Clinical Overview of Quizartinib for Acute Myeloid Leukemia

On July 20, 2023, the FDA approved quizartinib (Vanflyta; Daiichi Sankyo, Inc) oral tablets for patients newly diagnosed with acute myeloid leukemia with a FLT3-ITD mutation.¹ Quizartinib is taken in combination with standard cytarabine and anthracycline induction and cytarabine consolidation and as maintenance monotherapy following consolidation.²

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Quizartinib has an FDA boxed warning for QT prolongation, torsades de pointes, and cardiac arrest and is available only through a risk evaluation and mitigation strategy (REMS) program.^2,3 Providers and pharmacies must be certified through the quizartinib REMS program to treat patients with quizartinib and to dispense quizartinib. Eligible patients must have a QTc interval (corrected by the Fridericia formula [QTcF]) of 450 milliseconds or less with no evidence of severe hypokalemia, severe hypomagnesemia, long QT syndrome, or history of ventricular arrhythmias or torsades de pointes.⁴

Warnings and Precautions

QT Prolongation, Torsades de Pointes, Cardiac Arrest

Electrocardiograms must be conducted and serum electrolyte levels must be monitored while a patient is on quizartinib treatment. Quizartinib treatment may require dose reduction, therapy interruption, or permanent discontinuation as appropriate. Quizartinib shall not be initiated in patients with hypokalemia, severe hypomagnesemia, or long QT syndrome, or in patients with a history of ventricular arrhythmias or torsades de pointes.²

Embryo-Fetal Toxicity

Quizartinib can cause fetal harm in patients who are pregnant, and pregnant women should be informed of potential risks to the fetus while taking quizartinib. Effective contraception must be used during quizartinib treatment for 7 months after the last dose. Male patients who have female partners of reproductive potential must be instructed to use effective contraception during quizartinib treatment and for 4 months after the last dose.²

Mechanism of Action

Quizartinib is a selective small-molecule inhibitor of the tyrosine kinase receptor FLT3. Quizartinib and its active metabolite work by binding to the adenosine triphosphate binding domain of FLT3 with comparable affinity. This prevents autophosphorylation of the receptor, therefore inhibiting downstream FLT3 receptor signaling, which blocks FLT3-ITD–dependent cell proliferation.²

Dosage and Administration

Quizartinib is indicated only in patients undergoing induction and consolidation in combination with cytarabine and anthracycline, and high-dose cytarabine, respectively. A treatment course of quizartinib consists of up to 2 cycles of quizartinib with induction cytarabine and anthracycline, up to 4 cycles of quizartinib with high-dose cytarabine consolidation, and up to 36 cycles of quizartinib as maintenance therapy. Quizartinib oral tablets are available in 2 different strengths: 17.7 mg and 26.5 mg.²

Dosing

During induction, quizartinib 35.4 mg is given once daily on days 8 to 21 of the 28-day induction cycle. Quizartinib is administered in combination with cytarabine and anthracycline (7+3 regimen, per the American Cancer Society, this regimen involves giving cytarabine continuously for 7 days along with short infusions of an anthracycline on each of the first 3 days). If the patient continues to show evidence or has clinically significant residual leukemia, then a second induction cycle is indicated. In the second induction cycle, quizartinib 35.4 mg is given once daily on days 8 to 21 in combination with cytarabine and anthracycline (7+3 regimen). Another option is to give quizartinib 35.4 mg on days 6 to 19 in combination with cytarabine and anthracycline (5+2 regimen) of the 28-day cycle. During consolidation, quizartinib 35.4 mg is given once daily on days 6 to 19 of each 28-day consolidation cycle in combination with highdose cytarabine for up to 4 cycles.²

Lastly, in cycle 1 of the maintenance phase, quizartinib is initiated at 26.5 mg once daily on days 1 to 14 of cycle if the QTcF is 450 milliseconds or less. Quizartinib may be increased to 53 mg once daily on days 15 to 28 of a 28-day maintenance cycle if QTcF remains 450 milliseconds or less. Notably, if QTcF is more than 500 milliseconds during induction or consolidation, a dose of 26.5 mg once daily should be maintained. For cycles 2 and beyond, quizartinib should be administered with 26.5 mg or 53 mg once daily on days 1 to 28 of each 28-day maintenance cycle for up to 36 cycles as determined in cycle 1 of maintenance. Quizartinib must be discontinued 7 days prior to hematopoietic cell transplantation for patients proceeding to that regimen.²

Administration

Quizartinib should be taken orally with or without food around the same time each day. Tablets should be swallowed whole and should not be cut, crushed, or chewed. If a dose of quizartinib is vomited, a replacement dose should not be taken and the patient should continue with next scheduled dose.²

