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The Prognostic Impact and Stability of Isocitrate Dehydrogenase 2 Mutation in Adult Patients with Acute Myeloid Leukemia

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The Prognostic Impact and Stability of Isocitrate Dehydrogenase 2 Mutation in Adult Patients with Acute Myeloid Leukemia Leukemia (2011) 25, 246–253 & 2011 Macmillan Publishers Limited All rights reserved 0887-6924/11 www.nature.com/leu ORIGINAL ARTICLE The prognostic impact and stability of Isocitrate dehydrogenase 2 mutation in adult patients with acute myeloid leukemia W-C Chou1,2,4, W-C Lei2,4, B-S Ko2, H-A Hou2, C-Y Chen2, J-L Tang2, M Yao2, W Tsay2, S-J Wu2, S-Y Huang2, S-C Hsu1, Y-C Chen1, Y-C Chang1, K-T Kuo3, F-Y Lee3, M-C Liu3, C-W Liu3, M-H Tseng2, C-F Huang2 and H-F Tien2 1Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan; 2Department of Internal Medicine Division of Hematology, National Taiwan University Hospital, Taipei, Taiwan and 3Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan Although the clinical features of the Isocitrate dehydrogenase 2 The clinical and biological characterization of IDH mutations (IDH2) mutation in acute myeloid leukemia (AML) have been in myeloid malignancies have been reported in several studies. characterized, its prognostic significance remains contro- IDH mutations occur at low frequencies (3.6–5%) in myelodys- versial and its stability has not been investigated. We analyzed plastic syndrome,3,4 and in chronic-phase myeloproliferative 446 adults with primary non-M3 AML and found IDH2 R172, 5,6 R140 and IDH1 R132 mutations occurred at a frequency of 2.9, neoplasm (about 1.8%), but obviously increased as these 9.2 and 6.1%, respectively. Compared with wild-type IDH2, diseases progress to AML (7.5–21%),3–6 indicating a role of IDH mutation of IDH2 was associated with higher platelet counts, mutations in leukemogenesis. In AML, IDH2 mutations occur intermediate-risk or normal karyotype and isolated þ 8, but was more frequently than IDH1 mutations, with frequencies of 11 vs inversely correlated with expression of HLA-DR, CD34, CD15, 6% in patients younger than 60 years,7 15.4 vs 7.7% in total CD7 and CD56, and was mutually exclusive with WT1 mutation 8 9 and chromosomal translocations involving core-binding patients, and 19 vs 14% in adults with normal karyotype. factors. All these correlations became stronger when IDH1 Although IDH1 and IDH2 proteins locate differently, in cytosol and IDH2 mutations were considered together. Multivariate and mitochondria, respectively, they both function to generate analysis revealed IDH2 mutation as an independent favorable a À þ -ketoglutarate and are supposed to control redox status prognostic factor. IDH2 /FLT3-ITD genotype conferred espe- in cells.10,11 The IDH mutants gain the neomorphic enzyme cially negative impact on survival. Compared with IDH2 R140 mutation, IDH2 R172 mutation was associated with younger activity and lead to the production of an onco-metabolite, age, lower white blood cell count and lactate dehydrogenase 2-hydroxyglutarate (2-HG), which was speculated to upregulate level, and was mutually exclusive with NPM1 mutation. Serial hypoxia-inducing factor 1a by inhibition of prolyl hydroxylase.1,2,10,12 analyses of IDH2 mutations at both diagnosis and relapse in On the basis of the in vivo functions of IDH1 and IDH2, it is 121 patients confirmed high stability of IDH2 mutations. In intuitive to expect similar clinical and biological characteristics conclusion, IDH2 mutation is a stable marker during disease between AML bearing mutations of these two genes. Indeed, evolution and confers favorable prognosis. Leukemia (2011) 25, 246–253; doi:10.1038/leu.2010.267; mutations of both genes are more commonly present in patients 7,13–17 published online 16 November 2010 with normal cytogenetics. However, different features Keywords: IDH1; IDH2; acute myeloid leukemia between IDH1-mutated and IDH2-mutated AML were shown in several reports, and even there existed differences between IDH2 R140 and R172 mutations.9,17,18 In addition, the Introduction prognostic implications of these mutations also varied widely among different institutions.7,15,17 More perplexingly, IDH2 The increasing number of genetic alterations discovered in acute R172 mutation alone was found to have distinct gene- and myeloid leukemia (AML) has not only increased our under- microRNA-expression profiles,9 and appeared to be an inde- standing of this heterogeneous disease but also provided pendent poor prognostic factor.18 In contrary, results from two prognostic information through which individualized treatment studies suggested a possible favorable impact of IDH2 mutation for the best interests of patients may become possible. These in subgroups of AML patients.7,8 Overall, the prognostic impacts of genetic mutations have been underscored by the implication of IDH2 mutation is still controversial. Moreover, inclusion of NPM1 and CEBPA mutations in the 2008 World the side-by-side comparison is needed to delineate the Health Organization classification of AML. similarities and distinctions among mutations at IDH1 R132, Among these genetic