Drug-drug interactions associated with FLT3 inhibitors for acute myeloblastic leukemia: current landscape

ABSTRACT

Introduction

FLT3 inhibitors (FLT3i) are drugs in which there is limited experience and not yet enough information on the mechanisms of absorption, transport, and elimination; but especially on the potential drug-drug interactions (DDIs). There are therefore risks in the management of FLT3i DDIs (i.e. sorafenib, ponatinib, crenolanib, midostaurin, quizartinib, and gilteritinib) and ignoring them can compromise therapeutic success in acute myeloid leukemia (AML) treatment, in complex patients and secondary pathologies.

Areas covered

This review summarizes the DDIs of FLT3i with P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporting (OAT), organic cationic transporting (OCT), cytochrome P450 (CYP) subunits, and other minor metabolic/transport pathways. EMBASE, PubMed, the Cochrane Central Register and the Web of Science were searched. The last literature search was performed on the 14 February 2022.

Expert opinion

FLT3i will be combined with other therapeutic agents (supportive care, doublet, or triplet therapy) and in different clinical settings, which means a greater chance of controlling and even eradicating the disease effectively, but also an increased risk to patients due to potential DDIs. Healthcare professionals should be aware of the potential interactions that may occur and be vigilant in monitoring those patients who are receiving any potentially interacting drug.

KEYWORDS:

• FLT3 inhibitors
• drug-drug interactions
• midostaurin
• gilteritinib
• quizartinib
• sorafenib
• ponatinib
• crenolanib

Article highlights

• QT interval prolongation in patients with FLT3i is a priority AEs.

• Cirrhosis and cancer might cause a decrease in glucuronidation that is unaccounted by in vitro studies or by studies involving healthy volunteers alone and might affect in potential DDIs.

• Levels of FLT3i in plasma may be measured and could be useful for identifying patients with unusually plasma drug concentrations.

• Inhibition of a transporter or enzyme could be compensated by an alternative pathway and might not impact the pharmacokinetic parameters.

• Aerosolized liposomal amphotericin B combined with oral fluconazole or echinocandins could be implemented for invasive fungal infection prophylaxis as an alternative to posaconazole or voriconazole, but this should be restricted only for cases with tolerability issues.

• To avoid potential DDIs of FLT3i with tacrolimus or corticosteroids, an alternative and prophylactic therapy for patients with GVHD could be post-transplantation cyclophosphamide with sirolimus and mycophenolate mofetil as immunosuppressive drugs.

• FLT3i will be combined with other therapeutic agents (supportive care, and doublet or triplet therapy) and in different clinical settings.

Declaration of interest

P Montesinos reports these potential conflicts of interest, AbbVie: advisory board, speakers bureau, research support; Astellas: research support, consultant, speakers bureau, advisory board; Agios: consultant; Tolero Pharmaceutical: consultant; Glycomimetics: consultant; Forma Therapeutics: consultant; Celgene: research support, consultant, speakers bureau, advisory board; Daiichi Sankyo: research support, consultant, speakers bureau, advisory board; Incyte: speakers bureau, advisory board; Janssen: research support, speakers bureau, advisory board; Karyopharm: research support, advisory board; Novartis: research support, speakers bureau, advisory board; Pfizer: research support, speakers bureau, advisory board; Teva: research support, speakers bureau, advisory board. 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

A reviewer on this manuscript has disclosed that they own a patent on FLT3 inhibitors. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Author contributions

Substantial contributions to study conception and design: A Solana-Altabella, JE Megías-Vericat, P Montesinos; substantial contributions to analysis and interpretation of the data: A Solana-Altabella, JE Megías-Vericat, O Ballesta-López, P Montesinos; drafting the article or revising it critically for important intellectual content: A Solana-Altabella, JE Megías-Vericat, O Ballesta-López, D Martínez-Cuadrón, P Montesinos; final approval of the version of the article to be published: A Solana-Altabella, JE Megías-Vericat, O Ballesta-López, D Martínez-Cuadrón, P Montesinos.

Additional information

Funding

This paper was funded in part by a grant (2019-052-1) from the Instituto de Investigación Sanitaria La Fe (IISLAFE).