quizartinib
Sources réglementaires consultées
Indications approuvées
- Chez l’adulte atteint de leucémie aiguë myéloïde FLT3-ITD positive nouvellement diagnostiquée, en association avec une induction standard par cytarabine et anthracycline, une consolidation par cytarabine puis en entretien en monothérapie.
Contre-indications
Absolues
- Hypersensibilité au quizartinib ou à ses excipients.
- Syndrome du QT long congénital.
- Profil CIMA : allaitement.
- Profil FDA : hypokaliémie sévère, hypomagnésémie sévère ou antécédents d’arythmie ventriculaire ou de torsades de pointes.
Mises en garde cliniques
- Mise en garde encadrée · AVERTISSEMENT ENCADRÉ : prolonge le QT de façon dépendante de la dose et de la concentration, avec survenue de torsades de pointes et d’arrêts cardiaques. Corriger potassium et magnésium avant et pendant le traitement ; réaliser un ECG initial puis hebdomadaire pendant induction et consolidation, et en entretien avant le début, chaque semaine le premier mois après initiation et augmentation, puis selon l’indication clinique. — DailyMed, VANFLYTA set_id 29cdbcfe-497d-4e78-bb7b-2d4acafe8e86
- Mise en garde majeure · Surveiller étroitement les infections, surtout chez les patients de plus de 65 ans pendant l’induction ; les infections mortelles ont été plus fréquentes dans ce groupe. — CIMA/AEMPS, ficha técnica VANFLYTA 1231768002
Interactions médicamenteuses
- SévèreInhibiteurs puissants du CYP3A
Mécanisme: Ils doublent presque l’exposition au quizartinib et augmentent le risque de toxicité et de prolongation du QT.
Recommandation: Éviter si possible ; si l’association est indispensable, appliquer la réduction de dose spécifique et renforcer la surveillance ECG.
CIMA/AEMPS, ficha técnica VANFLYTA 1231768002https://cima.aemps.es/cima/dochtml/ft/1231768002/FT_1231768002.html
- SévèreInducteurs puissants ou modérés du CYP3A
Mécanisme: Ils réduisent fortement l’exposition et peuvent diminuer l’efficacité.
Recommandation: Éviter l’association, y compris le millepertuis.
CIMA/AEMPS, ficha técnica VANFLYTA 1231768002https://cima.aemps.es/cima/dochtml/ft/1231768002/FT_1231768002.html
- SévèreMédicaments prolongeant le QT
Mécanisme: Ils peuvent augmenter l’incidence de la prolongation du QT et des arythmies ventriculaires.
Recommandation: Éviter si possible ; si nécessaire, corriger les électrolytes et réaliser des ECG plus fréquents.
DailyMed, VANFLYTA set_id 29cdbcfe-497d-4e78-bb7b-2d4acafe8e86https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=29cdbcfe-497d-4e78-bb7b-2d4acafe8e86
- ModéréeSubstrats de la BCRP
Mécanisme: Le quizartinib peut augmenter leur exposition.
Recommandation: Éviter si possible les substrats à marge thérapeutique étroite ; en cas d’association, surveiller la toxicité et réduire le substrat si nécessaire.
CIMA/AEMPS, ficha técnica VANFLYTA 1231768002https://cima.aemps.es/cima/dochtml/ft/1231768002/FT_1231768002.html
Effets indésirables
Communs (≥1%)
élévation de l’ALT · thrombopénie · anémie · diarrhée · nausées · douleur abdominale · céphalées · vomissements · neutropénie
Rares mais graves
arrêt cardiaque · fibrillation ventriculaire
Grossesse et allaitement
Peut provoquer une toxicité embryofœtale. Vérifier la grossesse dans les 7 jours précédant le début. Les femmes doivent utiliser une contraception efficace pendant le traitement et pendant 7 mois après ; les hommes ayant une partenaire susceptible d’être enceinte pendant le traitement et pendant 4 mois après. Ne pas utiliser pendant la grossesse sauf nécessité clinique. Ne pas allaiter pendant le traitement ni pendant au moins 5 semaines après.
Bibliographie récente (PubMed)
The first 5 decades of research in acute myeloid leukemia (AML) were dominated by the cytarabine plus anthracyclines backbone, with advances in strategies including allogeneic hematopoietic stem cell transplantation, high-dose cytarabine, supportive care measures, and targeted therapies for the subset of patients with acute promyelocytic leukemia. Since 2017, a turning point in AML research, 12 agents have received regulatory approval for AML in the United States: venetoclax (BCL2 inhibitor); gemtuzumab ozogamicin (CD33 antibody-drug conjugate); midostaurin, gilteritinib, and quizartinib (fms-like tyrosine kinase 3 inhibitors); ivosidenib, olutasidenib, and enasidenib (isocitrate dehydrogenase 1 and 2 inhibitors); oral azacitidine (a partially absorbable formulation); CPX351 (liposomal encapsulation of cytarabine:daunorubicin at a molar ratio of 5:1); glasdegib (hedgehog inhibitor); and recently revumenib (menin inhibitor; approved November 2024). Oral decitabine-cedazuridine, which is approved as a bioequivalent alternative to parenteral hypomethylating agents in myelodysplastic syndrome, can be used for the same purpose in AML. Menin inhibitors, CD123 antibody-drug conjugates, and other antibodies targeting CD123, CD33, and other surface markers are showing promising results. Herein, the authors review the frontline and later line therapies in AML and discuss important research directions.
