A Multicenter, Phase III Study of Chidamide, Azacitidine Combined with CHOP Versus CHOP in Patients with Untreated Peripheral T-Cell Lymphoma

Abstract

Introduction The biology of peripheral T-cell lymphoma (PTCL) is characterized by recurrent mutations affecting epigenetic regulators such as TET2, DNMT3A, IDH2, and RHOA, particularly in patients with angioimmunoblastic T-cell lymphoma (AITL) or PTCL-not otherwise specified. Azacitidine, a DNA methyl transferase (DNMT) inhibitor, has shown clinical activity as a single agent and in combination in R/R PTCL. Single-agent of the histone deacetylase (HDAC) inhibitors, including romidepsin, belinostat, and chidamide are associated with overall response rates of 25-30% in R/R PTCL. These evidence suggests that PTCL may have a unique vulnerability to epigenetic modulators which also provide the rationale for combining an HDAC inhibitor with a DNMT inhibitor in the backbone of the CHOP regimen forming a novel double-epigenetic regulating chemotherapy as an initial treatment for PTCL. Herein, we report the finding of the phase III trial of chidamide and azacitidine combined with CHOP (AC-CHOP) versus CHOP in patients with untreated PTCL (ClinicalTrials.gov - NCT05075460). Methods This study is a multicenter, non-randomized, phase III trial conducted at 4 centers in China. Eligible patients were aged between 18-75 years with newly diagnosed PTCL. Patients were non-randomly assigned to the AC-CHOP or the CHOP group according to the investigator's and patient's choice. Patients in the AC-CHOP group received azacitidine 200 mg subcutaneously on days 1-2 and 100 mg on day 3, chidamide 20mg orally twice weekly, combined with the CHOP regimen in a 3-week cycle for six cycles. Patients in the CHOP group received the CHOP regimen alone. The primary endpoint was the overall response rate (ORR) after the protocol treatment. Results Between August 2021 and March 2022, 35 patients were enrolled in the study and finished protocol treatment (20 in the AC-CHOP arm and 15 in the CHOP arm). Main pathological subgroups were PTCL not specified (n = 14) and AITL (n = 21). The baseline characteristics and pathological subtypes were mostly similar between the two treatment arms. At the end of treatment, the ORR and complete response (CR) rates were 60.0% and 55.0% in the AC-CHOP arm versus 53.3% and 26.7% in the CHOP arm (P = 0.693 for ORR and P = 0.184 for CR rate) , respectively. With a median follow-up time of 9 months, the median progression-free survival was 8 months in the AC-CHOP arm and 7 months in the CHOP arm (P = 0.602). The most frequent grade 3 to 4 adverse events included neutropenia (55.0% in the AC-CHOP arm versus 40.0% in the CHOP arm), thrombocytopenia (20.0% in the AC-CHOP arm versus 13.3% in the CHOP arm), and Anemia (5.0% in the AC-CHOP arm versus 6.7% in the CHOP arm) which showed no significant difference between the two arms. Conclusions According to the preliminary result of the study, the addition of azacytidine and chidamide to the CHOP regimen did not show a significant improvement of ORR or PFS for patients with untreated PTCL. A trend of higher CR rate was observed which did not reach statistical significance. The safety profile of AC-CHOP regimen was manageable.