IDH1/2

ESH 2018 | Mutant IDH inhibitors in AML

At the European School of Hematology (ESH) Clinical Updates in Acute Leukemia Meeting on Saturday 5th of May 2018, Eytan M. Stein from the Memorial Sloan Kettering Cancer Center presented a talk titled “Inhibitors of Mutant Isocitrate Dehyrdogenase”.1

Isocitrate Dehydrogenase (IDH) mutations occur in approximately 20% of acute myeloid leukemia (AML) patients, with the prevalence increasing with patient age. IDH enzymes catalyze the conversion of isocitrate to α-Ketoglutarate (αKG). However, mutations in IDH1 (occurs in 7.5% of AML cases) and IDH2 (occurs in 15% of AML cases) lead to a reverse reaction of αKG to the oncometabolite D-2-Hydroxyglutarate (D-2HG). The accumulation of 2HG competitively inhibits αKG, thus leading to alterations in TET2-dependent hydroxymethylation, chromatin modification, activation of the hypoxic response, and increased dependence on BCL2. IDH inhibitors bind with the mutant IDH1 or IDH2 catalytic active site thus preventing the oncogenic reduction of αKG to D-2HG.2

The speaker, Eytan M. Stein discussed findings from a phase I/II dose-escalation/expansion study (NCT01915498) of enasidenib (A G-221), a first in class, oral, selective inhibitor of mutations in IDH2 in relapsed/refractory (R/R) AML patients. Enasidenib monotherapy was well tolerated, induced hematologic responses with an ORR of 38.8% and a median overall survival of 8.8 months. Additionally, one-third of patients with stable disease by day 90, eventually responded to enasidenib monotherapy. More results from this study were published by the AML Global Portal (AGP) here.  Based on this study, enasidenib was approved by the  U.S. Food and Drug Administration (FDA) for the treatment for adult patients with R/R AML with IDH2 mutation in August 2017.

Eytan M. Stein noted that IDH-inhibitor associated Differentiation Syndrome (IDH-DS) was observed in 12% of patients treated in this phase I/II study with enasidenib. Differentiation Syndrome is a potential serious condition that is associated with the proliferation of differentiated leukemic cells that can alter cytokine balance leading to tissue damage and inflammation. Overall response rate (ORR) in patients with or without IDH-DS were 45.5% (15/33) and 37.5% (93/248), respectively, which indicates that IDH-DS does not correlate with response. More on the prevalence, characteristics, and the course of IDH-DS in R/R AML patients treated in this phase I/II study are reported here.

IDH1/2 mutations represent valid therapeutic targets in AML. Additionally, targeted mutant IDH inhibitor, enasidenib have demonstrated encouraging activities in R/R AML. The speaker concluded by noting that combination of IDH inhibitors with other therapies are currently underway.

References
  1. Stein E.M. IDH inhibitors. ESH Clinical Updates in Acute Leukemias. May 4–6 2018, Budapest, Hungary.
  2. DiNardo C. et al. Characteristics, clinical outcome, and prognostic significance of IDH mutations in AML. Am J Hematol. 2015 Aug; 90(8): 732–736. DOI: 10.1002/ajh.24072
  3. Stein E. Met al. Enasidenib in mutant-IDH2 relapsed or refractory acute myeloid leukemia. Blood. 2017 June 6. DOI: 10.1182/blood-2017-04-779405. [Epub ahead of print].
  4. Fathi A. T. et al. Differentiation syndrome associated with enasidenib, a selective inhibitor of mutant isocitrate dehydrogenase 2: Analysis of a phase 1/2 study. JAMA Oncol. 2018 Jan 18. DOI: 10.1001/jamaoncol.2017.4695. [Epub ahead of print].
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