Mutations of Epigenetic Modifier Genes as a Poor Prognostic Factor in Acute Promyelocytic Leukemia Under Treatment With All-Trans Retinoic Acid and Arsenic Trioxide

Abstract

Background: Acute promyelocytic leukemia (APL) is a model for synergistic target cancer therapy using all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), which yields a very high 5-year overall survival (OS) rate of 85 to 90%. Nevertheless, about 15% of APL patients still get early death or relapse. We performed this study to address the possible impact of additional gene mutations on the outcome of APL.

Methods: We included a consecutive series of 266 cases as training group, and then validated the results in a testing group of 269 patients to investigate the potential prognostic gene mutations, including FLT3-ITD or -TKD, N-RAS, C-KIT, NPM1, CEPBA, WT1, ASXL1, DNMT3A, MLL (fusions and PTD), IDH1, IDH2 and TET2.

Results: More high-risk patients (50.4%) carried additional mutations, as compared with intermediate- and low-risk ones. The mutations of epigenetic modifier genes were associated with poor prognosis in terms of disease-free survival in both training (HR = 6.761, 95% CI 2.179-20.984; P = 0.001) and validation (HR = 4.026, 95% CI 1.089-14.878; P = 0.037) groups. Sanz risk stratification was associated with CR induction and OS.

Conclusion: In an era of ATRA/ATO treatment, both molecular markers and clinical parameter based stratification systems should be used as prognostic factors for APL.

Keywords: Acute promyelocytic leukemia; Epigenetic; Mutation; Prognosis.

Fig. 1

Correlation between gene mutations and clinical risk groups. High-risk patients contained more mutations additional to PML–RARα (50.4%, 66/131) as compared with intermediate- (25.0%, 62/248, P < 0.001) and low-risk (23.1%, 36/156, P < 0.001) groups.

Fig. 2

Kaplan–Meier curves for overall survival (OS) and disease-free survival (DFS) according to Sanz's risk stratification in univariate analysis. (A, B) OS and DFS of different risk groups in training group. (C, D) OS and DFS of different risk groups in validation group.

Fig. 3

Kaplan–Meier curves for overall survival (OS) and disease free survival (DFS) according to EMG mutational status in univariate analysis. (A, B) OS and DFS of patients with EMG mutations in training group. (C, D) OS and DFS of patients with EMG mutations in validation group.

Fig. 4

Kaplan–Meier curves for overall survival (OS) and disease free survival (DFS) according to FLT3 mutational status in univariate analysis. (A, B) OS and DFS of patients with FLT3 mutations in training group. (C, D) OS and DFS of patients with FLT3 mutations in validation group.