What is the recommended treatment approach for a patient with acute myeloid leukemia (AML) and a FMS-like tyrosine kinase 3 (FLT3) mutation?

Treatment Overview for FLT3-Mutated Acute Myeloid Leukemia

Risk Stratification and Prognostic Significance

FLT3 mutations occur in 25-30% of AML patients and confer intermediate to adverse risk, with FLT3-ITD (internal tandem duplication) affecting 19-25% of patients and FLT3-TKD (tyrosine kinase domain) mutations affecting 7-10%. 1, 2, 3 The presence of FLT3-ITD mutation is associated with higher relapse rates and poorer overall survival compared to FLT3-wildtype AML. 1, 2

• FLT3-ITD mutations are more common (19-25% of cases) and typically confer worse prognosis than FLT3-TKD mutations (7-10% of cases). 1, 2
• Both mutation types are more frequent in cytogenetically normal AML. 1
• The allelic ratio of FLT3-ITD (high versus low) further stratifies risk, with high allelic ratios indicating worse outcomes. 4

Treatment Approach for Fit Patients Eligible for Intensive Therapy

For newly diagnosed FLT3-mutated AML patients who are candidates for intensive chemotherapy, the standard of care is cytarabine and daunorubicin induction (7+3 regimen) combined with midostaurin 50 mg orally twice daily on days 8-21 of each induction and consolidation cycle. 1, 5, 6

Induction Therapy

• Administer standard-dose cytarabine (100-200 mg/m² continuous infusion for 7 days) combined with daunorubicin (60-90 mg/m² for 3 days). 1, 5, 7
• Add midostaurin 50 mg orally twice daily with food on days 8-21 of induction, which improves 4-year overall survival by 7.1% to 51.4%. 5, 6
• Midostaurin is FDA-approved specifically for FLT3-mutated AML and must be used in combination with chemotherapy, not as single-agent therapy. 6
• Perform bone marrow evaluation 14-21 days after start of therapy to assess response. 1

Reinduction for Residual Disease

• For patients with residual disease without hypoplasia after initial induction, administer additional standard-dose cytarabine with daunorubicin and midostaurin. 1
• If daunorubicin 90 mg/m² was used in induction, reduce the reinduction dose to 45 mg/m² for no more than 2 doses. 1

Consolidation Therapy

• Continue midostaurin 50 mg orally twice daily on days 8-21 of each consolidation cycle with high-dose cytarabine. 1, 6
• For intermediate-risk FLT3-mutated AML (which includes most FLT3-ITD cases), proceed to allogeneic hematopoietic cell transplantation (alloHCT) with HLA-matched sibling or unrelated donor if available. 5, 4
• AlloHCT in first complete remission is recommended for FLT3-mutated AML due to high relapse risk without transplantation. 1
• Identify potential donors early and aim to start conditioning within 4-6 weeks from start of induction therapy. 1

Treatment for Older or Unfit Patients

For patients aged ≥60 years or those not candidates for intensive chemotherapy, hypomethylating agents (HMAs) alone or in combination with sorafenib are recommended. 1

• Administer azacitidine or decitabine as monotherapy, or combine with sorafenib (an FLT3 inhibitor). 1
• In a phase II study, azacitidine combined with sorafenib achieved a 46% response rate in relapsed/refractory FLT3-mutated AML, with CR/CRi rates of 43%. 1
• Venetoclax combined with HMAs (azacitidine, decitabine, or low-dose cytarabine) is an alternative option for patients declining or unable to tolerate intensive therapy. 1
• For newly diagnosed FLT3-mutated AML in older patients, azacitidine combined with gilteritinib achieved a CR/CRi rate of 67% in early trials. 1

Relapsed or Refractory FLT3-Mutated AML

For relapsed or refractory FLT3-mutated AML, gilteritinib monotherapy is superior to salvage chemotherapy and is the preferred treatment. 8

• Gilteritinib, a highly specific second-generation FLT3 inhibitor, demonstrated significantly longer overall survival compared to salvage chemotherapy in the ADMIRAL trial. 8
• Gilteritinib is generally well tolerated but requires monitoring for myelosuppression, QTc prolongation, and differentiation syndrome. 8, 9
• Differentiation syndrome can occur early (even after a single dose) and may be severe, requiring prompt steroid therapy or steroid pulse therapy with additional chemotherapy if initial steroids are ineffective. 9
• After achieving second remission with gilteritinib or salvage chemotherapy, proceed to alloHCT if feasible. 1

Post-Transplant Maintenance

Post-transplant maintenance therapy with FLT3 inhibitors can reduce relapse risk after allogeneic HCT. 1, 2

• Consider FLT3 inhibitor maintenance therapy following alloHCT to prevent relapse, though optimal duration and agent selection remain areas of ongoing investigation. 1
• Sorafenib and midostaurin have been studied in the post-transplant setting. 1

Monitoring and Follow-Up

• Perform bone marrow morphology every 3 months for 24 months and differential blood counts every 3 months for 5 years after treatment. 5, 4
• Assess measurable residual disease (MRD) after 2 cycles of chemotherapy and at end of treatment. 5
• Monitor for FLT3 mutation status at relapse, as resistance mechanisms may emerge during FLT3 inhibitor therapy. 3, 10

Critical Considerations and Resistance Mechanisms

• FLT3 inhibitor resistance can develop through FLT3-dependent mechanisms (secondary FLT3 mutations) or FLT3-independent mechanisms (activation of alternative signaling pathways). 3, 10
• Midostaurin is not indicated as single-agent induction therapy and must be combined with chemotherapy. 6
• Avoid strong CYP3A4 inducers with midostaurin as they decrease drug exposure; consider alternative therapies or monitor closely if strong CYP3A4 inhibitors are necessary. 6
• Clinical trial enrollment should be considered whenever possible, particularly for novel FLT3 inhibitor combinations or strategies to overcome resistance. 1, 2