Quizartinib in FLT3-ITD-Positive Acute Myeloid Leukemia
Quizartinib is a highly potent and selective FLT3 inhibitor approved for treating FLT3-ITD-positive AML in two distinct settings: as combination therapy with chemotherapy for newly diagnosed patients, and as monotherapy for relapsed/refractory disease, with demonstrated survival benefits in both contexts. 1, 2
Mechanism and Pharmacology
Quizartinib is a second-generation type II FLT3 tyrosine kinase inhibitor that binds to the ATP binding domain of FLT3, preventing autophosphorylation and blocking downstream signaling pathways (RAS/RAF/MEK, MAPK/ERK, PI3K/AKT/mTOR, and JAK/STAT5). 2, 3 The drug achieves steady-state concentrations by day 15 with once-daily dosing, has 71% oral bioavailability, and exhibits an effective half-life of 81 hours during maintenance therapy. 2
First-Line Treatment (Newly Diagnosed FLT3-ITD-Positive AML)
For adults aged 18-75 years with newly diagnosed FLT3-ITD-positive AML, quizartinib should be combined with standard 7+3 induction chemotherapy (cytarabine plus anthracycline), continued through consolidation, and maintained as monotherapy for up to 3 years. 1, 4
Dosing Regimen for Newly Diagnosed Disease
- Induction: 35.4 mg orally once daily starting on day 8 of chemotherapy, continuing for 14 days 2
- Consolidation: 35.4 mg orally once daily starting on day 8, continuing for 14 days with each cycle 2
- Maintenance: 53 mg orally once daily for up to 3 years (but not after allogeneic HCT in the United States) 2
Efficacy in Newly Diagnosed Patients
The QuANTUM-First trial demonstrated that quizartinib plus chemotherapy significantly improved overall survival compared to placebo plus chemotherapy (median OS 31.9 months vs 15.1 months; HR 0.78,95% CI 0.62-0.98, p=0.032). 4 This survival benefit was maintained even when patients proceeded to allogeneic hematopoietic cell transplantation. 4
Relapsed/Refractory FLT3-ITD-Positive AML
For patients with relapsed or refractory FLT3-ITD-positive AML, quizartinib monotherapy provides a survival benefit over salvage chemotherapy, though gilteritinib is preferred when available based on superior overall survival data. 5
Comparative Efficacy in Relapsed/Refractory Disease
Quizartinib monotherapy showed a survival benefit in relapsed/refractory FLT3-ITD-mutated patients (median OS 6.2 months vs 4.7 months with chemotherapy), though this was less robust than gilteritinib's benefit (median OS 9.3 months vs 5.6 months). 5 The composite complete remission rate with quizartinib monotherapy was 56% in FLT3-ITD-positive patients aged ≥60 years with early relapse, and 46% in those with relapse after salvage therapy or transplant. 6
Dosing for Relapsed/Refractory Disease
The approved dose for relapsed/refractory disease is 60 mg orally once daily (based on QuANTUM-R trial), though earlier phase 2 studies used sex-based dosing (135 mg/day for men, 90 mg/day for women). 5, 6
Post-Transplant Relapse
For patients with FLT3-mutated AML relapsing after allogeneic HCT, both quizartinib and gilteritinib show encouraging results as monotherapy, with the potential to bridge patients to a second allogeneic HCT or donor lymphocyte infusion. 5 This represents a critical treatment option for a population with otherwise dismal prognosis, particularly for those relapsing later than 5 months post-transplant. 5
Safety Profile and Monitoring Requirements
Common Adverse Events
The most frequent adverse events with quizartinib are infectious complications and QT prolongation. 5
Infectious complications:
- Sepsis/septic shock: 19% (grade 3-5) 5
- Pneumonia: 12% (grade 3 or higher: 9-13%) 5
- Febrile neutropenia: 37-41% (grade 3-4) 5
Cardiac toxicity:
- QTcF prolongation (grade 3): 3-4% of patients 5
- Median QTcF prolongation: 18-24 ms at therapeutic doses 2
- One case of torsades de pointes reported in phase 2 studies 6
Critical Monitoring and Management
Monitor ECG at baseline, on days 8 and 15 of cycle 1, and regularly thereafter; avoid concomitant QT-prolonging medications and maintain electrolytes (potassium, magnesium) within normal limits. 2 The drug should be held if QTcF exceeds 500 ms or increases >60 ms from baseline. 2
Antimicrobial Prophylaxis Recommendations
No specific antimicrobial prophylaxis is required when quizartinib is given as monotherapy; standard of care prophylaxis should be applied when combined with intensive chemotherapy. 5 Standard neutropenic fever protocols apply for diagnostic workup and treatment of infections. 5
Drug Interactions
Avoid strong CYP3A4 inhibitors (azole antifungals, clarithromycin, protease inhibitors) and strong CYP3A4 inducers (rifampin) due to significant alterations in quizartinib exposure. 5 If azole antifungals are necessary, close monitoring for QT prolongation is essential, though alternative antifungal agents should be considered when possible. 5
Dose Modifications
No dose adjustment is required for mild-to-moderate renal impairment (CrCl 30-89 mL/min) or mild-to-moderate hepatic impairment (Child-Pugh A or B). 2 The drug has not been studied in severe renal impairment (CrCl <30 mL/min) or severe hepatic impairment (Child-Pugh C). 2
Regulatory Status and Clinical Context
Quizartinib is approved in the United States, Japan, Europe, and United Kingdom for newly diagnosed FLT3-ITD-positive AML in combination with chemotherapy. 1, 3 For relapsed/refractory disease, it is approved only in Japan, while gilteritinib holds broader approval and is generally preferred in this setting based on superior survival data. 5 The European Medicines Agency has not approved quizartinib for relapsed/refractory disease despite demonstrated survival benefit. 5
Resistance Mechanisms
Resistance to quizartinib typically develops through on-target FLT3 kinase domain mutations (particularly D835 and F691 mutations) or activation of alternative signaling pathways. 3 This underscores the importance of combination strategies and sequential use of different FLT3 inhibitors with distinct resistance profiles. 3