Enasidenib (Idhifa): Targeted treatment for relapsed or refractory AML

Enasidenib (Idhifa): Targeted treatment for relapsed or refractory AML

Last Updated on August 3, 2017 by Joseph Gut – thasso

August 02, 2017 – This is another cornerstone in the fight against acute myeloid leukemia (AML): The American Food and Drug Administration (FDA) just approved Enasidenib (Idhifa) for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) who have a specific genetic mutation. The drug is approved for

Chemical structure of Enasidenib (Idhifa)

use with a companion diagnostic, the RealTime IDH2 Assay, which is used to detect specific mutations in the IDH2 gene in patients with AML.

According to Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, “Enasidenib (Idhifa) is a targeted therapy that fills an unmet need for patients with relapsed or refractory AML who have an IDH2 mutation. Thus, the use of Enasidenib (Idhifa) was associated with a complete remission in some patients and a reduction in the need for both red cell and platelet transfusions”.


AML is a rapidly progressing cancer that forms in the bone marrow and results in an increased number of abnormal white blood cells in the bloodstream and bone marrow. The National Cancer Institute at the National Institutes of Health estimates that approximately 21,380 people will be diagnosed with AML this year; approximately 10,590 patients with AML will die of the disease in 2017.

Enasidenib (Idhifa) is an isocitrate dehydrogenase-2 inhibitor that works by blocking several enzymes that promote cell growth. If the IDH2 mutation is detected in blood or bone marrow samples using the RealTime IDH2 Assay, the patient may be eligible for treatment with Enasidenib (Idhifa).

The efficacy of Enasidenib (Idhifa) was studied in a single-arm trial of 199 patients with relapsed or refractory AML who had IDH2 mutations as detected by the RealTime IDH2 Assay. The trial measured the percentage of patients with no evidence of disease and full recovery of blood counts after treatment (complete remission (CR)), as well as patients with no evidence of disease and partial recovery of blood counts after treatment (complete remission with partial hematologic recovery (CRh)). With a minimum of six months of treatment, 19 percent of patients experienced CR for a median 8.2 months, and 4 percent of patients experienced CRh for a median 9.6 months. Of the 157 patients who required transfusions of blood or platelets due to AML at the start of the study, 34 percent no longer required transfusions after treatment with Enasidenib (Idhifa).

Common side effects of Enasidenib (Idhifa) include nausea, vomiting, diarrhea, increased levels of bilirubin (substance found in bile) and decreased appetite. Women who are pregnant or breastfeeding should not take Enasidenib (Idhifa) because it may cause harm to a developing fetus or a newborn baby.

The prescribing information for Enasidenib (Idhifa) includes a boxed warning that an adverse reaction known as differentiation syndrome can occur and can be fatal if not treated. Sign and symptoms of differentiation syndrome may include fever, difficulty breathing (dyspnea), acute respiratory distress, inflammation in the lungs (radiographic pulmonary infiltrates), fluid around the lungs or heart (pleural or pericardial effusions), rapid weight gain, swelling (peripheral edema) or liver (hepatic), kidney (renal) or multi-organ dysfunction. At first suspicion of symptoms, doctors should treat patients with corticosteroids and monitor patients closely until symptoms go away.

Enasidenib (Idhifa) was granted Priority Review designation, under which the FDA’s goal is to take action on an application within six months where the agency determines that the drug, if approved, would significantly improve the safety or effectiveness of treating, diagnosing or preventing a serious condition. Enasidenib (Idhifa) also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

A cautionary word is justified here: The fact that Enasidenib (Idhifa) comes with a boxed warning, the highest level of warning used by the FDA to alert  healthcare providers and patients alike about a very serious health adverse effect, differentiation syndrome in the present case, indicates that this may pose, in clinical practice, a serious limitation on the use of Enasidenib (Idhifa), even in patients that qualify for the targeted therapy with Enasidenib (Idhifa). For patients, it is important to know that the terms “targeted therapy” or “personalized medicine” or similars do not exclude the possibility that a patient may experience serious, sometimes even fatal adverse drug reactions. Enasidenib (Idhifa) is no exception to this observation, and only time will reveal the true spectrum of clinical behaviour of Enasidenib (Idhifa) when in real clinical practice many more than the 199 patients included in the above cited clinical studies are being treated with Enasidenib (Idhifa).

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Ph.D.; Professor in Pharmacology and Toxicology. Senior expert in theragenomic and personalized medicine and individualized drug safety. Senior expert in pharmaco- and toxicogenetics. Senior expert in human safety of drugs, chemicals, environmental pollutants, and dietary ingredients.