IDH1 mutations in patients with myelodysplastic syndromes are associated with an unfavorable prognosis

Abstract

BackgroundMyelodysplastic syndromes are a heterogeneous group of hematopoietic stem cell disorders with a high propensity to transform into acute myeloid leukemia. Heterozygous missense mutations in IDH1 at position R132 and in IDH2 at positions R140 and R172 have recently been reported in acute myeloid leukemia. However, little is known about the incidence and prognostic impact of IDH1 and IDH2 mutations in myelodysplastic syndromes. Design and MethodsWe examined 193 patients with myelodysplastic syndromes and 53 patients with acute myeloid leukemia arising from myelodysplastic syndromes for mutations in IDH1 (R132), IDH2 (R172 and R140), and NPM1 by direct sequencing. ResultsWe 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). Three mutations in codon R140 of IDH2 and one mutation in codon R172 were found in patients with acute myeloid leukemia following myelodysplastic syndromes (7.5%). No IDH2 R140 or R172 mutations were identified in patients with myelodysplastic syndromes. The presence of IDH1 mutations was associated with a shorter overall survival (HR 3.20; 95% CI 1.47-6.99) and a higher rate of transformation into acute myeloid leukemia (67% versus 28%, P=0.04). In multivariate analysis when considering karyotype, transfusion dependence and International Prognostic Scoring System score, IDH1 mutations remained an independent prognostic marker in myelodysplastic syndromes (HR 3.57; 95% CI 1.59-8.02; P=0.002). ConclusionsThese results suggest that IDH1 mutations are recurrent molecular aberrations in patients with myelodysplastic syndromes, and may become useful as a poor risk marker in these patients. These findings await validation in prospective trials.Key words: IDH1, IDH2, myelodysplastic syndrome, secondary acute myeloid leukemia, prognosis.Citation: Thol F, Weissinger EM, Krauter J, Wagner K, Damm F, Wichmann F, Göhring G, Schumann C, Bug G, Ottmann O, Hofmann W-K, Schlegelberger B, Ganser A, and Heuser M. IDH1 mutations in patients with myelodysplastic syndromes are associated with an unfavorable prognosis. Haematologica 2010;95(10):1668-1674. doi:10.3324/haematol.2010 This is an open-access paper. © F e r r a t a S t o r t i F o u n d a t i o n IDH1 mutations in patients with myelodysplastic syndromes are associated with an unfavorable prognosis

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

“…3,11 -14 In contrast, very few studies have looked into this matter in chronic myeloid malignancies. Both IDH1 and IDH2 mutations occur in MDS, although some studies 6 have reported a preponderance of IDH1 mutations, whereas others have shown the opposite. 7 In the current MDS study, the overwhelming majority of IDH mutations were IDH2R140Q.…”

“…18 There is currently limited information on the prognostic impact of IDH mutations in MDS and other chronic myeloid malignancies. 6,8 We recently reported on IDH1 and IDH2 mutational frequencies among 1473 patients with BCR-ABL1-negative MPN, 8 1 -4% in chronic-phase MPN and approximately 25% in blast-phase polycythemia vera or primary myelofibrosis. Subsequently, we examined the prognostic impact of IDH mutations in chronic-phase primary myelofibrosis and showed inferior overall and leukemia-free survival in the presence of IDH mutations.…”

“…1 A smaller proportion of patients with acute myeloid leukemia (AML) and other myeloid malignancies also harbor both IDH1 and IDH2 mutations; reported mutational frequencies are approximately 10% for AML, 2 -5 5% for myelodysplastic syndromes (MDS), 6,7 4% for myeloproliferative neoplasms (MPN), 5,8 9% for MDS/MPN, 7 15% for post-MDS AML, 6 22% for post-MPN AML, 8 10% for post-MDS/MPN AML, 7 22% for del(5q)-associated high-risk MDS or AML 9 and 4% for blast-phase chronic myelogenous leukemia (B4%). 10 In AML, IDH mutations cluster with normal or intermediaterisk karyotype, sole trisomy 8 and NPM1 mutations.…”

The prognostic impact and stability of Isocitrate dehydrogenase 2 mutation in adult patients with acute myeloid leukemia

“…IDH mutations occur at low frequencies (3.6-5%) in myelodysplastic syndrome, 3,4 and in chronic-phase myeloproliferative neoplasm (about 1.8%), 5,6 but obviously increased as these diseases progress to AML (7.5-21%), [3][4][5][6] indicating a role of IDH mutations in leukemogenesis. In AML, IDH2 mutations occur more frequently than IDH1 mutations, with frequencies of 11 vs 6% in patients younger than 60 years, 7 15.4 vs 7.7% in total patients, 8 and 19 vs 14% in adults with normal karyotype.…”

IDH1 and IDH2 mutations are rare in pediatric myeloid malignancies

“…1 Subsequent studies also revealed that acquired somatic mutations in IDH1 frequently occurred in adult hematological malignancies, such as acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). 2,3 More recently, Paschka et al 4 reported that not only IDH1 but also IDH2 mutations occurred relatively frequently in adult AML, and that these mutations were associated with older age, poor prognosis, cytogenetically normal AML (CN-AML) and the genotype of mutated NPM1 without FLT3-internal tandem duplication (ITD). Exon 4 of both IDH1 and IDH2, which was previously identified as a hot spot for mutations in these genes, encodes three arginine residues (R100, R109 and R132 in IDH1 and R140, R149, and R172 in IDH2) that are important for protein activities.…”