Highlight
– The phase II randomized, double‑blind QUIWI trial (n=273) tested quizartinib 60 mg daily added to standard induction and consolidation chemotherapy followed by maintenance in adults (18–70 years) with newly diagnosed FLT3‑ITD–negative AML.
– Median event‑free survival (EFS) was 20.4 months with quizartinib vs 9.9 months with placebo (P = .046). Median overall survival (OS) was not reached with quizartinib vs 29.3 months with placebo (P = .012); 3‑year OS rates were 60.8% vs 45.7%.
Background and clinical context
Acute myeloid leukemia (AML) is a genomically heterogeneous hematologic malignancy in which FLT3 mutations—most commonly internal tandem duplications (ITD)—define a biologically and clinically important subgroup. Historically, FLT3‑ITD has been associated with higher relapse risk and poorer outcomes, and the development of FLT3 inhibitors has altered the therapeutic landscape. Midostaurin improved survival when added to induction and consolidation chemotherapy in FLT3‑mutated AML in the phase III RATIFY trial, establishing the model of combining FLT3 inhibitors with standard cytotoxic therapy.
Quizartinib is an oral second‑generation, type II FLT3 inhibitor with high affinity for FLT3‑ITD and activity against FLT3 wild‑type (WT). While trial programs have primarily emphasized FLT3‑ITD‑positive disease given the clear pathogenic role of ITD mutations, preclinical and early clinical evidence suggested quizartinib might have activity in subsets of patients without detectable FLT3‑ITD—either by inhibiting FLT3‑WT signaling, targeting occult or low‑allelic‑ratio mutations, or through effects on leukemic subclones.
Study design
QUIWI was a multicenter, randomized, double‑blind, placebo‑controlled phase II trial enrolling adults 18–70 years with newly diagnosed FLT3‑ITD–negative AML. FLT3‑ITD negativity was defined stringently as a mutant‑to‑wild‑type allelic ratio of <0.03. Participants were randomized 2:1 to receive either quizartinib 60 mg once daily or matching placebo in combination with standard induction (cytarabine + anthracycline) and consolidation chemotherapy. Patients who achieved response received single‑agent maintenance therapy with quizartinib or placebo thereafter. The primary endpoint was event‑free survival (EFS); secondary endpoints included overall survival (OS) and safety/tolerability. The trial enrolled 273 patients (quizartinib n = 180; placebo n = 93).
Key findings
Primary efficacy
At data cutoff, median EFS was 20.4 months in the quizartinib arm versus 9.9 months in the placebo arm (P = .046), meeting the study’s primary efficacy signal for improved EFS with quizartinib added to standard chemotherapy in FLT3‑ITD–negative AML.
Overall survival
Median OS was not reached for patients randomized to quizartinib and was 29.3 months in the placebo arm (P = .012). Estimated 3‑year OS rates were 60.8% with quizartinib versus 45.7% with placebo, suggesting a clinically meaningful survival advantage.
Response and durability
The publication reports superior time‑to‑event outcomes (EFS, OS) with quizartinib but does not provide detailed breakdowns in this summary for complete remission (CR) rates, CR durations, or relapse incidence. The EFS and OS benefits suggest that quizartinib either increased initial disease control, prolonged remission, or both, potentially augmented by post‑remission maintenance therapy.
Safety and tolerability
The most frequently reported adverse events of any grade in the quizartinib arm were fever, rash, diarrhea, and mucositis. The report summarized overall tolerability as consistent with prior experience combining FLT3 inhibitors with cytotoxic chemotherapy. Notably, quizartinib has been associated with QT interval prolongation in earlier studies; while the QUIWI summary lists common toxicities, clinicians should consult the full manuscript for detailed safety tables, rates of grade 3–4 events, dose modifications, treatment discontinuations, and cardiac monitoring results.
Effect sizes, statistical considerations
The trial demonstrated statistically significant improvements in both the primary endpoint (EFS) and a key secondary endpoint (OS) with P values of .046 and .012, respectively. The absolute difference in median EFS was approximately 10.5 months, and the absolute 3‑year OS improvement was 15.1 percentage points favoring quizartinib. Hazard ratios and confidence intervals are not reported in the summary provided here; these should be reviewed in the full publication to assess the magnitude and precision of effect and to evaluate proportional hazards assumptions.
Interpretation and biological plausibility
The finding that a FLT3 inhibitor improved outcomes in patients categorized as FLT3‑ITD–negative is biologically and clinically intriguing. Possible explanations include:
- Inhibition of wild‑type FLT3 signaling in leukemic cells that rely on FLT3 pathway activation despite lack of a detectable ITD at the sensitivity threshold used.
