Efficacy and safety of chidamide and Bruton tyrosine kinase inhibitors  combination therapy in relapsed/refractory diffuse large B-cell lymphoma

Abstract Background: Relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) shows poor clinical outcomes, particularly in patients ineligible for stem cell transplantation or who failed induction therapy or salvage therapy. Monotherapy Bruton tyrosine kinase inhibitors (BTKi) have established modest antitumor effect in R/R DLBCL by targeting B-cell receptor signaling, with median progression-free survival (PFS) and overall survival (OS) of 1.64-2.8 months and 6.4-8.4 months, respectively. Chidamide is a selective oral histone deacetylase inhibitors (HDACi) that shows promising treatment for DLBCL and may overcome BTKi resistance. So, in this prospective, we evaluated the efficacy and safety of BTKis and chidamide-combined therapy in R/R DLBCL (ChiCTR2300073233). Methods This prospective clinical study consists of 31 R/R DLBCL who received combination therapy of chidamide and BTK inhibitors between January 2023 and July 2025. Chidamide was orally administered at a dose of 20 mg twice a week,while the BTK inhibitor was administered daily. Patient clinical characteristics were collected upon patient enrollment. Efficacy outcomes included overall response rate (ORR), PFS and OS, whereas safety outcomes included incidence of adverse events. Results Thirty-one R/R DLBCL patients were enrolled. Median age was 61 years (range, 31-90), and 84% of the patients had non-germinal center B-cell-like (non-GCB) DLBCL, 3 patients had GCB DLBCL, 2 had transformed DLBCL. The median number of previous treatment lines was 3 (range, 3-8). 18 patients (58%) received treatment with BTK inhibitors before. Five patients (16%) failed to chimeric antigen receptor T-cell/NK-cell(CAR-T/CAR-NK) therapy. The best ORR was 61%, with 19 patients acquired objective disease remission after 1-2 cycles. Among them, 9 patients (29%) achieved complete response, and 10 patients (32%) achieved partial remission. With a median follow-up of 24 months, the median PFS was 6 months (95%CI 4-8) and median OS was not yet reached. In terms of adverse events, the most common hematologic toxicities observed were grade ≥3 neutropenia (35%) and grade ≥3 thrombocytopenia (32%). Two patients (6%) had pneumonia, and one patient (3%) had herpes zosters. Conclusion This prospective clinical study revealed promising results. Despite the majority of patients had been treated with BTK inhibitors and experienced relapse and resistance, the addition of chidamide brought patients back into remission, suggesting that chidamide can enhance the efficacy of BTK inhibitors and overcome acquired resistance. Notably, chidamide combined with BTK inhibitors showed high efficacy and manageable tolerability, making it a promising treatment option for patients with R/R DLBCL.