The somatic IDH1(R132) mutation in the isocitrate dehydrogenase 1 gene occurs in high frequency in glioma and in lower frequency in acute myeloid leukemia and thyroid cancer but not in other types of cancer.
We found that mutations in IDH1 occurred with a frequency of 3.6% in myelodysplastic syndromes (7 mutations in 193 patients) and 7.5% in acute myeloid leukemia following myelodysplastic syndromes (4 mutations in 53 patients).
From a phase 1 study of 258 patients with IDH1-mutant advanced hematologic malignancies, we report results for 34 patients with newly diagnosed acute myeloid leukemia (AML) ineligible for standard therapy who received ivosidenib 500 mg once daily.
Mutations involving <i>IDH1</i> or <i>IDH2</i> (<i>IDH1/2</i>) (<i>P</i> = .007) and <i>FLT3</i> (internal tandem duplication, <i>P</i> < .0001; noninternal tandem duplication, <i>P</i> = .01) were less frequent in <i>NPM1</i><sup>+</sup> MN than in <i>NPM1</i><sup>+</sup> AML.
Our results demonstrate an association between the R132HIDH1 mutation and intermediate risk cytogenetics in AML, suggesting that R132HIDH1 mutation may be associated with improved clinical outcome and demonstrate the feasibility of using mutation-specific antibodies to genotype and subclassify AML.
IDH1 mutations are closely related to the development and progression of various human cancers, such as glioblastoma, sarcoma, and acute myeloid leukemia.
We then evaluated the follow-up specimens with a known IDH1 mutation status including acute myeloid leukemia (n=23), MDS (n=2), MDS/MPN (n=2), and MPN (n=2).
This analysis defines the clinical outcome associated with IDH-mutations in both the front-line and salvage AML treatment settings, and confirms that response rate and OS for both IDH-mutated and IDH wild-type AML patients is comparable.
Due to the fact that mutations in IDH1 and IDH2 are acquired early during AML clonal evolution as well as because these mutations tend to remain stable during AML progression, the pharmaceutical industry has prompted the development of specific mutant IDH enzyme inhibitors.
In multivariate analysis, when considering karyotype, transfusion dependence, and IDH1 mutation status, ASXL1 frameshift mutations remained an independent prognostic marker in MDS (overall survival: HR, 1.85; 95% CI, 1.03 to 3.34; P = .040; time to AML progression: HR, 2.39; 95% CI, 1.12 to 5.09; P = .024).
Taken together, our results indicated that IDH2 mutation is critical for the development and maintenance of AML stem-like cells, and they provided a preclinical justification for targeting mutant IDH enzymes as a strategy for anticancer therapy.
Over the past few years, large-scale genomic studies of patients with myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML) have unveiled recurrent somatic mutations in genes involved in epigenetic regulation (DNMT3A, IDH1/2, TET2, ASXL1, EZH2 and MLL) and the spliceosomal machinery (SF3B1, U2AF1, SRSF2, ZRSR2, SF3A1, PRPF40B, U2AF2, and SF1).
This review surveys the prevalence of IDH mutations in cancer and explores current mechanistic understanding of IDH mutations with implications for diagnostic and therapeutic development for the treatment of gliomas and AML.
We retrospectively identified forty-two patients with AML treated with DNA methyltransferase inhibitors (DNMTIs) decitabine (n = 36) or azacitidine (n = 6) and performed analysis of stored samples for the presence of IDH1 and IDH2 mutations.
These results suggest that the multiple somatic mutations of the IDH1 and NPM1 genes in hemangioblasts are related to the development of cup-like AML associated with Maffucci syndrome.
We here analyzed the frequency and distribution pattern of DNMT3A and IDH mutations and their associations with other molecular markers in normal karyotype AML patients.