- Suppression of subclonal or low‑allelic‑ratio FLT3 mutations below the predefined cutoff (mutant‑to‑WT allelic ratio <0.03), which may still contribute to disease biology and relapse risk.
- Off‑target effects of quizartinib or broader impacts on leukemic progenitor populations that complement chemotherapy.
These hypotheses require correlative molecular studies (deep sequencing, single‑cell genomics) to determine whether particular molecular subgroups derived disproportionate benefit and to explore mechanisms of resistance.
Expert commentary and limitations
Strengths of QUIWI include randomized double‑blind design, contemporaneous control arm, and clinically meaningful endpoints. The positive EFS and OS outcomes support the concept that FLT3 inhibition may have therapeutic value beyond conventionally defined FLT3‑ITD–positive disease in selected settings.
However, several limitations temper immediate clinical adoption:
- Phase II design: The study provides hypothesis‑generating randomized evidence but lacks the size and confirmatory power of a large phase III study to establish practice‑changing certainty.
- Patient selection: The trial enrolled adults 18–70 years; outcomes may not generalize to older patients who constitute a large proportion of newly diagnosed AML cases.
- FLT3‑ITD negativity definition: The allelic ratio cutoff (<0.03) is strict; whether benefits apply to truly FLT3‑WT disease across different assay sensitivities requires scrutiny. Deep sequencing might reveal low‑level mutations not captured by routine assays.
- Safety details: The summary lists common adverse events but lacks granular presentation of serious cardiac events (QTc prolongation), treatment discontinuations, or treatment‑related mortality. Prior quizartinib programs reported QTc concerns and dose‑dependent toxicities that mandate ECG monitoring and management guidelines.
- Mechanistic uncertainty: Without correlative biomarker analyses, the population(s) driving benefit remain uncertain, complicating patient selection and cost‑effectiveness considerations.
Clinicians should therefore view QUIWI as compelling phase II evidence that requires confirmatory validation and integration with molecular profiling strategies to identify patients most likely to benefit.
Clinical implications and next steps
If replicated in a larger confirmatory trial, the QUIWI results could expand the indication of quizartinib (or other potent FLT3 inhibitors) to a broader population of newly diagnosed AML patients who are classified as FLT3‑ITD–negative by conventional assays. Practical implications would include routine consideration of FLT3 pathway inhibition during induction/consolidation and maintenance in selected patients, with standardized cardiac monitoring protocols and molecular correlative testing to refine selection.
Key next steps include:
- Publication and close review of the full trial report, including hazard ratios, subgroup analyses, and detailed safety data.
- Correlative genomic and pharmacodynamic analyses to identify molecular predictors of benefit and mechanisms of resistance.
- Confirmation in larger phase III studies or pooled analyses to corroborate survival benefits and inform guideline updates.
- Assessment of real‑world feasibility, including ECG monitoring, drug–drug interactions, and implementation of maintenance strategies.
Conclusion
The phase II QUIWI study provides randomized, double‑blind evidence that adding quizartinib 60 mg daily to standard chemotherapy and as maintenance significantly improved event‑free and overall survival in adults 18–70 years with newly diagnosed FLT3‑ITD–negative AML. The results are hypothesis‑generating and clinically important, suggesting that potent FLT3 inhibition may benefit some patients who do not meet conventional definitions of FLT3‑ITD positivity. Confirmation in larger, definitive trials and integration of molecular correlative work are needed before routine adoption. Meanwhile, clinicians should review the full publication for detailed safety data and consider quizartinib within clinical trial frameworks and multidisciplinary decision making.
Funding and clinicaltrials.gov
Funding sources and trial registration details are reported in the original J Clin Oncol publication (Montesinos et al., J Clin Oncol. 2025). For full disclosure, consulting the published manuscript is recommended to review sponsor, funding, and clinicaltrials.gov identifier(s).
References
1. Montesinos P, Rodríguez‑Veiga R, Bergua JM, et al.; PETHEMA Group. Quizartinib for Newly Diagnosed FLT3‑Internal Tandem Duplication‑Negative AML: The Randomized, Double‑Blind, Placebo‑Controlled, Phase II QUIWI Study. J Clin Oncol. 2025 Oct 13:JCO2501841. doi: 10.1200/JCO-25-01841. Epub ahead of print. Erratum in: J Clin Oncol. 2025 Dec 1:JCO2502762. doi: 10.1200/JCO-25-02762. PMID: 41082703.
2. Stone RM, Mandrekar SJ, Sanford BL, et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017;377(5):454‑464. doi:10.1056/NEJMoa1614359.
3. Döhner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129(4):424‑447. doi:10.1182/blood-2016-08-733196.