On August 1, 2017, the U.S. Food and Drug Administration (FDA) approved a new drug for acute myeloid leukemia (AML) – -It is an oral drug for the treatment of AML. It is an oral drug for the treatment of acute myeloid leukemia in patients with isocitrate dehydrogenase-2 (IDH2) mutations who have relapsed or are refractory to at least 1 prior systemic antitumor therapy.
In parallel, the FDA approved the real-time IDH2 test (manufactured by Abbott) as a companion diagnostic to screen patients with AML for treatment with enasidenib by detecting IDH2 gene-specific mutations in blood or bone marrow samples from patients with AML.
Enasidenib is the only approved small-molecule targeted agent for IDH2 that has been granted Fast Track and Priority Review designation by the FDA and has also received Orphan Drug Designation.
What is relapsed or refractory AML?
AML is a rapidly progressive cancer that results in a large number of abnormal white blood cells in the patient’s blood and bone marrow. Acute myeloid leukemia is also the most common form of acute leukemia in adults. For adult patients younger than 60 years of age, the standard treatment for AML is erythromycin combined with cytarabine (also known as 7+3) induction chemotherapy, followed by consolidation chemotherapy, autologous hematopoietic stem cell transplantation (Auto HSCT), and allogeneic hematopoietic stem cell transplantation (Allo-HSCT) after complete remission is achieved.
However, 10% to 20% of all patients with AML have no remission at all after initial therapy, and this group of patients is called refractory AML. And among patients who are effective with initial treatment and achieve complete remission, 50% to 80% of cancers also recur. Once refractory or relapse has occurred, there is essentially no prior treatment and patients have limited survival time.
What is enasidenib?
IDH2 mutations are present in 9% to 13% of AML patients. The mutated IDH2 protein forms 2-hydroxyglutaric acid, which leads to DNA and histone hypermethylation, resulting in impaired cell differentiation. This also means that the mutation inhibits normal blood cell development, leading to an excess of immature blood cells.
On the other hand, wild-type IDH in normal humans is involved in energy metabolism. Therefore, if IDH2 is to be used as a therapeutic target, then the drugs targeting this target must be well selective, otherwise serious side effects can occur.
Enasidenib is a small-molecule, orally targeted drug that not only inhibits the action of IDH2, but also blocks several other cell growth-promoting enzymes that promote cancer cell differentiation and exert anti-cancer effects. At the same time, enasidenib does not affect IDH wild type.
Evidence of efficacy: 19% complete remission, also reduced transfusion dependence
The approval of Enasidenib was based primarily on the results of a single-arm trial. The study included 199 adult patients with relapsed or refractory acute myeloid leukemia who carried the IDH2 mutation. After at least 6 months of treatment, 19% of patients achieved complete remission with a median remission time of 8.2 months, and 4% of patients experienced complete remission with partial hematologic recovery with a median survival time of 19.7 months. Complete remission (CR) is defined as no detectable leukemic cells and complete return to normal blood counts after treatment. Complete remission with partial hematologic recovery (CRh) is defined as no detectable leukemia cells, but some blood counts (or just platelet counts) have not returned to normal levels.
At the start of treatment, 34% of the 157 patients who required blood or platelet transfusions because of acute myeloid leukemia no longer required transfusions after enasidenib treatment.
Black box warning: be wary of fractionation syndrome
Common adverse reactions to Enasidenib include nausea, vomiting, diarrhea, elevated bilirubin levels, and decreased appetite. Women who are pregnant or breastfeeding should not take enasidenib because it may cause harm to the fetus or newborn.
It is important to note that the instructions for enasidenib include a black box warning that the drug may cause the lethal differentiation syndrome, also known as isocitrate The FDA requires physicians to use glucocorticoids as soon as symptoms of differentiation syndrome are detected. The FDA requires physicians to treat with glucocorticoids as soon as symptoms of differentiation syndrome are detected and to monitor the patient’s condition closely.
How to use enasidenib?
According to the approved product insert, the recommended use and dosage of enasidenib is as follows:
- Recommended dose: The starting dose is 100 mg orally once a day for 6 months if the drug is tolerated.
- Blood tests and biochemistry are required prior to dosing and at least once every 2 weeks for the first 3 months of treatment.
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enasidenib has not yet been approved by the State Food and Drug Administration, but eight IDH inhibitors, including this drug, have been marketed abroad, and more targeted drugs may emerge in the future to replace traditional chemotherapy and bring better outcomes to patients.