Missed Doses

If a dose of quizartinib is missed, that dose should be taken by the patient as soon as possible on the same day; following this, the patient can resume normal scheduling for doses. However, doubling doses on the same day should never occur.²

Drug Interactions

Quizartinib is a major substrate of CYP3A4, resulting in a number of drug interactions with strong CYP3A inhibitors and strong or moderate CYP3A inducers. Additionally, quizartinib should be carefully monitored with other QT interval–prolonging drugs due to the added prolonging effect.²

Strong CYP3A Inhibitors

Concomitant use with strong CYP3A inhibitors and quizartinib may increase the risk of quizartinib adverse reactions. Dose adjustments are recommended for patients on quizartinib with concomitant use of a strong CYP3A inhibitor.² The dosage adjustments are as follows²:

Current and modified dosages for patients on quizartinib and a strong CYP3A inhibitor.

If the patient’s current dosage is 17.7 mg once daily, quizartinib should be interrupted for the duration of the strong CYP3A inhibitor use. Once the CYP3A inhibitor is discontinued for at least 5 half-lives, quizartinib may be resumed at the dose prior to starting the CYP3A inhibitor. Examples of strong CYP3A inhibitors include but not are limited to clarithromycin (Biaxin; Abbott Pharmaceuticals); cobicistat (Tybost; Gilead Sciences); darunavir (Prezista; Janssen Therapeutics); itraconazole; ketoconazole; lonafarnib (Zokinvy; Eiger BioPharmaceuticals); posaconazole (Noxafil; Endo International plc); ritonavir (Norvir; AbbVie); tucatinib (Tukysa; Seagen); and voriconazole (Vfend; Pfizer).²

Strong or Moderate CYP3A Inducers

Concomitant use of other strong or moderate CYP3A inducers with quizartinib may decrease systemic exposure to quizartinib, which may reduce its efficacy. The use of strong or moderate CYP3A inducers should be avoided in patients taking quizartinib.²

Examples of strong or moderate CYP3A inducers include but are not limited to the following²:

• Strong: apalutamide; carbamazepine; enzalutamide (Xtandi; Astellas Pharma); lumacaftor; lumacaftor/ivacaftor (Orkambi; Vertex Pharmaceuticals Incorporated); phenobarbital; phenytoin; primidone (Mysoline; Bausch Health Companies); and rifampin (Rifadin; Sanofi)
• Moderate: bosentan (Tracleer; Actelion Pharmaceuticals US); dabrafenib (Tafinlar; Novartis); dexamethasone; elagolix (Orilissa; AbbVie); estradiol; norethindrone; lorlatinib (Lorbrena; Pfizer); modafinil (Provigil; Cephalon); nafcillin; rifabutin (Mycobutin; Pfizer); rifapentine (Priftin; Sanofi); sotorasib; and St John’s wort

QT Interval–Prolonging Drugs

Quizartinib has been shown to prolong the QT/QTc interval. Coadministration of quizartinib with other agents that prolong the QT/QTc interval may further increase the risk.²

Examples of QT interval–prolonging medications include but are not limited to antifungal azoles; atovaquone (Mepron; GSK); azithromycin; doxycycline; granisetron; moxifloxacin; ondansetron; pentamidine; prochlorperazine (Compro; Padagis US LLC); and tacrolimus.²

Important Patient Counseling

Patients must be informed of the potential risks associated with the use of quizartinib (eg, QT prolongation, torsades de pointes, and cardiac arrest) and be advised to report any dizziness, lightheadedness, and fainting to their providers. Patients should also be encouraged to report the use of all medications, including OTC medications and herbal supplements, to anyone involved in their care to ensure potential drug interactions are accounted for.²

Inform patients that quizartinib is available only through the quizartinib REMS program and instruct them to carry around the provided patient wallet card at all times. This card should be presented to all their health care providers, as it describes the possible signs and symptoms related to QT prolongation.²

References

1. FDA approves quizartinib for newly diagnosed acute myeloid leukemia. FDA. July 20, 2023. Accessed September 26, 2023. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approvesquizartinib-newly-diagnosed-acute-myeloidleukemia

2. Vanflyta. Prescribing information. Daiichi Sankyo, Inc; 2023. Accessed September 26, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/216993s000lbl.pdf

3. Vanflyta risk evaluation and mitigation strategy (REMS). Daiichi Sankyo. Accessed September 26, 2023. https://www.vanflytarems.com/#Main

4. Stutsky M, Lindner C. The challenge of financial toxicity in cancer care: a focus on oral oncology. Shields Health Solutions. October 5, 2023. Accessed January 4, 2024. https://www.shieldshealthsolutions.com/wp-content/uploads/2023/10/Shields_WP_2023_OncologyFinTox_10.5.23.pdf

About the Author

Katelynn Tran, PharmD, BCPS, is a clinical pharmacist at Samaritan Health Services.