On August 1, 2017, the IDH2 inhibitor enasidenib (Idhifa) was granted regular approval for treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with an isocitrate dehydrogenase-2 (IDH2) mutation as detected by a U.S. Food and Drug Administration (FDA)-approved test.^1,2 The approval is the first for relapsed or refractory AML specifically with an IDH2 mutation. The FDA concurrently approved a companion diagnostic, the RealTime IDH2 Assay, for detecting the IDH2 mutation.

Supporting Efficacy Data

Approval was based on the quality and duration of responses in Study AG221-C-001, in which 199 adults with relapsed or refractory AML with IDH2 mutation as detected by the previously mentioned assay received oral enasidenib at 100 mg daily.^2,3 The median age of patients was 68 years (62% ≥ 65 years); 52% were male; 77% were white; the Eastern Cooperative Oncology Group performance status was 0 or 1 in 85%; 48% had relapsed and 52% had refractory disease; IDH2 mutation was R140 in 78% and R172 in 22%; the median time from AML diagnosis was 11.3 months; cytogenetic risk was intermediate in 49% and poor in 27%; 25% had prior stem cell transplantation; 79% were transfusion-dependent at baseline; and the number of prior anticancer regimens (median = 2, range = 1–6) was 1 for 45%, 2 for 32%, and ≥ 3 for 23%.

After a median follow-up of 6.6 months, 23% of patients had experienced a complete response or complete response with partial hematologic recovery lasting a median of 8.2 months, with 19% having a complete response lasting a median of 8.2 months and 4% having a complete response with partial hematologic recovery lasting a median of 9.6 months. The median time to first response was 1.9 months (range = 0.5–7.5 months), and the median time to best response of complete response/complete response with partial hematologic recovery was 3.7 months (range = 0.6–11.2 months). Of 157 patients who were transfusion-dependent at baseline, 34% no longer required transfusions during at least one 56-day period with enasidenib treatment. Of 42 patients who did not require transfusions at the start of the trial, 76% maintained transfusion independence.

How It Works

Enasidenib is a small-molecule inhibitor of the IDH2 enzyme. It targets the mutant IDH2 variants R140Q, R172S, and R172K at approximately 40-fold lower concentrations than the wild-type enzyme in vitro. Inhibition of the mutant IDH2 enzyme led to decreased 2-hydroxyglutarate (2-HG) levels and induced myeloid differentiation in vitro and in vivo in mouse xenograft models of IDH2-mutated AML. In blood samples from patients with AML and mutated IDH2, enasidenib decreased 2-HG levels, reduced blast counts, and increased the percentages of mature myeloid cells.

How It Is Used

The recommended starting dose of enasidenib is 100 mg orally once daily with or without food until disease progression or unacceptable toxicity. For patients without disease progression or unacceptable toxicity, treatment should continue for a minimum of 6 months to allow time for a clinical response.

Blood cell counts and blood chemistries should be assessed for leukocytosis and tumor-lysis syndrome prior to initiation of treatment and monitored at a minimum of every 2 weeks for at least the first 3 months during treatment. Abnormalities should be managed promptly. Dose modifications for adverse reactions follow:

Differentiation syndrome: If differentiation syndrome is suspected, administer systemic corticosteroids and initiate hemodynamic monitoring; interrupt treatment if there are severe pulmonary symptoms requiring intubation or ventilator support and/or renal dysfunction persists for > 48 hours after initiation of corticosteroids; resume treatment when signs and symptoms improve to grade ≤ 2.

Noninfectious leukocytosis (white blood cell [WBC] count > 30 10⁹/L): Initiate treatment with hydroxyurea, as per standard institutional practices; interrupt enasidenib if leukocytosis is not improved with hydroxyurea and then resume treatment at 100 mg daily when the WBC is < 30 10⁹/L.

Elevation of bilirubin > 3 times upper limit of normal (ULN) sustained for ≥ 2 weeks without elevated transaminases or other hepatic disorders: Reduce enasidenib dose to 50 mg daily; resume dose at 100 mg daily if bilirubin level elevation resolves to less than 2 times ULN.

Other grade ≥ 3 toxicity considered related to treatment including tumor-lysis syndrome: Interrupt treatment until toxicity resolves to grade ≤ 2; resume treatment at 50 mg daily and may increase to 100 mg daily if toxicities resolve to grade ≤ 1; discontinue treatment for recurrent grade ≥ toxicity.

Safety Profile

The safety evaluation of single-agent enasidenib is based on 214 patients with relapsed or refractory AML who were assigned to receive 100 mg daily. The most common adverse events of any grade were nausea (50%), diarrhea (43%), vomiting (34%), and decreased appetite (34%); the most common grade ≥ 3 adverse events were diarrhea (8%), differentiation syndrome (7%), tumor-lysis syndrome (6%), and noninfectious leukocytosis (6%). The most common laboratory abnormalities of any grade/grade ≥ 3 were increased bilirubin level (81%/15%), decreased calcium level (74%/8%), decreased potassium level (41%/15%), and decreased phosphorus level (27%/8%).

Serious adverse reactions occurred in 77% of patients, with the most common being leukocytosis (10%), differentiation syndrome (8%), diarrhea (6%), tumor-lysis syndrome (5%), nausea (5%), vomiting (3%) and decreased appetite (3%); differentiation syndrome events characterized as serious included pyrexia, renal failure acute, hypoxia, respiratory failure, and multiorgan failure. Adverse events led to dose interruption in 43% of patients (due to differentiation syndrome in 4% and leukocytosis in 3%), dose reduction in 5%, and permanent treatment discontinuation in 17%, with the most common event leading to discontinuation of treatment being leukocytosis (1%). The 30-day and 60-day mortality rates during treatment were 4.2% and 11.7%, respectively.

Enasidenib carries a boxed warning for differentiation syndrome, which can be fatal if not treated. Symptoms may include fever; dyspnea; acute respiratory distress; pulmonary infiltrates; pleural or pericardial effusions; rapid weight gain or peripheral edema; lymphadenopathy; bone pain; and hepatic, renal, or multiorgan dysfunction. Enasidenib also carries warnings/precautions for embryofetal toxicity. ■

REFERENCES

1. U.S. Food and Drug Administration: FDA granted regular approval to enasidenib for the treatment of relapsed or refractory AML. Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm569482.htm. Accessed January 22, 2018.

2. Idhifa (enasidenib) tablets prescribing information, Celgene Corporation, August 2017. Available at www.accessdata.fda.gov/drugsatfda_docs/-label/2017/209606s000lbl.pdf. Accessed January 22, 2018.

3. Stein EM, DiNardo CD, Pollyea DA, et al: Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood 130:722-731, 2017.