IDH1 and IDH2 mutation studies in 1473 patients with chronic-, fibrotic- or blast-phase essential thrombocythemia, polycythemia vera or myelofibrosis

Abstract

In a multi-institutional collaborative project, 1473 patients with myeloproliferative neoplasms (MPN) were screened for isocitrate dehydrogenase 1 (IDH1)/IDH2 mutations: 594 essential thrombocythemia (ET), 421 polycythemia vera (PV), 312 primary myelofibrosis (PMF), 95 post-PV/ET MF and 51 blast-phase MPN. A total of 38 IDH mutations (18 IDH1-R132, 19 IDH2-R140 and 1 IDH2-R172) were detected: 5 (0.8%) ET, 8 (1.9%) PV, 13 (4.2%) PMF, 1 (1%) post-PV/ET MF and 11 (21.6%) blast-phase MPN (P<0.01). Mutant IDH was documented in the presence or absence of JAK2, MPL and TET2 mutations, with similar mutational frequencies. However, IDH-mutated patients were more likely to be nullizygous for JAK2 46/1 haplotype, especially in PMF (P=0.04), and less likely to display complex karyotype, in blast-phase disease (P<0.01). In chronic-phase PMF, JAK2 46/1 haplotype nullizygosity (P<0.01; hazard ratio (HR) 2.9, 95% confidence interval (CI) 1.7–5.2), but not IDH mutational status (P=0.55; HR 1.3, 95% CI 0.5–3.4), had an adverse effect on survival. This was confirmed by multivariable analysis. In contrast, in both blast-phase PMF (P=0.04) and blast-phase MPN (P=0.01), the presence of an IDH mutation predicted worse survival. The current study clarifies disease- and stage-specific IDH mutation incidence and prognostic relevance in MPN and provides additional evidence for the biological effect of distinct JAK2 haplotypes.

One Thousand Patients With Primary Myelofibrosis: The Mayo Clinic Experience

“…[26][27][28][29] IDH1 and IDH2 mutations were analyzed by direct sequencing and/or high-resolution melting assay. 30 Unfavorable karyotype designation 31 and International Prognostic Scoring System (IPSS), 32 DIPSS, 33 and DIPSSplus 21 21 Leukemic transformation risk was considered high in the presence of unfavorable karyotype or platelet count less than 100 ϫ 10 9 /L or low in the absence of both of these risk factors. 21 All statistical analyses considered clinical and laboratory parameters obtained at time of first referral to Mayo Clinic.…”

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.…”

IDH2 somatic mutations in chronic myeloid leukemia patients in blast crisis

“…2,29,30 A recent multi-institutional study in 1473 MPN patients has reported IDH mutation frequencies of 25% for blast phase polycytemia vera and for blast phase primary myelofibrosis, as against 1% for essential thrombocytemia, 2% for polycytemia vera and 4% for primary myelofibrosis in CP. 4 Similarly, IDH mutations have been detected in up to 15% of secondary AML evolved from an MDSFas against 3.6-5% of early stage MDS. 3,31 This striking association of IDH mutations with transformed/progressive disease in the context of MPN/MDS has further been strengthened by the results of a very recent study comparing mutation frequencies within a relatively well-defined, genetically homogeneous patient population, that is, between low-risk MDS and high-risk MDS/AML cases with isolated deletion of chromosome 5q (0 and 22%, respectively).…”

“…We read with interest a series of manuscripts, [1][2][3][4][5][6] reporting somatic mutations of the isocitrate dehydrogenase 1 and 2 enzyme isoforms (IDH1, IDH2) in patients with de novo acute myeloid leukemia (AML), in patients with chronic and blast phase Philadelphia chromosome-negative (Ph-) myeloproliferative neoplasms (MPNs) and in patients with early and accelerated phase myelodysplastic syndromes (MDSs).…”

“…Morphological disease 2 or persistent minimal residual disease (MRD) levels of 410 À4 leukemic blasts 3 before allogeneic HSCT have been shown to be associated with a high risk of relapse after transplantation and a poor outcome. Despite the use of recently introduced chemotherapeutic agents for refractory leukemia, 4 patients who relapse after allogeneic HSCT often have refractory disease and are particularly susceptible to chemotherapy-related toxicity. T-cell engaging antibodies are a novel strategy for treatment of lymphoma and leukemia.…”