Idhifa (Enasidenib), First-in-Class IDH2 Inhibitor, Approved for Relapsed Acute Myeloid Leukemia with IDH2 Mutation

March 2018, Vol 11, Ninth Annual Payers' Guide - Select Drug Profiles, Payers' Guide
Loretta Fala
Medical Writer

Acute myeloid leukemia (AML) is a rapidly progressing cancer that develops in the myeloid cells of the bone marrow and travels into the blood, sometimes spreading to other parts of the body, including the lymph nodes, liver, brain, spinal cord, spleen, and testicles.1

A total of 21,380 new cases of AML were estimated to be diagnosed in the United States in 2017 and 10,590 patients to die from the disease.2 AML is a relatively rare disease that affects 4.2 individuals per 100,000 and is more common in men than in women. AML is most often diagnosed in people aged 65 years to 74 years; the median age at diagnosis is 68 years.2

Cytogenetic testing and genetic variation assessment via molecular analysis are vital risk stratification and prognostic tools for managing patients with AML.3 Mutations in the isocitrate dehydrogenase (IDH)2 gene are found in approximately 8% to 12% of patients with AML.4 The IDH2 mutation, one of several common genetic variants in AML, plays a role in the deregulation of gene expression associated with cancer development.5

Novel agents that target specific AML mutations are emerging to fill an unmet need, particularly for patients with relapsed or refractory disease who have a poor prognosis.6 One of these targeted therapies recently became available for appropriate patients with IDH2 mutation–positive AML.7

Idhifa Approved for Relapsed or Refractory AML with IDH2 Mutation

On August 1, 2017, the US Food and Drug Administration (FDA) approved enasidenib (Idhifa; Celgene), an IDH2 inhibitor that blocks key enzymes implicated in cell growth, for the treatment of adults with relapsed or refractory AML and an IDH2 gene mutation, as detected by an FDA-approved test.7,8 Enasidenib is the first IDH2 inhibitor approved by the FDA. The FDA granted enasidenib a priority review and an orphan drug designation.7,8

“AML is a complex, heterogeneous disease, which is particularly difficult to treat in the relapsed or refractory setting,” said Martin Tallman, MD, Hematologic Oncologist and Chief, Leukemia Service at Memorial Sloan Kettering Cancer Center. “IDH2 mutations inhibit the normal maturation of myeloid cells, so having a treatment that targets this mechanism is promising for patients and encouraging to us as physicians who have it as our goal to provide options for every patient,” added Dr Tallman.9

Mechanism of Action

Enasidenib, a small-molecule inhibitor of the IDH2 enzyme, targets and inhibits mutations in the IDH2 enzyme, leading to decreased 2-hydroxyglutarate (HG) levels and induced myeloid differentiation. In patients with IDH2 mutation–positive AML, enasidenib was shown to decrease 2-HG levels, reduce blast counts, and increase the volume of mature myeloid cells.8

Dosing and Administration

The recommended dose of enasidenib is 100 mg orally once daily until disease progression or until unacceptable toxicity.8 Enasidenib is available as a 50-mg or a 100-mg tablet for oral administration.8

Pivotal Clinical Trial

The efficacy of enasidenib was assessed in an open-­label, single-arm, 2-cohort study in patients with IDH2 mutation–positive AML.6,8 This study included 199 patients (101 in cohort 1 and 98 in cohort 2), ranging in age from 19 years to 100 years (median age, 68 years), who received a median of 2 previous anticancer therapies. Overall, 52% of the patients had disease refractory to previous therapy.8

The median follow-up was 6.6 months.8 The median time to first response for patients who achieved a complete remission or a complete remission with partial hematologic recovery was 1.9 months, and the median time to best response of complete remission or complete remission with partial hematologic recovery was 3.7 months.8

Overall, 46 (23%) patients achieved a best response of complete remission or complete remission with partial hematologic recovery; 39 (85%) of these patients achieved best responses within 6 months of initial treatment with enasidenib (Table).8 Enasidenib demonstrated a median complete remission of 8.2 months in 19% of patients, and a median complete remission with partial hematologic recovery of 9.6 months in 4% of patients, with a minimum of 6 months of treatment (Table).8