alterations, mutations of Isocitrate IDH2 R140 and IDH2 R172. Finally, the stability of IDH2 dehydrogenase 1 (IDH1) and IDH2, which encode two isoforms mutation remains uninvestigated. of isocitrate dehydrogenase, are special in that these genes are We have previously reported the clinical and biological involved in metabolism,1,2 rather than signaling pathways or characteristics of AML patients with IDH1 mutation at R132.14 transcription factors, which are commonly deranged in AML. To further clarify the above issues of IDH1 and IDH2 mutations in AML, we then analyzed 446 adults with non-M3 AML in our Correspondence: Dr H-F Tien, Department of Internal Medicine, institute. We found that IDH2 mutations were associated with National Taiwan University Hospital, Taipei 100, Taiwan. some distinct biological features and implicated a longer overall E-mail: [email protected] survival (OS) in all non-M3 patients and in those with a normal or Dr W-C Chou, Department of Laboratory Medicine and Internal karyotype. Moreover, IDH2 mutation was an independent Medicine, National Taiwan University Hospital, Taipei 100, Taiwan. favorable prognostic factor in multivariate analysis. Finally, by E-mail: [email protected] 4These authors contributed equally to this work. a comprehensive sequential study, we confirmed that IDH2 14,19 Received 19 August 2010; revised 13 September 2010; accepted 8 mutation, like IDH1 mutation we previously described, was October 2010; published online 16 November 2010 a stable mutation during disease evolution. IDH1 and IDH2 mutations in AML W-C Chou et al 247 Materials and methods Statistics The w2 test was used to compare discrete variables of patients Patients with and without gene mutation. Fisher exact test was used for From 1995 to 2007, a total of 674 adult patients with de novo comparing the incidence of IDH2 mutation between different AML were diagnosed at the National Taiwan University Hospital cohorts. Mann–Whitney test method was used to compare according to the French-American-British Cooperative Group continuous variables and medians of distributions. Only 309 Criteria. There were 497 patients with cryopreserved bone patients who received conventional induction chemotherapy marrow cells and complete clinical and laboratory data for and subsequent consolidation chemotherapy after achieving analysis. These 497 patients were representative of the whole CR were included in the survival analysis. OS was measured cohort because the clinical data and treatment outcome were from the date of first diagnosis to the date of last follow-up not different from the whole population (data not shown). or death from any cause. Kaplan–Meier estimation was used to Patients with AML M3 subtype were not included in the study plot survival curves, and log-rank tests were used to calculate because of their distinct treatment and prognosis. Therefore, a the difference among groups. Patients receiving hematopoietic total of 446 adult patients (X18 years) were included in this transplantation were censored on the day of transplantation. study. Written informed consent in accordance with the Multivariate Cox proportional hazard regression analysis Declaration of Helsinki was obtained from all participants and was used to investigate independent prognostic factors for the study was approved by the Institutional Review Board of the OS. A P-value o0.05 was considered statistically significant. National Taiwan University Hospital. The bone marrow cells All statistical analyses were performed using the SPSS 17 were collected serially at the time of diagnosis, after chemo- software (SPSS Inc., Chicago, IL, USA). therapy and at relapse. Among these 446 patients, 309 patients (69.3%) received conventional induction chemotherapy (idar- ubicin 12 mg/m2 per day on days 1–3 and cytarabine 100 mg/m2 Results per day on days 1–7), followed by consolidation chemotherapy 2 with 2–4 cycles of high-dose cytarabine (2000 mg/m every 12 h IDH2 R140 and R172 mutations on days 1–4, total eight doses) with or without an anthracycline These 446 non-APL patients consisted of 251 males and 195 (idarubicin or mitoxantrone) after achieving complete remission females, with a median age of 53 years (range, 18–90 years). (CR). The remaining 137 patients received palliative therapy or The IDH2 mutation was detected in 54 patients (12.1%), low-dose chemotherapy because of poor performance status or including 13 (2.9%) with R172 mutation and 41 (9.2%) with per patients’ wish. R140 mutation, whereas the IDH1 mutation was found in 27 patients (6.1%). Among the cytogenetically normal AML Mutation analysis patients, the IDH2 mutation was demonstrated in 15.2% Mutation analyses were performed on CEBPA in the only (34/223) of patients and IDH1 mutation in 8.9% (20/223) exon,20 WT1 in exons 7, 8 and 9,21 MLL-PTD that spanned (Table 1). There were three types of R140 mutations, including exons 2–8,22JAK2 on V617F hot spot,23 PTPN11 in exons 3 and 13,24 R140Q (39 of 41, 95.1%), R140L (1 of 41, 2.4%) and R140W (1 RUNX1 in exons 3–8,25 c-KIT in exons 8, 10, 11, 12 and 17,26 of 41, 2.4%), whereas all the R172 mutations were R172K.
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