Background
Phase 3, open-label, randomized controlled trial (QuANTUM-R). N=245 patients with R/R FLT3-ITD-positive AML who had received 1–2 prior therapies, including a FLT3 inhibitor in first-line induction (approximately half had received midostaurin with 7+3). Quizartinib is a highly potent, selective FLT3 inhibitor with greater FLT3-ITD potency than midostaurin or sorafenib, but is inactive against FLT3-TKD (D835) point mutations. This is the registrational phase 3 trial supporting FDA approval of quizartinib monotherapy in R/R FLT3-ITD AML. Randomized 2:1 quizartinib vs salvage chemotherapy (SC). Published Lancet Oncology 2019.
Interventions and follow up
Arm A: Quizartinib 60 mg PO once daily on days 1–28 of each 28-day cycle until progression or allo-SCT
Arm B: Salvage chemotherapy — investigator's choice: low-dose cytarabine (LDAC), azacitidine, MEC (mitoxantrone + etoposide + cytarabine), or FLAG-Ida (fludarabine + cytarabine + granulocyte CSF + idarubicin)
Primary endpoint: OS
mFollow up: 23.5 month
Arm B: Salvage chemotherapy — investigator's choice: low-dose cytarabine (LDAC), azacitidine, MEC (mitoxantrone + etoposide + cytarabine), or FLAG-Ida (fludarabine + cytarabine + granulocyte CSF + idarubicin)
Primary endpoint: OS
mFollow up: 23.5 month
Results
mOS: 6.2 vs 4.7 months (quizartinib vs SC), HR 0.76 (95% CI 0.58–0.98), P=.02
CR+CRi+CRp rate: 48% (quizartinib) vs 27% (SC)
Bridge to allo-SCT: 32% vs 12%
mOS (patients proceeding to allo-SCT): Not reached (quizartinib) vs 11.2 months (SC)
D835 mutation (FLT3-TKD): Resistance to quizartinib — pre-treatment testing recommended
CR+CRi+CRp rate: 48% (quizartinib) vs 27% (SC)
Bridge to allo-SCT: 32% vs 12%
mOS (patients proceeding to allo-SCT): Not reached (quizartinib) vs 11.2 months (SC)
D835 mutation (FLT3-TKD): Resistance to quizartinib — pre-treatment testing recommended
Adverse events
Overall: Grade ≥3 AEs 88% (quizartinib) vs 77% (SC); discontinuation due to AEs 9.7% vs 6.3%.
Cardiac: QTc prolongation grade ≥3 5.7% — ECG at baseline and during treatment; avoid QT-prolonging drugs.
Hematologic: Anemia grade ≥3 38%, thrombocytopenia 33%, neutropenia 36%.
Infectious: Febrile neutropenia grade ≥3 26% vs 38%.
Gastrointestinal: Nausea 27%, diarrhea 18% — mostly grade 1–2. Differentiation syndrome rare (<1%).
Cardiac: QTc prolongation grade ≥3 5.7% — ECG at baseline and during treatment; avoid QT-prolonging drugs.
Hematologic: Anemia grade ≥3 38%, thrombocytopenia 33%, neutropenia 36%.
Infectious: Febrile neutropenia grade ≥3 26% vs 38%.
Gastrointestinal: Nausea 27%, diarrhea 18% — mostly grade 1–2. Differentiation syndrome rare (<1%).
Conclusions
Quizartinib significantly improved OS versus salvage chemotherapy in R/R FLT3-ITD AML (HR 0.76, P=.02), with higher composite remission rates (48% vs 27%) and greater ability to bridge patients to allo-SCT (32% vs 12%). It represents the preferred option for R/R FLT3-ITD AML and a critical bridge to potentially curative transplantation.
Key Limitations
Modest absolute OS benefit (mOS 6.2 vs 4.7 months, HR 0.76) reflects the historically poor prognosis of R/R FLT3-ITD AML. QTc prolongation requires ECG monitoring and caution with concurrent QT-prolonging medications and electrolyte abnormalities. Quizartinib does not cover FLT3-TKD (D835) point mutations — these confer primary resistance and require gilteritinib (ADMIRAL). Prior FLT3 inhibitor exposure (midostaurin from RATIFY) was present in ~50% of patients — quizartinib remains active post-midostaurin but resistance mutations emerge rapidly. Long-term benefit concentrated in patients reaching allo-SCT. Gilteritinib (ADMIRAL) is an active alternative with activity against both FLT3-ITD and FLT3-TKD.
Clinical Context
FDA approved quizartinib (Vanflyta) for R/R FLT3-ITD-positive AML in June 2023. QuANTUM-First established quizartinib as the preferred frontline FLT3 inhibitor + 7+3 (over midostaurin), and QuANTUM-R established quizartinib in R/R. Gilteritinib (ADMIRAL) has broader coverage (ITD + TKD) and is an alternative; choice between quizartinib and gilteritinib in R/R may depend on mutational profile and prior therapy. FLT3 allelic ratio and co-mutations (NPM1, DNMT3A) influence prognosis. ESMO-MCBS: not assigned.