Clinical efficacy and molecular biomarkers in a phase II study of tucidinostat plus R-CHOP in elderly patients with newly diagnosed diffuse large B-cell lymphoma

Mu-Chen Zhang, Ying Fang, Li Wang, Shu Cheng, Di Fu, Yang He, Yan Zhao, Chao-Fu Wang, Xu-Feng Jiang, Qi Song, Peng-Peng Xu, Wei-Li Zhao, Mu-Chen Zhang, Ying Fang, Li Wang, Shu Cheng, Di Fu, Yang He, Yan Zhao, Chao-Fu Wang, Xu-Feng Jiang, Qi Song, Peng-Peng Xu, Wei-Li Zhao

Abstract

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 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).

Results: 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.

Conclusion: 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.

Keywords: CREBBP/EP300; Diffuse large B-cell lymphoma; Double expressor lymphoma; Histone deacetylase inhibitor; Tucidinostat.

Conflict of interest statement

All authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
CONSORT diagram of the study
Fig. 2
Fig. 2
Outcomes of patients treated with CR-CHOP. a PFS and OS of all patients. b PFS and OS stratified by IPI. c PFS and OS stratified by cell of origin. CR-CHOP = tucidinostat (formerly known as chidamide), rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone. PFS = Progression-free survival. OS = Overall survival. IPI = International Prognostic Index
Fig. 3
Fig. 3
Outcomes of patients treated with CR-CHOP and historical control based on BCL2/MYC double expression. a PFS and OS of patients treated with CR-CHOP. b PFS and OS of patients from historical control (NCT01852435). CR-CHOP = tucidinostat (formerly known as chidamide), rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone. PFS = Progression-free survival. OS = Overall survival
Fig. 4
Fig. 4
Correlation of genomic alterations with response to CR-CHOP. a Epigenetic gene mutations by whole genome sequencing and targeted sequencing in 36 patients. The number of patients with mutations was listed on the right. b Forest plot of univariate analysis on PFS and OS in patients with or without epigenetic gene mutations. PFS = Progression-free survival. OS = Overall survival

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