Abstract
BACKGROUND: Histone deacetylase (HDAC) inhibitors demonstrated a synergistic anti-tumor effect with rituximab and chemotherapy in preclinical studies on diffuse large B-cell lymphoma (DLBCL). This phase 2 trial aimed to evaluate the efficacy and safety of chidamide, an orally active HDAC inhibitor, plus the R-GemOx regimen for relapsed/refractory (R/R) DLBCL. METHODS: Patients with transplantation-ineligible R/R DLBCL received chidamide (20 mg, oral, days 1, 4, 8, 11, 15, and 18), rituximab (375 mg/m(2), day 1), gemcitabine (1000 mg/m(2), day 2), and oxaliplatin (100 mg/m(2), day 2) in a 21-day cycle for 6 cycles (induction phase), followed by chidamide (20 mg, oral, twice weekly on Mondays and Thursdays) until disease progression or intolerable toxicity (maintenance phase). The primary endpoint was overall response rate (ORR). RESULTS: Between June 19, 2019 and July 5, 2022, 54 patients were enrolled. The ORR was 59.3% (95% CI: 45.0-72.4). With a median follow-up of 38.1 months (interquartile range: 19.5-48.2), the median progression-free survival and overall survival were 7.4 (95% CI: 5.2-14.2) and 23.9 (95% CI: 15.2-not reached) months, respectively. The most common grade 3/4 treatment-emergent adverse events (TEAEs) were neutropenia (40.7%), thrombocytopenia (33.3%), and leukopenia (27.8%). Whole-exome sequencing showed that CREBBP mutations and BTG2 mutations were associated with poor response and survival. CONCLUSION: Chidamide plus R-GemOx demonstrated promising anti-tumor activity with acceptable toxicities in transplantation-ineligible R/R DLBCL patients. Patients with CREBBP mutations and BTG2 mutations had inferior response and survival. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04022005.