Gilteritinib for the treatment of patients with FLT3 mutated relapsed or refractory acute myeloid leukemia

ABSTRACT

Introduction: FLT3 mutations are identified in 20–30% of acute myeloid leukemia (AML) and are associated with a poor prognosis due to chemotherapy refractory disease and short relapse-free survival. Numerous FLT3 tyrosine kinase inhibitors have been evaluated. The first FLT3 inhibitor approved for therapy of FLT3 mutant relapsed/refractory AML (RR-AML) is gilteritinib.

Areas covered: We discuss how gilteritinib represents the next generation of FLT3 tyrosine kinase inhibitors with highly potent and specific activity against FLT3 activating mutations (ITD and TKD) found in AML. We review how gilteritinib differs from prior FLT3 inhibitors, which exhibited broad-spectrum kinase activity but poor in vivo pharmacokinetics, off-target toxicities, and no clinically meaningful single agent responses. We discuss clinical trial results demonstrating the safety and improved clinical activity of gilteritinib over standard chemotherapy in FLT3 mutant RR-AML patients. Lastly, we discuss ongoing trials of gilteritinib with chemotherapy and other targeted approaches.

Expert opinion: Gilteritinib represents the next generation of FLT3 inhibitors for AML therapy. Upfront regimens incorporating this agent are likely to become the new standard of care for FLT3 mutant de novo AML, and newer combinations hold promise to further transform the therapeutic landscape for this AML subset in the near future.

KEYWORDS:

• Gilteritinib
• FLT3 inhibitor
• acute myeloid leukemia

Article highlights

• FLT3 mutations (both ITD and TKD) should be performed at the time of refractory and/or relapsed AML disease, particularly in patients with unknown or prior known FLT3 mutations at diagnosis.

• Individuals identified to have FLT3 ITD and TKD mutations at the time of relapsed/refractory AML should be considered for treatment with gilteritinib dosed at 120 mg orally daily instead of salvage chemotherapy therapy with intensive (such as FLAG-Ida, MEC) or non-intensive (LDAC, azacitidine or decitabine) regimens.

• Gilteritinib monotherapy is well tolerated and results in clear clinical benefit with 49-54% overall response rates and 21% complete remission rates in patients with FLT3 mutant RR-AML.

• Patients achieving remission were eligible for subsequent potentially curative allogeneic stem cell transplant, which resulted in the greatest long-term remission. Responding patients independent of subsequent transplant lived for several months on therapy.

• Combinatorial regimens of gilteritinib with both intensive (cytarabine and anthracycline-based) and non-intensive (azacitidine) chemotherapy approaches have preliminarily yielded high response rates with no significant adverse events of concern in newly diagnosed FLT3 mutant AML patients with variable performance status. These regimens have the potential to become the future standard of care for these patients in the near future.

Declaration of interest

ES Wang has received funds for participating in speaker bureaus for Jazz Pharmaceuticals, Astellas and Novartis and advisory boards for Pfizer, Amgen, Agios, and Celyad. The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported by a National Cancer Institute (NCI) grant to Roswell Park Comprehensive Cancer Center (P30CA016056) and Roswell Park Alliance Foundation (Jacquie Hirsch Leukemia Research Fund)(EW).