quizartinib
Regulatory sources consulted
Approved indications
- In adults with newly diagnosed FLT3-ITD-positive acute myeloid leukemia, in combination with standard cytarabine and anthracycline induction, cytarabine consolidation, and then as maintenance monotherapy.
Contraindications
Absolute
- Hypersensitivity to quizartinib or its excipients.
- Congenital long-QT syndrome.
- CIMA profile: breastfeeding.
- FDA profile: severe hypokalemia, severe hypomagnesemia, or a history of ventricular arrhythmias or torsades de pointes.
Clinical warnings
- Boxed warning · BOXED WARNING: it prolongs QT in a dose- and concentration-dependent manner, and torsades de pointes and cardiac arrest have occurred. Correct potassium and magnesium before and during treatment; obtain a baseline ECG and weekly ECGs during induction and consolidation, and during maintenance before starting, weekly for the first month after initiation and dose escalation, and thereafter as clinically indicated. — DailyMed, VANFLYTA set_id 29cdbcfe-497d-4e78-bb7b-2d4acafe8e86
- Major warning · Closely monitor infections, especially in patients older than 65 during induction; fatal infections occurred more often in this group. — CIMA/AEMPS, ficha técnica VANFLYTA 1231768002
Drug interactions
- HighStrong CYP3A inhibitors
Mechanism: They nearly double quizartinib exposure and increase toxicity and QT-prolongation risk.
Recommendation: Avoid if possible; if unavoidable, apply the specific dose reduction and intensify ECG monitoring.
CIMA/AEMPS, ficha técnica VANFLYTA 1231768002https://cima.aemps.es/cima/dochtml/ft/1231768002/FT_1231768002.html
- HighStrong or moderate CYP3A inducers
Mechanism: They markedly reduce exposure and may decrease efficacy.
Recommendation: Avoid the combination, including St John’s wort.
CIMA/AEMPS, ficha técnica VANFLYTA 1231768002https://cima.aemps.es/cima/dochtml/ft/1231768002/FT_1231768002.html
- HighQT-prolonging medicines
Mechanism: They may increase the incidence of QT prolongation and ventricular arrhythmias.
Recommendation: Avoid if possible; if required, correct electrolytes and perform ECGs more frequently.
DailyMed, VANFLYTA set_id 29cdbcfe-497d-4e78-bb7b-2d4acafe8e86https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=29cdbcfe-497d-4e78-bb7b-2d4acafe8e86
- ModerateBCRP substrates
Mechanism: Quizartinib may increase their exposure.
Recommendation: Avoid narrow-therapeutic-index substrates when possible; if combined, monitor toxicity and reduce the substrate as appropriate.
CIMA/AEMPS, ficha técnica VANFLYTA 1231768002https://cima.aemps.es/cima/dochtml/ft/1231768002/FT_1231768002.html
Adverse events
Common (≥1%)
increased ALT · thrombocytopenia · anemia · diarrhea · nausea · abdominal pain · headache · vomiting · neutropenia
Rare but serious
cardiac arrest · ventricular fibrillation
Pregnancy and lactation
It can cause embryo-fetal harm. Verify pregnancy within 7 days before starting. Females must use effective contraception during treatment and for 7 months afterward; males with partners who can become pregnant must use it during treatment and for 4 months afterward. It should not be used during pregnancy unless clinically necessary. Do not breastfeed during treatment or for at least 5 weeks afterward.
Recent literature (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.