Clinical Efficacy and Molecular Biomarkers of Chidamide Plus R-CHOP In Elderly Patients with Newly Diagnosed Diffuse Large B-Cell Lymphoma: An Open-Label Phase II Clinical Trial

Background: 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 combined with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) in treating DLBCL. Methods: Elderly patients with newly diagnosed DLBCL (IPI≥2) received oral HDACI chidamide (20mg twice a week for two weeks) and R-CHOP every 21 days (CR-CHOP) for six cycles. The primary endpoint was complete response rate at the end of the treatment. Whole exome sequencing, targeted sequencing and RNA-sequencing were performed in patients with available tumor samples. Findings: Among 49 patients, the complete response rate was 86%, with overall response rate achieving 94%. 2-year PFS and OS rate were 68% (95%CI 52-80) and 80% (95%CI 64-90), respectively. There was no difference in 2-year PFS (83% vs 65%, P=0.210) or OS (91% vs 81%, P=0.313) rate between double-expressor lymphoma (DEL) and non-DEL phenotype. However, 2-year PFS and OS rate of DEL patients was significantly improved by CR-CHOP, comparing with historical control (NCT01852435, P=0.030 and 0.036). Instead of histone acetyltransferases CREBBP/EP300, histone methyltransferases KMT2D mutations were associated with inferior PFS and OS (P=0.043 and <0.001). 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. Interpretation: 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: This trial is registered with ClinicalTrials.gov, number NCT02753647. Funding Statement: This study was supported, in part, by research funding from the National Natural Science Foundation of China (81520108003, 81830007, and 81670176), Chang Jiang Scholars Program, Shanghai Municipal Education Commission Gaofeng Clinical Medicine Grant Support (20152206 and 20152208), Clinical Research Plan of Shanghai hospital development center (SHDC, 16CR2017A), Multicenter Clinical Research Project by Shanghai Jiao Tong University School of Medicine (DLY201601), Collaborative Innovation Center of Systems Biomedicine, and the Samuel Waxman Cancer Research Foundation Declaration of Interests: All authors declare no conflict of interest. Ethics Approval Statement: The study was approved by ethics committee and institutional review board of Shanghai Rui Jin Hospital. Written informed consent was obtained from all participants in accordance with the Declaration of Helsinki