Safety of FLT3 inhibitors in patients with acute myeloid leukemia

ABSTRACT

Introduction: Acute myeloblastic leukemia (AML) is the most frequent type of acute leukemia in adults with an incidence of 4.2 cases per 100,000 inhabitants and poor 5-year survival. Patients with mutations in the FMS-like tyrosine kinase 3 (FLT3) gene have poor survival and higher relapse rates compared with wild-type cases.

Areas covered: Several FLT3 inhibitors have been proved in FLT3^mut AML patients, with differences in their pharmacokinetics, kinase inhibitory and adverse events profiles. First-generation multi-kinase inhibitors (midostaurin, sorafenib, lestaurtinib) target multiple proteins, whereassecond-generation inhibitors (crenolanib, quizartinib, gilteritinib) are more specific and potent inhibitors of FLT3, so they are associated with less off-target toxic effects. All of these drugs have primary and acquired mechanisms of resistance, and therefore their combinations with other drugs (checkpoint inhibitors, hypomethylating agents, standard chemotherapy) and its application in different clinical settings are under study.

Expert opinion: The recent clinical development of various FLT3 inhibitors for the treatment of FLT3^mut AML is an effective therapeutic strategy. However, there are unique toxicities and drug–drug interactions that need to be resolved. It is necessary to understand the mechanisms of toxicity in order to recognize and manage them adequately.

KEYWORDS:

• Acute myeloblastic leukemia (AML)
• FMS-like tyrosine kinase 3 (FLT3)
• midostaurin
• crenolanib
• gilteritinib
• quizartinib
• sorafenib

Article highlights

• The recent clinical development of various FLT3 inhibitors for the treatment of FLT3^mut AML has proved to be an effective therapeutic strategy in different clinical settings.

• FLT3 inhibitors have particular toxicities that require specific management.

• Antifungal prophylaxis deserves special attention in patients treated with midostaurin and other FLT3 inhibitors due to their metabolic interactions with azole drugs (such as posaconazole, the standard of care antifungal agent used as prophylaxis in AML patients).

• More studies need to be carried out in order to understand the exact role of the FLT3 inhibitors in the different clinical settings of AML, as well as their possible association with other new drugs.

Declaration of interest

The authors have 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.

Author contributions

Andrés Peleteiro, Claudio Cerchione and Adrián Mosquera Orgueira has given substantial contributions to the organization and revision of the manuscript, contributing to the review of FLT3 inhibitors toxicity, mechanism of action, management and usefulness in their different AML clinical setting explained in the expert opinion and writing the conclusions, Alicia Mosquera Torre to the contribution of information and revision of the section about pharmacology of FLT3 inhibitors, Laura Bao Pérez, Manuel Mateo Pérez Encinas and Giovanni Martinelli to the revision of the final version of the manuscript. All authors read and approved the final version of the manuscript.

Additional information

Funding

This paper was not funded.