The potential of triplet combination therapies for patients with FLT3-ITD -mutated acute myeloid leukemia

ABSTRACT

Introduction

Acute myeloid leukemia (AML) encompasses a heterogeneous group of aggressive myeloid malignancies, where FMS-like tyrosine kinase 3 (FLT3) mutations are prevalent, accounting for approximately 25–30% of adult patients. The presence of this mutation is related to a dismal prognosis and high relapse rates. In the lasts years many FLT3 inhibitors have been developed.

Areas covered

This review provides a comprehensive overview of FLT3^mut AML, summarizing the state of art of current treatment and available data about combination strategies including an FLT3 inhibitor.

Expert opinion

In addition, the review discusses the emergence of drug resistance and the need for a nuanced approaches in treating patients who are ineligible for or resistant to intensive chemotherapy. Specifically, it explores the historical context of FLT3 inhibitors (FLT3Is) and their impact on treatment outcomes, emphasizing the pivotal role of midostaurin, as well as gilteritinib and quizartinib, and providing detailed insights into ongoing trials exploring the safety and efficacy of novel triplet combinations involving FLT3Is in different AML settings.

KEYWORDS:

• Acute myeloid leukemia
• FLT3 mutation
• FLT3-ITD
• FLT3 inhibition
• triplet therapy in AML

Article highlights

• FLT3mut AML is characterized by poor prognosis and high relapse rates.

• FLT3 inhibitors (FLT3Is) have improved the outcomes of these patients.

• Several studies have tested the combination of FLT3Is with chemotherapy both in TN and RR patients.

• Limited data is now available about the addition of FLT3Is to non – intensive therapeutic strategies.

• Further studies are needed to understand which combinations are better in overcoming FLT3Is resistance.

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.

Additional information

Funding

This study is supported in part by Progetto Ricerca Finalizzata PNRR-MAD-2022-12375673 (Next Generation EU, M6/C2_CALL 2022), Italian Ministry of Health, Rome, Italy.