Prognostic value of isocitrate dehydrogenase mutations in myelodysplastic syndromes: a retrospective cohort study and meta-analysis - PubMed (original) (raw)

Meta-Analysis

Prognostic value of isocitrate dehydrogenase mutations in myelodysplastic syndromes: a retrospective cohort study and meta-analysis

Jie Jin et al. PLoS One. 2014.

Abstract

Background: Recent genomic sequencing efforts have identified a number of recurrent mutations in myelodysplastic syndromes (MDS) that may contribute to disease progression and overall survival, including mutations in isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2).

Methods: Pretreatment bone marrow (BM) samples were acquired from mononuclear cells in 146 adult patients with de novo MDS from January 2006 to June 2013. Polymerase chain reaction (PCR) and direct sequencing were performed on exon 4 of IDH1/2 genes and mutation status was correlated with overall survival (OS) and leukemia-free survival (LFS). We then performed a meta-analysis combining previously published and current studies to explore the effect of IDH mutations on OS and LFS in MDS.

Results: In our study, somatic mutations of either IDH gene were discovered in 11 MDS patients (7.53%) and were significantly correlated with poorer OS (P = 0.007). IDH mutations were specifically associated with a poorer OS in the intermediate-1 risk group by the International Prognostic Scoring System (IPSS) (P = 0.039). In addition, we discovered decitabine achieved a better therapeutic effect compared to other treatments in IDH mutation-positive patients (P = 0.023). We identified six previous studies of IDH mutations in MDS. A meta-analysis of these studies included 111 MDS patients IDH mutations and 1671 MDS patients with wild-type IDH1/2. The hazard ratios (HRs) of OS and LFS for patients with IDH mutations were 1.62 (95% CI, 1.27-2.09) and 2.21 (95% CI, 1.48-3.30), respectively.

Conclusion: The results from our study and the meta-analysis provide firm evidence that IDH mutations are significantly associated with poorer clinical outcomes in MDS. Identification of IDH mutations may be pivotal for better risk stratification in MDS patients and improving IPSS score. Additionally, hypomethylating agents may be an effective treatment option for MDS patients with IDH mutations.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1

Figure 1. Flow diagram of study selection.

Figure 2

Figure 2. Kaplan–Meier survival curves for survival of MDS patients.

(A) Overall survival data for MDS patients stratified by IDH1/2 mutational status. (B) Leukemia-free survival data for MDS patients stratified by IDH1/2 mutational status. (C) Overall survival data for MDS patients stratified by IDH1 mutational status. (D) Leukemia-free survival data for MDS patients stratified by IDH1 mutational status. (E) Overall survival data for MDS patients stratified by IDH2 mutational status. (F) Leukemia-free survival data for MDS patients stratified by IDH2 mutational status.

Figure 3

Figure 3. Kaplan–Meier survival curves for overall survival of MDS patients.

(A) Overall survival of MDS patients in the intermediate-1 risk group of IPSS. (B) Overall survival of MDS patients in the intermediate-2 risk group of IPSS. (C) Overall survival of MDS patients in the high risk group of IPSS. (D) Kaplan–Meier survival of IDH mutant patients with decitabine chemotherapy compared with other treatments.

Figure 4

Figure 4. Forest plots describing the association between IDH mutations and MDS.

(A) Forest plots of HR and 95% CI for IDH1/2 mutations in MDS comparing with IDH wild-type by OS endpoints. (B) Forest plots of HR and 95% CI for IDH1/2 mutations in MDS comparing with IDH wild-type by LFS endpoints. (C) Forest plots of HR and 95% CI for _IDH_1 mutations in MDS comparing with _IDH_1 wild-type by OS endpoints. (D) Forest plots of HR and 95% CI for _IDH_1 mutations in MDS comparing with _IDH_1 wild-type by LFS endpoints. (E) Forest plots of HR and 95% CI for _IDH_2 mutations in MDS comparing with _IDH_2 wild-type by OS endpoints. (F) Forest plots of cumulative meta-analysis of IDH mutations in association with MDS for OS by published year.

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Grants and funding

This study was supported by grants from Zhejiang Province Fund for Distinguished Young Scholars (LR12H08001), the Foundation of Key Innovation Team of Zhejiang Province (2011R50015), National Public Health Grand Research Foundation (201202017), major program of Science Technology Department of Zhejiang Province fund (2013c03043-2) and the National Natural Science Foundation of China (No.30870914, No.81270582). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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