patients randomized to (b) the prophylactic arm will receive quizartinib during their two cycles of HAM therapy irrespective of MRD results (see Fig. Patients achieving MRD negativity in the MRD-triggered arm will not receive treatment during the maintenance phase. MRD-positive patients have to move to the prophylactic arm receiving quizartinib as single agent and will continue the study for up to 12 treatment cycles presenting themselves at monthly visits to assess the course of therapy. Patients in the MRD-triggered arm are attending visits in 3-monthly intervals only. During maintenance therapy, starting from cycle 2, the quizartinib dosage will be increased up to 60mg orally, if the average QTcF of the triplicate ECGs is lower than 450 ms on cycle 1, day 28. Once the dose is increased to 60mg/day, the subject may continue on this dose as long as no dose reduction is needed. In case of therapy with a strong CYP3A4 inhibitor a dose reduction to 20mg per day is required. The maintenance phase is followed by a safety follow-up of 28 days counted from the end of treatment (EOT) for all patients from the prophylactic arm. Dose modifications are listed in Tables Inclusion and exclusion criteria- Patients with diagnosed acute myeloid leukemia according to the 2016 WHO classification.who are either• refractory to induction therapy or• relapsed after first line treatment including chemotherapy, autologous and/or allo-HCT*- Positive for FLT3-ITD (defined as a ratio of mutant to wild-type alleles of at least 0.05; measured within 4 weeks before inclusion)- Age ≥ 18 years and ≤ 75 years- ECOG performance status ≤2.- Effective contraception method.- AML with PML-RARA or BCR-ABL1.- Patients with known active CNS leukemia.- Isolated extramedullary manifestation of AML- Clinically relevant GvHD requiring initiation of treatment or treatment escalation within 21 days prior to screening- Pregnancy and lactation.- Known or suspected active alcohol or drug abuse.- Known positivity for HIV, active HBV, HCV, or hepatitis A infection.- Severe neurologic or psychiatric disorder interfering with ability of giving informed consent.- Hyperleukocytosis (leukocytes > 30,000/μl) at the time of study entry.**- Refractoriness to platelet or packed red cell transfusions- Discontinuation of prior AML treatment for at least• 10 days for cytotoxic agents and• 28 days for investigational drug treatment before the start of study treatment (except hydroxyurea to control hyperleukocytosis)- allo-HCT within the previous 100 days- Prior treatment with quizartinib- Inadequate renal function.- Inadequate liver function.- Known liver cirrhosis.- History of Sinusoidal Obstruction Syndrome (SOS)- Uncontrolled hypertension.- Severe obstructive restrictive. ventilation disorder.- Myocardial infarction.- Congenital long QT syndrome.- Torsades de pointes.- Arrhythmias (including sustained ventricular tachyarrhythmia).- Right or left bundle branch block and bifascicular block.- Unstable angina.- Coronary/peripheral artery bypass graft.- symptomatic congestive heart failure (NYHA III/IV).- Cerebrovascular accident.- transient ischemic attack.- Symptomatic pulmonary. embolism.- Bradycardia defined as <50 bpms.- QTc interval >470 ms.- Uncontrolled infection.- Evidence or history of severe non-leukemia-associated bleeding diathesis or coagulopathy.- Patients with a “currently active” second malignancy other than non-melanoma skin cancer.- Severe neurologic or psychiatric disorder interfering with ability of giving informed consent.- Signed written informed consent.- Ability of patient to understand the character and consequences of the clinical trial.- No consent for biobanking.- History of hypersensitivity to the investigational medicinal product or to any drug with similar chemical structure.- Participation in a clinical study involving an investigational drugs.- No consent for registration, storage, and processing of the individual disease characteristics.Inclusion and exclusion criteria: The following eligibility criteria are designed to select patients for whom protocol treatment is considered appropriate.* Refractory to induction therapy is defined as no CR, or CRi, or PR (according to standard criteria) [
