Differential prognostic effect of IDH1 versus IDH2 mutations in myelodysplastic syndromes: a Mayo Clinic Study of 277 patients

Abstract

Unlike the case with acute myeloid leukemia, there is limited information on the prognostic impact of isocitrate dehydrogenase (IDH) mutations in myelodysplastic syndromes (MDS). In the current study of 277 patients with MDS, IDH mutations were detected in 34 (12%) cases: 26 IDH2 (all R140Q) and 8 IDH1 (6 R132S and 2 R132C). Mutational frequency was 4% (2 of 56) in refractory anemia with ring sideroblasts, 12% (16 of 130) in refractory cytopenia with multilineage dysplasia, 14% (2 of 14) in MDS-unclassifiable, 14% (6 of 42) in refractory anemia with excess blasts (RAEB)-1 and 23% (8 of 35) in RAEB-2. Normal karyotype was noted in all but one IDH1-mutated cases and 13 IDH2-mutated cases. Multivariable analysis identified presence of mutant IDH1 (P ¼ 0.0004; hazard ration 4.0, 95% confidence interval 1.9 -8.8), revised International Prognostic Scoring System risk category (Po0.0001), and red cell transfusion need (P ¼ 0.002) as independent predictors of inferior survival. In a similar multivariable analysis, mutant IDH1 was the only variable associated with shortened leukemia-free survival (P ¼ 0.001; hazard ration 7.0, 95% confidence interval 2.3 -20.8). The presence of IDH2R140Q did not affect the overall (P ¼ 0.54) or leukemia-free (P ¼ 0.81) survival. The current study suggests a powerful adverse prognostic effect for mutant IDH1 in MDS.

Cancer-associated IDH2 mutants drive an acute myeloid leukemia that is susceptible to Brd4 inhibition

“…IDH2 mutant proteins promote AML by blocking the differentiation of HSPCs; in the absence of a cooperating event, this produces an MDS-like state, a disorder in which IDH2 mutations are frequent in humans (Patnaik et al 2012). While these effects correlate with the ability of IDH2 mutants to produce 2-HG and alter DNA methylation, our experiments do not prove a causal role for these downstream changes and disease etiology or maintenance.…”

Roles of IDH1/2 and TET2 mutations in myeloid disorders

“…TET2 mutation is more common in MDS/MPN than in AML, whereas IDH1/2 mutations are more frequent in AML than MDS/MPN [1,2]. When present in MDS, IDH1 mutation is associated with shorter leukemia-free survival and decreased overall survival, whereas these impacts are not found in TET2-mutated MDS [38,39]. Furthermore, Fig.…”

Clonal leukemic evolution in myelodysplastic syndromes with TET2 and IDH1/2 mutations

“…Interestingly, it has been demonstrated that TET2 function is also compromised by 2-hydroxyglutarate, an oncogenic metabolite produced by gain-of-function mutations of isocitrate dehydrogenase (IDH) 1 and 2, which has been shown to occur mutually exclusive with regard to TET2 mutations in 3.5-12% of MDS patients. 5,8,[11][12][13][14][15][16] Until now, several studies carried out have addressed the clinical relevance of TET2 and IDH1/2 mutations in MDS. 4,6,8,[11][12][13] The prevalent view is that there is no significant impact of TET2 mutations on overall survival (OS).…”