OVERVIEW

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Enasidenib – IDHIFA®

DRUG CLASS

Antineoplastic Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

ANNOTATED BIBLIOGRAPHY

References updated: 06 January 2024

Abbreviations: AML, acute myeloid leukemia; IDH2, isocitrate dehydrogenase-2.

• Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999.

  (Review of hepatotoxicity published in 1999 before the availability of kinase inhibitors).
• DeLeve LD. Erlotinib. Cancer chemotherapy. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 556.

  (Review of hepatotoxicity of cancer chemotherapeutic agents published in 2013 before the availability of enasidenib).
• Wellstein A, Giaccone G, Atkins MB, Sausville EA. Pathway-targeted therapies: monoclonal antibodies, protein kinase inhibitors, and various small molecules. In, Brunton LL, Hilal-Dandan R, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 13th ed. New York: McGraw-Hill, 2018, pp. 1203-36.

  (Textbook of pharmacology and therapeutics).
• FDA. https://www​.accessdata​.fda.gov/drugsatfda_docs​/nda/2017/209606Orig1s000MultidisciplineR.pdf

  (FDA Drug Approvals website that has product labels [package inserts], letters of approval and full FDA scientific review of the new drug application for safety and efficacy).
• Kim ES. Enasidenib: First global approval. Drugs 2017; 77: 1705-11. [PubMed: 28879540]

  (Review of the mechanism of action, pharmacology, clinically efficacy and safety of enasidenib, a "first-in-class" small molecule inhibitor of IDH2, shortly after its approval for use in AML in the US; mentions that elevations in bilirubin occur in 81% of patients, nausea in 50%, diarrhea 43%, anorexia 34%, vomiting 34%, differentiation syndrome 14% and tumor lysis syndrome 6%; no mention of ALT elevations or hepatotoxicity).
• Stein EM, DiNardo CD, Pollyea DA, Fathi AT, Roboz GJ, Altman JK, Stone RM, et al. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood 2017; 130: 722-31. [PMC free article: PMC5572791] [PubMed: 28588020]

  (Dose finding and pilot study of enasidenib in 239 patients with mutant IDH2 positive AML, the complete remission rate was 19% and severe adverse events included hyperbilirubinemia [12%], differentiation syndrome [6%] and tumor lysis syndrome [3%]; no mention of ALT elevations or hepatotoxicity).
• Amatangelo MD, Quek L, Shih A, Stein EM, Roshal M, David MD, Marteyn B, et al. Enasidenib induces acute myeloid leukemia cell differentiation to promote clinical response. Blood 2017; 130: 732-41. [PMC free article: PMC5553578] [PubMed: 28588019]

  (Companion manuscript to Stein [2017] measured mutant IDH2 burden in patients receiving enasidenib showing increases in differentiation of myeloid cells and declines in mutant IDH2 positive cells in recipients of acalabrutinib).
• Yen K, Travins J, Wang F, David MD, Artin E, Straley K, Padyana A, et al. AG-221, a first-in-class therapy targeting acute myeloid leukemia harboring oncogenic IDH2 mutations. Cancer Discov 2017; 7: 478-93. [PubMed: 28193778]

  (Description of the discovery of a specific inhibitor of IDH2 [AG-221: enasidenib] using high throughput screening and demonstration of its activity in decreasing the mutant IDH2 induced block in cellular differentiation in human AML cells leading differentiation rather than necrosis of malignant blasts).
• Fathi AT, DiNardo CD, Kline I, Kenvin L, Gupta I, Attar EC, Stein EM, et al.; AG221-C-001 Study Investigators. Differentiation syndrome associated with enasidenib, a selective inhibitor of mutant isocitrate dehydrogenase 2: analysis of a phase 1/2 study. JAMA Oncol 2018; 4: 1106-10. [PMC free article: PMC5885269] [PubMed: 29346478]

  (Among 281 patients with AML treated with enasidenib [50 to 650 mg daily] in open label trials, 33 [12%] were judged to have differentiation syndrome marked by dyspnea, fever, lung infiltrates and hypoxia with onset after 7-129 days [median 30 days], usually responding to corticosteroid therapy, half requiring dose interruption, none dying acutely, and all were able to restart enasidenib after its resolution; no mention of ALT elevations).
• Patel SA. Enasidenib-induced differentiation syndrome in IDH2-mutant acute myeloid leukemia. JAMA Oncol 2018; 4: 1110-1. [PubMed: 29346477]

  (Commentary on Fathi [2018] stressing the need to promptly recognize differentiation syndrome and manage it correctly).
• In brief: Two new drugs for AML. Med Lett Drugs Ther 2018; 60 (1543): e56. [PubMed: 29635267]

  (Brief summary of the mechanism of action, clinical efficacy, and safety of enasidenib shortly after its approval for use in the US; mentions indirect hyperbilirubinemia without apparent liver toxicity occurring in 38% and differentiation syndrome in 10% of patients [2 of which were fatal] in a pooled analysis of prelicensure clinical trials).
• Mohamed A. Enasidenib-induced Sweet syndrome with differentiation syndrome. Clin Case Rep. 2021;9:e04099. [PMC free article: PMC8133062] [PubMed: 34026142]

  (65 year old woman with IDH2 mutant refractory AML developed fever and rash within one week of starting enasidenib with severe neutropenia and with subsequent pulmonary infiltrates responding to corticosteroid therapy and diagnosed with Sweet and differentiation syndrome).
• DiNardo CD, Schuh AC, Stein EM, Montesinos P, Wei AH, de Botton S, Zeidan AM, et al. Enasidenib plus azacitidine versus azacitidine alone in patients with newly diagnosed, mutant-IDH2 acute myeloid leukaemia (AG221-AML-005): a single-arm, phase 1b and randomised, phase 2 trial. Lancet Oncol. 2021;22:1597-1608. [PubMed: 34672961]

  (Among 101 adults with newly diagnosed IDH2 mutant AML treated with azacytidine with or without enasidenib, those receiving both drugs had a better overall response rate than the azacytidine only group [74% vs 36%] but overall survival rates were the same; total and serious adverse event rates [43% vs 44%] were also similar but the addition of enasidenib resulted in higher rates of significant thrombocytopenia, neutropenia, and anemia as well as higher rates of hyperbilirubinemia [19% vs 0%] and differentiation syndrome [10% vs 0%]; no mention of ALT elevations or hepatotoxicity).
• de Botton S, Montesinos P, Schuh AC, Papayannidis C, Vyas P, Wei AH, Ommen H, et al. Enasidenib vs conventional care in older patients with late-stage mutant-IDH2 relapsed/refractory AML: a randomized phase 3 trial. Blood. 2023;141:156-167. [PMC free article: PMC10644040] [PubMed: 35714312]

  (Among 319 adults [ages 60 years or greater] with refractory or relapsed AML with mutated IDH2 treated with enasidenib [100 mg daily] or conventional therapy [azacytidine or cytarabine], event-free survival was longer with enasidenib [4.9 vs 2.6 months] but median overall survival was not different [6.5 vs 6.2 months], and adverse event rates were 77% vs 61%, serious adverse event rates 22% vs 22%, hyperbilirubinemia [not requiring discontinuation] being common with enasidenib [20% vs 1%] as was differentiation syndrome [14% vs none], and one patient on enasidenib died of hepatic failure during the second 28-day cycle, but no details given).