After treatment with enasidenib, 53 of the 157 (34%) patients who were dependent on red blood cell and/or platelet transfusions at baseline no longer required such transfusions during any 56-day postbaseline period.8

Adverse Reactions

The most common (≥20%) all-grade adverse reactions associated with enasidenib were elevated bilirubin levels (81%), nausea (50%), diarrhea (43%), vomiting (34%), and decreased appetite (34%).8 The most common (≥3%) grade ≥3 adverse reactions included nausea (5%), diarrhea (8%), decreased appetite (4%), tumor lysis syndrome (6%), differentiation syndrome (7%), and noninfectious leukocytosis (6%).

Enasidenib has no contraindications.8

Drug Interactions

In vitro studies suggest that enasidenib inhibits the activity of cytochrome (CY)P1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and UGT1A1. In addition, enasidenib inhibits P-glycoprotein, BCRP, OAT1, OATP1B1, OATP1B3, and OCT2. Enasidenib induces CYP2B6 and CYP3A4.

In vitro studies suggest that the metabolite AGI-16903 inhibits the activity of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6. AGI-16903 inhibits BCRP, OAT1, OAT3, OATP1B1, and OCT2. The coadministration of enasidenib may increase or decrease the concentrations of combined hormonal contraceptives.

Use in Specific Populations

No data are available regarding the effects of enasidenib on the breastfed infant or on milk production. Women should not breastfeed while receiving enasidenib and for at least 1 month after the last dose.8

Before starting enasidenib therapy, women of reproductive potential should have a pregnancy test; they should also be advised to avoid becoming pregnant while receiving enasidenib, and to use effective contraception during treatment and for at least 1 month after the last dose. Males with female partners of reproductive potential should use effective contraception during enasidenib treatment and for at least 1 month after the last dose.8

No dose adjustment is required for enasidenib based on the patient’s age. In clinical studies, no overall differences in the effectiveness or safety of enasidenib were observed between patients aged ≥65 years and younger patients.8

Warnings and Precautions

The prescribing information for enasidenib includes a boxed warning about the potential for differentiation syndrome in patients who receive enasidenib. Differentiation syndrome, a condition associated with rapid proliferation and differentiation of myeloid cells, can be life-threatening or fatal if not treated.8

Enasidenib can cause fetal harm when administered to a pregnant woman. Patients who are pregnant or may become pregnant while taking enasidenib should be advised of the potential risk to the fetus.8


The FDA approval of enasidenib marks the availability of the first-in-class, targeted IDH2 inhibitor for patients with difficult-to-treat relapsed or refractory IDH2 mutation–positive AML.7,9 Taken as a once-daily oral medication, enasidenib may provide appropriate patients with AML a practical treatment option.

1. American Cancer Society. What is acute myeloid leukemia? Accessed October 16, 2017.
2. National Cancer Institute. SEER cancer stat facts: acute myeloid leukemia (AML). Accessed September 12, 2017.
3. Seegmiller A, Jagasia M, Wheeler S, Vnencak-Jones CL. Molecular profiling of acute myeloid leukemia. My Cancer Genome. Updated January 26, 2016. Accessed September 18, 2017.
4. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Acute Myeloid Leukemia. Version 3.2017. June 6, 2017. Accessed September 18, 2017.
5. Wheeler S, Seegmiller A, Vnencak-Jones C; for My Cancer Genome. IDH2 c.419G>T (R140L) mutation in acute myeloid leukemia. Updated October 16, 2018. Accessed September 18, 2017.
6. Stein EM, DiNardo CD, Pollyea DA, et al. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood. 2017;130:722-731.
7. US Food and Drug Administration. FDA approves new targeted treatment for relapsed or refractory acute myeloid leukemia. August 1, 2017. Accessed September 8, 2017.
8. Idhifa (enasidenib) tablets [prescribing information]. Summit, NJ: Celgene Corporation; August 2017.
9. Celgene Corporation. FDA grants approval of IDHIFA, the first oral targeted therapy for adult patients with relapsed/refractory acute myeloid leukemia and an IDH2 mutation. Press release. August 1, 2017. Accessed September 14, 2017.

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Last modified: May 9, 2018
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