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Enasidenib
Alwin Krämer1,2, Tilmann Bochtler3,4
1Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center (DKFZ), University of Heidelberg, Heidelberg, Germany. a.kraemer@dkfz.de.
Abstract:
Enasidenib is an orally available, selective, potent, small molecule inhibitor of mutant isocitrate dehydrogenase 2 (IDH2). Neomorphic mutations in IDH2 are frequently found in both hematologic malignancies and solid tumors and lead to the production of the oncometabolite (R)-2-hydroxyglutarate. Increased levels of (R)-2-hydroxyglutarate cause histone and DNA hypermethylation associated with blocked differentiation and tumorigenesis. In PDX mice transplanted with human IDH2-mutant acute myeloid leukemia cells, enasidenib treatment led to normalization of (R)-2-hydroxyglutarate serum levels, differentiation of leukemic blasts and increased survival. Early clinical data in patients with relapsed/refractory IDH2-mutant acute myeloid leukemia show that enasidenib is well tolerated and induces durable complete remissions as a single agent in about 20% of cases. One notable drug-related adverse effect is differentiation syndrome. On the basis of these results the compound has recently been approved for the treatment of relapsed/refractory IDH2-mutant acute myeloid leukemia in the USA. Although no data are available yet, clinical trials on the treatment of patients with several types of IDH2-mutant solid tumors including gliomas, chondrosarcomas and cholangiocarcinomas are currently being performed.
Insights
Enasidenib, an inhibitor of mutant isocitrate dehydrogenase 2 (IDH2), shows promise in treating IDH2-mutant acute myeloid leukemia. Clinical trials indicate it is well-tolerated and induces durable remissions, with ongoing studies for solid tumors.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Mutations in isocitrate dehydrogenase 2 (IDH2) drive tumorigenesis by producing the oncometabolite (R)-2-hydroxyglutarate.
- Elevated (R)-2-hydroxyglutarate levels cause epigenetic alterations, blocking cell differentiation and promoting cancer development.
- IDH2 mutations are prevalent in hematologic malignancies and solid tumors.
Purpose of the Study:
- To evaluate the efficacy and safety of enasidenib, a selective IDH2 inhibitor.
- To assess the impact of enasidenib on (R)-2-hydroxyglutarate levels and cancer cell differentiation.
- To explore the potential of enasidenib in treating IDH2-mutant cancers.
Main Methods:
- Enasidenib treatment in patient-derived xenograft (PDX) mice with IDH2-mutant acute myeloid leukemia.
- Analysis of serum (R)-2-hydroxyglutarate levels, leukemic blast differentiation, and survival rates.
- Review of early clinical data from patients with relapsed/refractory IDH2-mutant acute myeloid leukemia.
Main Results:
- Enasidenib normalized (R)-2-hydroxyglutarate levels, induced differentiation, and improved survival in preclinical models.
- Enasidenib demonstrated good tolerability and induced durable complete remissions in approximately 20% of patients as a single agent.
- Differentiation syndrome was identified as a notable drug-related adverse effect.
Conclusions:
- Enasidenib is an effective treatment for relapsed/refractory IDH2-mutant acute myeloid leukemia, leading to durable remissions.
- Enasidenib has received FDA approval for IDH2-mutant acute myeloid leukemia.
- Clinical trials are underway to investigate enasidenib's efficacy in IDH2-mutant solid tumors, including gliomas, chondrosarcomas, and cholangiocarcinomas.