Table of Contents
What is IDH1 inhibitor?
Ivosidenib is the first approved oral, targeted, small-molecule inhibitor of the isocitrate dehydrogenase 1 (IDH1) mutation seen in AML. IDH1 mutations have been associated with significantly worse outcomes in disease-free survival, relapse-free survival, and overall survival (NCCN, 2018).
What is the role of IDH?
Isocitrate dehydrogenase (IDH) is an enzyme that is best known from its role in the Krebs cycle, catalyzing the oxidative decarboxylation of isocitrate, resulting in alpha-ketoglutarate and carbon dioxide. The isoforms IDH1 and IDH2 encode a cytosolic and a mitochondrial protein, respectively.
What is IDH2 mutation?
The IDH2 gene mutations involved in CN-AML are called somatic mutations; they are found only in cells that become cancerous and are not inherited. These mutations change single protein building blocks (amino acids) in the isocitrate dehydrogenase 2 enzyme.
What is the IDH1 gene?
The IDH1 gene provides instructions for making an enzyme called isocitrate dehydrogenase 1. This enzyme is primarily found in the fluid-filled space inside cells (the cytoplasm). It is also found in cellular structures called peroxisomes, which are small sacs within cells that process many types of molecules.
What is IDH in tumors?
Isocitrate dehydrogenase (IDH) is an essential enzyme for cellular respiration in the tricarboxylic acid (TCA) cycle. Recurrent mutations in IDH1 or IDH2 are prevalent in several cancers including glioma, acute myeloid leukemia (AML), cholangiocarcinoma and chondrosarcoma.
What does IDH1 mutation mean?
The IDH1 gene mutations involved in CN-AML are somatic mutations, found only in cells that become cancerous. They change a single protein building block (amino acid) in the isocitrate dehydrogenase 1 enzyme, replacing the amino acid arginine at position 132 with another amino acid.
What is the difference between AML and IDH inhibitors?
AML = acute myeloid leukemia; IDH = isocitrate dehydrogenase. IDH inhibitors as monotherapy The IDH1 inhibitor ivosidenib and the IDH2 inhibitor enasidenib were both evaluated in patients with advanced hematological disorders, predominantly either refractory or relapsed (R/R) AML.
How common are IDH1 mutations in acute myeloid leukemia (AML)?
To date, virtually all studies have focused on IDH1mutations in AML, with a total of 1512 AMLs reported; 146 (9.7%) cases being mutated (Table 6).
Does Enasidenib have an on-target effect in idh2-mutated AML?
In a series of 16 patients with IDH2-mutated AML who relapsed on enasidenib therapy, sustained suppression of plasma 2-HG was observed in 14/16 patients, implying an ongoing on-target effect of enasidenib.37Indeed, in these patients the appearance of subclones with additional mutations in other recurring AML genes was documented.
How often is AML without maturation classified as IDH2 wild-type?
IDH2mutated cases were significantly more often classified as AML without maturation compared with IDH2wild-type AML cases 3/4 (75%) versus 27/192 (14%); (Fisher’s exact test; p<0.01). Auer rods were detected in 3 of 4 (75%) cases.