Advancing treatment of acute myeloid leukemia: the future of FLT3 inhibitors

ABSTRACT

Introduction: Mutations of the FLT3 gene are among most common genetic abnormalities occurring in acute myeloid leukemia (AML) and are associated with dismal prognosis. Tremendous effort has been devoted to developing clinically effective FLT3 inhibitors. First generation inhibitors consisted of multi-kinase inhibitors (sorafenib, lestaurtinib, midostaurin), which blocked FLT3 as well as multiple other kinase receptors. The failure of these agents to induce durable responses led to the development of second generation FLT3 tyrosine kinase inhibitors (quizartinib, crenolinib, gilteritinib) exhibiting high potency and specificity for mutant FLT3 kinases and sustained in vivo FLT3 inhibition. These myriad FLT3 inhibitors possess diverse kinase inhibitory properties, toxicity profiles, and pharmacokinetics, which impact on their incorporation into therapeutic regimens.

Areas covered: This article reviews the medical literature on current and future FLT3 inhibitors for AML therapy. We provide algorithms for which kinase inhibitor should be utilized for different FLT3 mutations (ITD±TKD) and clinical scenarios (de novo, relapsed/refractory, fit vs. unfit) and discuss novel FLT3 targeted therapeutic approaches.

Expert commentary: Integration of clinically active FLT3 inhibitors into all stages of therapy for all individuals with FLT3 mutant AML promises to significantly improve outcomes for this poor prognosis disease.

KEYWORDS:

• Acute myeloid leukemia
• FLT3 gene mutation
• kinase inhibition
• targeted therapy

Article Highlights

• FLT3 mutations are among the most common genetic abnormalities occurring in AML and are associated with poor prognosis with short disease-free and overall survival.

• FLT3 mutation testing should be performed on all AML samples at the time of diagnosis regardless of patient age or performance status.

• It is important to repeat FLT3-ITD or TKD mutation testing at all subsequent treatment decision points in every AML patient, regardless of FLT3 status at diagnosis.

• All fit patients with newly diagnosed FLT3 mutant AML should be treated with midostaurin in combination with cytarabine and daunorubicin induction chemotherapy and high dose cytarabine consolidation chemotherapy followed by allogeneic stem cell transplantation in first complete remission. Patients completing chemotherapy or allogeneic transplant should strongly consider clinical trials evaluating the potential benefit of maintenance FLT3 TKI for at least 12 months.

• Off label use of sorafenib in combination with decitabine or azacitidine has emerged as a treatment option for newly diagnosed FLT3 mutant AML patients unfit for standard induction chemotherapy.

• Patients with relapsed/refractory FLT3 mutant AML should preferentially be treated with second-generation highly specific FLT3 TKIs (quizartinib or gilteritinib) over multi-kinase FLT3 inhibitors (sorafenib, midostaurin) on clinical trial if possible.

• Future directions for FLT3 targeted therapies include novel combinations of FLT3 TKIs with other agents targeting other aspects of AML biology (bcl-2, mdm2) as well as immunotherapeutic approaches (bispecific antibodies, CAR T cells) targeting FLT3 expression on AML cells as a tumor antigen.

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Declaration of interest

E Wang has served on the advisory boards for Astellas, Arog Pharmaceuticals, and Daiichi Sancho, as well as acting as a speaker for Novartis. A Elshoury has served on the community advisory board for Daiichi Sancho. The authors have no other 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 apart from those disclosed.

Reviewer disclosures

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

Additional information

Funding

This manuscript has received funding from the National Institutes of Health, National Cancer Institute (P30CA016056) and the Roswell Park Alliance Foundation (Jacquie Hirsch Leukemia Research Fund).