1. Lohr, Lisa PharmD, BCPS, BCOP

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What is enasidenib?

Enasidenib is an oral small molecule inhibitor of IHD2 (isocitrate dehydrogenase 2).


How does enasidenib work?

IHD2 mutations are seen in about 12 percent (8-19%) of patients with acute myeloid leukemia (AML), which lead to the accumulation of 2-hydroxyglutarate, an oncometabolite that blocks cellular differentiation in the myeloid line. Enasidenib blocks the mutated enzymes, which allows for myeloblast differentiation.


What is this approved for?

Enasidenib was approved by the FDA in August 2017 for the treatment of relapsed/refractory AML with a documented IDH2 mutation as detected by an FDA-approved test.


What is the basis for this approval?

Enasidenib was studied in patients with refractory or relapsed AML with an IDH2 mutation in a non-comparative phase I/II trial. In the dose-escalation phase, 113 patients were given enasidenib in BID doses of 30-150 mg and in once-daily doses of 50-650 mg. The maximum tolerated dose was not reached in this dose range. In the phase II intention-to-treat analysis, 126 patients were treated with 100 mg once daily of enasidenib.


The most common grade 3 or 4 treatment-emergent adverse effects were hyperbilirubinemia, IDH-differentiation syndrome, anemia, thrombocytopenia, and tumor lysis syndrome. The overall response rate was 38.5 percent in those treated with 100 mg daily.


The complete remission (CR) rate was 20.2 percent, another 6.4 percent had CR with incomplete hematologic recovery, partial remission in 2.8 percent, stable disease in 53.2 percent, and progressive disease in 4.6 percent. The median time to first response was 1.9 months, with a range of 0.5-9.4 months. The duration of response was 5.6 months, with a range of 3.8-9.7 months, and the duration in those achieving a CR was 8.8 months, ranging from 5.3 months, but had not been reached at the time of the analysis (Blood 2017;130:722-731).


How do you administer this drug?

Enasidenib is given orally once daily with or without food. The normal starting dose is 100 mg orally once daily. As the onset may be delayed, it is recommended to treat for at least 6 months, in the absence of progression or intolerable side effect.


Are there any premedications needed?

No. Although nausea is seen in some patients, most patients will not require antiemetics before administration.


What are the common side effects associated with enasidenib (>= 10%)?


* Hypocalcemia, hypokalemia, hypophosphatemia


* Nausea, diarrhea, decreased appetite, vomiting, dysgeusia


* Differentiation syndrome, noninfectious leukocytosis


* Hyperbilirubinemia (due to inhibition of UGT1A1)


What are the uncommon side effects associated with enasidenib (>= 10%)?

Tumor lysis syndrome, acute respiratory distress, and pulmonary edema.


Are there any important drug interactions I should be aware of?

There are no significant drug-drug interactions identified at this time.


How do I adjust the dose in the setting of renal or hepatic insufficiency?

No dosing adjustments are required for renal or hepatic impairment, as there isn't a significant effect on enasidenib levels. Patients who develop hyperbilirubinemia greater than 3 times the upper limit of normal for greater than 2 weeks without elevated transaminases will require a dose reduction to 50 mg daily. The dose may be increased back to 100 mg daily if the bilirubin resolves to less than 2 times the upper limit of normal.


Practical tips

Enasidenib is available in 50 mg and 100 mg tablets. The dose should be held or adjusted for differentiation syndrome, noninfectious leukocytosis, hyperbilirubinemia, or other grade 3 or higher adverse effect.


What should my patients know about enasidenib?

Patients should report symptoms of differentiation syndrome immediately. Signs and symptoms of differentiation syndrome include fever, dyspnea, acute respiratory distress, rapid weight gain, or peripheral edema.


What else should I know about enasidenib?

Enasidenib may cause fetal harm. Females of reproductive capacity should use effective contraception during treatment and for at least 1 month after, and a negative pregnancy test should be obtained before treatment. Males with female partners should also use effective contraception.


Differentiation syndrome, similar to that seen with tretinoin, was seen in about 14 percent of patients. Onset can be as early as 10 days after starting or as late as 5 months after starting enasidenib. Treatment with dexamethasone and close monitoring is necessary. Further information is contained in the prescribing information.


Less commonly, tumor lysis syndrome has occurred. Appropriate monitoring is recommended.


What useful links are available regarding enasidenib?


* Highlights of prescribing information:


* FDA drug approval information:


Any ongoing clinical trials related to enasidenib?

Enasidenib is being studied primarily in patients with AML/MDS with IDH2 mutations in settings including: 1) maintenance treatment after stem cell transplant; 2) with azacitidine in relapsed/refractory AML; and 3) in combination with induction/consolidation treatment for newly diagnosed AML/MDS. More information is available about the clinical trials at


LISA LOHR, PHARMD, BCPS, BCOP, is Oncology Clinical Pharmacy Specialist at the Masonic Cancer Clinic, University of Minnesota Health/Fairview, Minneapolis. JANELLE E. MANN, PHARMD, BCOP, is an Ambulatory Clinical Oncology Pharmacist, Washington University School of Medicine, Alvin J. Siteman Cancer Center, St. Louis, Mo., and serves as the Pharmacy Forum column editor. RAMASWAMY GOVINDAN, MD, Professor of Medicine; Anheuser Busch Chair in Medical Oncology; Director, Section of Medical Oncology, Division of Oncology, Washington University School of Medicine, serves as the Pharmacy Forum column physician advisor.

Lisa Lohr, PharmD, B... - Click to enlarge in new windowLisa Lohr, PharmD, BCPS, BCOP. Lisa Lohr, PharmD, BCPS, BCOP
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