Chidamide, decitabine, cytarabine, aclarubicin, and granulocyte colony-stimulating factor (CDCAG) in patients with relapsed/refractory acute myeloid leukemia: a single-arm, phase 1/2 study

Lixin Wang, Jianmin Luo, Guofeng Chen, Meiyun Fang, Xudong Wei, Yinghua Li, Zhuogang Liu, Yin Zhang, Sujun Gao, Jianliang Shen, Xin Wang, Xiaoning Gao, Wei Zhou, Yigai Ma, Hui Liu, Xinquan Li, Linhua Yang, Kai Sun, Li Yu, Lixin Wang, Jianmin Luo, Guofeng Chen, Meiyun Fang, Xudong Wei, Yinghua Li, Zhuogang Liu, Yin Zhang, Sujun Gao, Jianliang Shen, Xin Wang, Xiaoning Gao, Wei Zhou, Yigai Ma, Hui Liu, Xinquan Li, Linhua Yang, Kai Sun, Li Yu

Abstract

Background: Epigenetic mechanisms play an important role in the chemoresistance of acute myeloid leukemia (AML). The clinical response to epigenetic modifier-based chemotherapy in patients with relapsed/refractory AML (r/r AML) is unclear. This multicenter clinical trial evaluated the safety and efficacy of epigenetic modifiers (chidamide and decitabine) in combination with aclarubicin, cytarabine, and granulocyte colony-stimulating factor (G-CSF) in patients with r/r AML.

Results: Adult patients with r/r AML were treated with chidamide, decitabine, cytarabine, aclarubicin, and G-CSF (CDCAG). The primary measures were overall response (OR), overall survival (OS), and safety. Next-generation sequencing was performed to analyze the correlation between gene mutations and response. A total of 93 patients with r/r AML were enrolled. Overall, 24 patients had a complete remission (CR) and 19 patients achieved CR with incomplete blood count recovery (CRi). The overall response rate (ORR) was 46.2%. The overall survival of these 43 patients who achieved CR/CRi was significantly longer than that of patients who failed to achieve remission (563 vs 152 days, P < 0.0001). Of the patients with mutations in epigenetic and transcription factor-related genes, but without internal tandem duplications in FMS-like tyrosine kinase3 (FLT3-ITDs), 55.6% achieved CR/CRi, whereas the ORR was 28.2% for patients with mutations in other genes.

Conclusions: The CDCAG regimen was well tolerated and effective in r/r AML. Patients with epigenetic and transcription factor-related gene mutations, but without FLT3-ITD mutations, may benefit from this regimen.

Trial registration: Clinical Trials, NCT02886559 . Registered 01 September 2016.

Keywords: DNA methyltransferase inhibitor; Histone deacetylase inhibitor; Next-generation sequencing; Relapsed/refractory acute myeloid leukemia.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Survival curves. a Overall survival curves for 93 patients with r/r AML. b Relapse-free survival curves for 43 patients with r/r AML. c Overall survival curves for 93 patients with r/r AML. Data are categorized according to whether CR/CRi was achieved. r/r AML, relapse/refractory acute myeloid leukemia; CR/CRi, complete remission or complete remission with incomplete count recovery
Fig. 2
Fig. 2
Correlation between somatic mutations and clinical responses. a Landscape of mutations detected in 88 patients at enrollment. Each row represents a gene, and each column corresponds to a participant in the study. The number of patients with mutations is listed on the left. Bar plots indicate the number of mutations per patient (top bar plot) and the number of mutations detected for each gene (side bar plot). b Co-mutations among the 88 patients with gene mutation detection. The thickness of the connecting lines indicates the frequency with which the two mutations co-occurred. c Landscape of mutations detected in 88 patients at enrollment, according to whether the patient achieved a response (complete remission or complete remission with incomplete count recovery) or not. Each row represents a gene, and each column corresponds to a participant in the study. CEBPA-dm, CEBPA double mutation
Fig. 3
Fig. 3
Overall survival curves for 76 patients with detectable mutation. Data are categorized according to whether mutation was in panel ET*. *Panel ET: epigenetic modifier-related or transcription factor-related gene mutations, but without FLT3-ITD co-mutation

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