Abstract
BackgroundEpigenetic 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.ResultsAdult 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.ConclusionsThe 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 registrationClinical Trials, NCT02886559. Registered 01 September 2016
Highlights
Approximately 30% of acute myeloid leukemia (AML) cases will be classified as refractory AML due to failure of induction chemotherapy
The prognosis for relapsed AML (r/r AML) remains dismal despite significant effort devoted to the development of novel single-agent drugs and the design of new combination regimens
Consistent with the study, we found in our trial that patients with FLT3-ITDs had a lower chance of achieving complete remission (CR)
Summary
30% of acute myeloid leukemia (AML) cases will be classified as refractory AML due to failure of induction chemotherapy. The addition of HDAC inhibitors, such as chidamide or panobinostat, can enhance decitabine’s chemosensitization and cytotoxicity effects on leukemia cells when combined with conventional chemotherapy [6,7,8,9]. 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
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