Gilteritinib vs. Chemotherapy: A New Dawn for FLT3-Mutated AML Treatment

A The chemical structure of Gilteritinib

The treatment landscape for acute myeloid leukemia (AML) has seen a significant breakthrough with the advent of gilteritinib, a targeted therapy for FLT3-mutated AML. A pivotal study published in The New England Journal of Medicine (DOI: 10.1056/NEJMoa1902688) compared gilteritinib with salvage chemotherapy, presenting compelling evidence of its efficacy and safety. Here, we delve into the findings of this transformative trial and its implications for AML management.

Study Overview: The ADMIRAL Trial

The ADMIRAL study scheme

The ADMIRAL trial, a phase 3, multicenter, randomized study, aimed to assess whether gilteritinib could outperform traditional chemotherapy in patients with relapsed or refractory FLT3-mutated AML. Key details of the trial included:

  • Design: 371 patients randomized in a 2:1 ratio (gilteritinib:chemotherapy).
  • Interventions:
    • Gilteritinib: Administered orally at 120 mg/day.
    • Salvage chemotherapy: Four options, including high- and low-intensity regimens.
  • Primary Endpoints: Overall survival (OS) and complete remission (CR) rates.
  • Secondary Endpoints: Event-free survival (EFS), composite remission rates, and safety.

Key Findings

1. Survival Advantage

  • Median Overall Survival (OS):
    • Gilteritinib: 9.3 months
    • Chemotherapy: 5.6 months
    • Hazard Ratio (HR): 0.64 (p < 0.001)
  • Patients treated with gilteritinib had nearly double the 1-year survival rate compared to chemotherapy (37.1% vs. 16.7%).

2. Higher Remission Rates

  • Complete Remission (CR):
    • Gilteritinib: 21.1%
    • Chemotherapy: 10.5%
  • Composite Complete Remission (CCR) (includes partial hematologic recovery):
    • Gilteritinib: 34%
    • Chemotherapy: 15.3%

3. Superior Event-Free Survival (EFS)

  • Median EFS:
    • Gilteritinib: 2.8 months
    • Chemotherapy: 0.7 months

4. Safety and Tolerability

  • Gilteritinib demonstrated a lower incidence of serious adverse events (SAEs) than chemotherapy.
  • Common Grade ≥3 adverse events in the gilteritinib group included:
    • Febrile neutropenia: 45.9%
    • Anemia: 40.7%
    • Thrombocytopenia: 22.8%
  • Hepatic toxicity signals (e.g., elevated liver enzymes) were noted but manageable.

Mechanistic Insights

Gilteritinib is a potent FLT3 inhibitor with activity against both:

  1. FLT3-ITD (Internal Tandem Duplication): Associated with aggressive AML phenotypes.
  2. FLT3-TKD (Tyrosine Kinase Domain Mutations): A common resistance mechanism to earlier FLT3 inhibitors.

Additionally, gilteritinib inhibits AXL kinase, a mediator of FLT3 inhibitor resistance, enhancing its therapeutic potential.

Clinical Implications

The results of the ADMIRAL trial underscore the paradigm shift in AML treatment, particularly for patients with relapsed or refractory disease:

  • Improved Outcomes: Gilteritinib offers better survival and remission rates than salvage chemotherapy, which has historically been the standard of care.
  • Transplantation Bridge: A higher proportion of patients in the gilteritinib group proceeded to hematopoietic stem cell transplantation (HSCT), a curative option for AML.
  • Reduced Toxicity: The lower toxicity profile of gilteritinib enhances patient quality of life during treatment.

Limitations and Future Directions

While the ADMIRAL trial demonstrated clear benefits, challenges remain:

  1. Resistance Mechanisms: Secondary mutations (e.g., RAS pathway activation) may limit long-term efficacy.
  2. First-Line Integration: Studies exploring gilteritinib in newly diagnosed AML (e.g., NCT02927262) will clarify its role in upfront therapy.
  3. Combination Strategies: Combining gilteritinib with other agents, such as hypomethylating drugs or immunotherapies, may further improve outcomes.


Conclusion

Gilteritinib represents a monumental step forward in the fight against FLT3-mutated AML, providing hope for a population historically faced with limited options. The ADMIRAL trial has firmly established its role as the preferred therapy in the relapsed/refractory setting, paving the way for more targeted, effective, and patient-centric approaches in AML treatment.