Management of Acute Myeloid Leukemia (AML) Associated with FLT3-ITD Gene Alterations
For AML patients with FLT3 mutations, treatment should include FLT3 inhibitors such as midostaurin or gilteritinib in combination with standard chemotherapy regimens to improve survival outcomes. 1
Initial Assessment and Risk Stratification
Before initiating treatment, comprehensive molecular testing is essential:
- Flow cytometry characterization of bone marrow blasts
- Standard cytogenetics on bone marrow cells
- Molecular analysis for FLT3 mutations and other prognostic markers (NPM1, CEBPA)
- HLA typing for patients who may be eligible for allogeneic stem cell transplantation
FLT3 mutations are associated with higher relapse rates and poorer overall survival, making them critical for treatment planning.
Treatment Approach for FLT3-Mutated AML
Induction Therapy
- First-line regimen: Standard "7+3" chemotherapy (cytarabine 100-200 mg/m² continuous IV infusion for 7 days plus an anthracycline for 3 days) combined with midostaurin 50 mg twice daily on days 8-21 2, 1
- Midostaurin significantly improves overall survival in newly diagnosed FLT3-mutated AML patients
- Alternative for patients ≥60 years with secondary AML: CPX-351 (liposomal formulation of daunorubicin and cytarabine) 1
Post-Remission/Consolidation Therapy
- High-dose cytarabine plus midostaurin for 3-4 cycles 1
- Allogeneic stem cell transplantation should be strongly considered in first complete remission for FLT3-mutated patients due to high relapse risk 2, 1
- Maintenance therapy with FLT3 inhibitors post-transplant may reduce relapse risk
Relapsed/Refractory Disease
- Gilteritinib (FLT3 inhibitor) is the preferred agent for relapsed/refractory FLT3-mutated AML 1, 3
- Consider clinical trials with novel FLT3 inhibitors or combination approaches
- For patients who received HMAs in induction, maintenance therapy with HMAs may be appropriate 2
Lower-Intensity Options for Unfit Patients
- Venetoclax plus hypomethylating agent (azacitidine or decitabine) combined with FLT3 inhibitor
- Venetoclax plus low-dose cytarabine with FLT3 inhibitor
- Hypomethylating agents combined with sorafenib for FLT3-mutated AML 2
Monitoring and Response Assessment
- Bone marrow evaluation 14-21 days after induction therapy
- Molecular monitoring of FLT3 mutation status to detect early relapse
- Regular assessment for FLT3 inhibitor-related toxicities:
- QT prolongation (gilteritinib)
- Myelosuppression
- Gastrointestinal toxicities
Important Considerations and Pitfalls
- Rapid molecular testing: FLT3 testing results should be expedited to guide timely initiation of targeted therapy
- Clonal evolution: FLT3 mutation status can change at relapse, necessitating repeat testing
- Drug interactions: FLT3 inhibitors interact with many medications through CYP3A4; careful medication review is essential
- Resistance mechanisms: Secondary mutations in the FLT3 kinase domain can emerge during treatment
- Transplant timing: Don't delay allogeneic transplantation in eligible patients who achieve remission
Special Populations
- Elderly patients: Consider comorbidities and performance status when selecting therapy intensity
- Secondary AML: CPX-351 may be preferred for induction in patients with therapy-related AML or AML with myelodysplasia-related changes 1
FLT3 mutations represent one of the most important actionable targets in AML, and incorporation of FLT3 inhibitors has significantly improved outcomes for this historically poor-prognosis subgroup.