chidamide and Lymphoma--Large-B-Cell--Diffuse

Elderly patients with diffuse large B-cell lymphoma (DLBCL) present with poor clinical outcome and intolerance to intensive chemotherapy. Histone deacetylase inhibitors (HDACIs) show anti-lymphoma activities and can be applied to treat DLBCL. This study aimed to evaluate efficacy and safety of oral HDACI tucidinostat (formerly known as chidamide) plus R-CHOP (CR-CHOP) in elderly patients with newly diagnosed DLBCL (International Prognostic Index ≥ 2).. Among 49 patients, the complete response rate was 86%, with overall response rate achieving 94%. The 2-year progression survival (PFS) and overall survival (OS) rates were 68% (95% CI 52-79) and 83% (95% CI 68-91). Comparing with historical control (NCT01852435), the 2-year PFS and OS rates of double-expressor lymphoma phenotype (DEL) were improved, and negative prognostic effect of histone acetyltransferases CREBBP/EP300 mutations was also mitigated by CR-CHOP. Grade 3-4 neutropenia was reported in 171, grade 3-4 thrombocytopenia in 27, and grade 3 anemia in 11 of 283 cycles. No grade 4 non-hematological adverse event was reported.. CR-CHOP is effective and safe in elderly patients with newly diagnosed DLBCL. Relevance of DEL phenotype and molecular biomarkers on CR-CHOP response warrants further investigation in DLBCL. Trial registration ClinicalTrial.gov, NCT02753647. Registered on April 28, 2016.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Biomarkers; Case-Control Studies; CREB-Binding Protein; Cyclophosphamide; Doxorubicin; E1A-Associated p300 Protein; Epigenomics; Female; Histone Deacetylase Inhibitors; Humans; Lymphoma, Large B-Cell, Diffuse; Male; Middle Aged; Mutation; Phenotype; Prednisone; Prognosis; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogene Proteins c-myc; Pyridines; Rituximab; Survival Rate; Treatment Outcome; Vincristine

Histone deacetylases (HDAC) are clinically validated and attractive epigenetic drug targets for human cancers. Several HDAC inhibitors have been approved for cancer treatment to date, however, clinical applications have been limited due to the poor pharmacokinetics, bioavailability, selectivity of the HDAC inhibitors and most of them need to be combined with other drugs to achieve better results. Here, we describe our efforts toward the discovery of a novel series of lactam-based derivatives as selective HDAC inhibitors. Intensive structural modifications lead to the identification of compound 24g as the most active Class I HDAC Inhibitor, along with satisfactory metabolic stability in vitro (t

Topics: Animals; Binding Sites; Cell Cycle Checkpoints; Cell Proliferation; Dogs; Drug Design; Drug Screening Assays, Antitumor; Half-Life; Histone Deacetylase 1; Histone Deacetylase Inhibitors; Humans; Lymphoma, Large B-Cell, Diffuse; Mice; Microsomes, Liver; Molecular Docking Simulation; Protein Isoforms; Rats; Structure-Activity Relationship