An evaluation of enasidenib for the treatment of acute myeloid leukemia

ABSTRACT

Introduction: Despite recent progress, the prognosis of acute myeloid leukemia remains poor, mainly in older and in relapsed/refractory patients. Recently, a large number of novel agents have been developed thanks to a better understanding of its pathogenesis. Among these, the potent inhibitor of the isocitrate dehydrogenase-2 (IDH2) mutant protein, enasidenib (formerly AG-221), has demonstrated promising antileukemic activity by targeting IDH2 mutations.

Area covered: This review describes the mechanisms of action, the pharmacodynamic and pharmacokinetic properties, the safety, and efficacy of enasidenib. Phase I/II/III clinical trials are also reported and discussed.

Expert opinion: Enasidenib is a novel agent able to differentiate leukemic blasts in functional, maturating cells. This drug is characterized by oral bioavailability and good tolerability. As a monotherapy, it demonstrates clinical and laboratorial improvement, in 19.6% and 38.8% of cases respectively. Differentiation syndrome is the most relevant, potentially life-threatening side effect, which physicians must be aware of. The authors believe that the way forwards now is to explore the role of enasidenib as a chemoresistance revertant when associated with chemotherapy, as a ‘bridge to transplant’ or when associated other novel agents if we wish to maximize its use.

KEYWORDS:

• Acute myeloid leukemia
• isocitrate dehydrogenase-2 mutation
• enasidenib
• differentiation syndrome
• novel target therapy

Article highlights

• Enasidenib is a first in class oral, selective, inhibitor of the mutant isocitrate dehydrogenase-2 (IDH2) enzymes recently approved for the treatment of adult patients with relapsed/refractory mutant IDH2-acute myeloid leukemia.

• Enasidenib acts as a differentiation and not cytotoxic agent, being able to differentiate leukemic blasts in functional, maturating cells.

• Enasidenib has hypomethylating agents-like epigenetic effects and could require several treatment cycles to induce a response. Therefore, it is important to continue therapy for at least 6 months or until progression or intolerable toxicity.

• This novel agent is safe and well tolerated. The most serious adverse event, IDH-inhibitor-associated differentiation syndrome, occurs in 12% of treated patients.

• The best use of enasidenib seems to be in combination with chemotherapy or agents with other mechanism of action to better control side effects and to reduce the onset of 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 manuscript was not funded.