Ivosidenib in acute myeloid leukemia

ABSTRACT

Introduction

Traditional treatment strategies for acute myeloid leukemia (AML) have primarily relied on standard chemotherapy regimens for four decades. Indeed, the landscape of AML therapy has evolved substantially in recent years, mainly due to the introduction of hypomethylating agents and small molecules.

Bcl2 inhibitor venetoclax, Fms-like tyrosine kinase 3 (FLT3) inhibitors such as midostaurin and gilteritinib, and isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2) inhibitors ivosidenib and enasidenib, as well as hedgehog (HH) pathway inhibitor glasdegib represented a significant step forward in AML therapeutic armamentarium. Smoothened (SMO) inhibitor in combination with low-dose cytarabine marks a recent milestone.

Areas covered

Ivosidenib, the first-in-class, selective, allosteric IDH1R132 inhibitor, showed the capability to induce in vitro differentiation of primary mIDH1 AML blasts. Clinical data highlighted its exceptional safety profile, as a standalone therapy and in combination strategy. Additionally, comprehensive studies consistently demonstrated its effectiveness, both in monotherapy and in association with chemotherapy.

Expert opinion

The identified ivosidenib’s strengths, including its remarkable safety record and ability to yield positive therapeutic outcomes, position it as an ideal partner for both classic chemotherapy and biological treatments, i.e. hypometilant agents and/or venetoclax. Further studies are warranted to explore strategies for overcoming the occurrence of ivosidenib resistance.

KEYWORDS:

• Ivosidenib
• AML
• biologic therapies
• IDH1 mutation
• precision medicine

Article highlights

• The landscape of AML treatment is continuously evolving, driven by the advent of new biological drugs.

• Ivosidenib (formerly AG120), a first-in-class, selective, allosteric IDH1R132 inhibitor, induces in vitro differentiation of primary mIDH1 AML cells.

• Several clinical studies have provided substantial evidence of ivosidenib’s efficacy in controlling AML, coupled with a worthy safety profile. Presently, the American Food and Drugs Administration (FDA) has granted ivosidenib’s use in relapsed or refractory (R/R) and treatment-naive (TN) AML patients. Moreover, the European Medicine Agency (EMA) has recently approved ivosidenib for TN IDH1 mutated AML cases in association with azacitidine.

• These approvals underscore ivosidenib’s importance as a viable and valuable option in the treatment arsenal against AML.

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

The present 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.