Patients with acute myeloid leukaemia (AML) positive for internal tandem duplication (ITD) mutations of FLT3 have poor outcomes. Quizartinib, an oral, highly potent, selective, type 2 FLT3 inhibitor, plus chemotherapy showed antitumour activity with an acceptable safety profile in patients with FLT3-ITD-positive newly diagnosed AML. The aim of the study was to compare the effect of quizartinib versus placebo on overall survival in patients with FLT3-ITD-positive newly diagnosed AML aged 18-75 years. We conducted a randomised, double-blind, placebo-controlled, phase 3 trial comparing quizartinib and placebo in combination with chemotherapy in induction and consolidation, followed by quizartinib or placebo single-agent continuation, in patients with FLT3-ITD-positive newly diagnosed AML at 193 hospitals and clinics in 26 countries in Europe; North America; and Asia, Australia, and South America. Patients aged 18-75 years were eligible. Patients were randomly assigned (1:1) to the quizartinib group or the placebo group by an independent biostatistician through an interactive web and voice response system, stratified by region, age, and white blood cell count at diagnosis. Patients, investigators, funders, and contract research organisations were masked to treatments assigned. Induction therapy comprised a standard 7 + 3 induction regimen of cytarabine 100 mg/m2 per day (or 200 mg/m2 per day allowed if institutional or local standard) by continuous intravenous infusion from day 1 to day 7 and anthracycline (daunorubicin 60 mg/m2 per day or idarubicin 12 mg/m2 per day) by intravenous infusion on days 1, 2, and 3, then quizartinib 40 mg orally or placebo once per day, starting on day 8, for 14 days. Patients with complete remission or complete remission with incomplete neutrophil or platelet recovery received standard consolidation with high-dose cytarabine plus quizartinib (40 mg per day orally) or placebo, allogeneic haematopoietic cell transplantation (allo-HCT), or bo
Acute myeloid leukemia (AML) is a clonal hematopoietic cancer that disrupts normal hematopoiesis, ultimately leading to bone marrow failure and death. The annual incidence rate of AML is 4.1 per 100 000 people in the US and is higher in patients older than 65 years. Acute myeloid leukemia includes numerous subgroups with heterogeneous molecular profiles, treatment response, and prognosis. This review discusses the evidence supporting frontline therapies in AML, the major principles that guide therapy, and progress with molecularly targeted therapy. Acute myeloid leukemia is a genetically complex, dynamic disease. The most commonly altered genes include FLT3, NPM1, DNMT3A, IDH1, IDH2, TET2, RUNX1, NRAS, and TP53. The incidence of these alterations varies by patient age, history of antecedent hematologic cancer, and previous exposure to chemotherapy and/or radiotherapy for any cancer. Since 2010, molecular data have been incorporated into AML prognostication, gradually leading to incorporation of targeted therapies into the initial treatment approach of induction chemotherapy and subsequent management. The first molecularly targeted inhibitor, midostaurin, was approved to treat patients with AML with FLT3 variants in 2017. Since then, the understanding of the molecular pathogenesis of AML has expanded, allowing the identification of additional potential targets for drug therapy, treatment incorporation of molecularly targeted therapies (midostaurin, gilteritinib, and quizartinib targeting FLT3 variants; ivosidenib and olutasidenib targeting IDH1 variants, and enasidenib targeting IDH2), and identification of rational combination regimens. The approval of hypomethylating agents combined with venetoclax has revolutionized the therapy of AML in older adults, extending survival over monotherapy. Additionally, patients are now referred for hematopoietic cell transplant on a more rational basis. In the era of genomic medicine, AML treatment is customized to the patient's co
The understanding of the molecular pathobiology of acute myeloid leukemia (AML) has spurred the identification of therapeutic targets and the development of corresponding novel targeted therapies. Since 2017, twelve agents have been approved for the treatment of AML subsets: the BCL2 inhibitor venetoclax; the CD33 antibody drug conjugate gemtuzumab ozogamicin; three FLT3 inhibitors (midostaurin, gilteritinib, quizartinib); three IDH inhibitors (ivosidenib and olutasidenib targeting IDH1 mutations; enasidenib targeting IDH2 mutations); two oral hypomethylating agents (oral poorly absorbable azacitidine; fully absorbable decitabine-cedazuridine [latter approved as an alternative to parenteral hypomethylating agents in myelodysplastic syndrome and chronic myelomonocytic leukemia but commonly used in AML]); and CPX-351 (encapsulated liposomal 5:1 molar ratio of cytarabine and daunorubicin), and glasdegib (hedgehog inhibitor). Other targeted therapies (menin inhibitors, CD123 antibody-drug conjugates) are showing promising results. To achieve optimal results in such a rare and heterogeneous entity as AML requires expertise, familiarity with this rare cancer, and the access to, and delivery of disparate therapies under rigorous supportive care conditions. In this review, we update the standard-of-care and investigational therapies and outline promising current and future research directions.