Dual epigenetic modulation with obinutuzumab/liposomal mitoxantrone in refractory or Relapsed Diffuse large B-cell lymphoma patients post-salvage therapy: A phase II study Free

Background: Patients with refractory or relapsed (R/R) diffuse large B-cell lymphoma (DLBCL) who had failed salvage therapy have an extremely poor prognosis. We previously investigated the efficacy of CD-R-GemOx, a dual epigenetic agent-primed immunochemotherapy regimen, consisting of chidamide, decitabine, rituximab, gemcitabine, and oxaliplatin, in this high-risk population. The findings showed promising outcomes with an overall response rate (ORR) of 78.6% and a complete response rate (CRR) of 42.9%. However, 92.7% of patients occurred grade III/IV hematological toxicity. This emphasizes the critical need to optimize the dual epigenetic immunochemotherapy approach to enhance patient outcomes while mitigating adverse effects.

Aims:This study aims to evaluate the efficacy and safety of a modified dual epigenetic priming immunochemotherapy regimen, termed CAGM, consisting of chidamide, azacitidine, obinutuzumab, and mitoxantrone liposome, in R/R DLBCL patients who had failed salvage therapy.

Methods:This ongoing, prospective, multicenter, open-label phase II study (NCT05823701) enrolled patients with R/R DLBCL who had failed salvage therapy. The study initiated with two cycles of induction therapy using CAGM, which includes Chidamide(20 mg orally on days 1, 4, 8, and 11 of each cycle), Azacitidine(100 mg subcutaneously on days 1-5 of each cycle), Obinutuzumab(1000 mg intravenously on day 4 of each cycle) and Liposomal Mitoxantrone(20 mg/m² intravenously on day 5 of each cycle). Following induction phase, patients who achieved complete remission (CR) or partial remission (PR) were considered for autologous stem cell transplantation (ASCT) or chimeric antigen receptor T-cell therapy (CAR-T), depending on their eligibility. For patients ineligible for ASCT/CAR-T, an additional four cycles of CAGM were administered. The primary endpoints were the ORR and CRR after two cycles of CAGM. Secondary endpoints included ORR and CRR after six cycles for patients ineligible for ASCT/CAR-T, 2-year overall survival (OS), 2-year progression-free survival (PFS), and safety profiles for all participants.

Results: As of August 1, 2025, 26 patients had completed at least two cycles of CAGM and undergone efficacy assessments. The majority of these patients had non-GCB subtype diffuse large B-cell lymphoma (DLBCL) and were at advanced stages (III/IV). Over one-third had received three or more prior lines of therapy and were refractory to previous treatments before initiating CAGM. After two cycles of CAGM, 10 patients achieved complete response (CR), 10 achieved partial response (PR), and 6 experienced disease progression, leading to their withdrawal from the trial. The overall response rate (ORR) and complete response rate (CRR) after two cycles were 76.9% and 38.5%, respectively. Among the 20 responders, 6 patients received additional CAGM therapy, with an ORR of 83.3% and a CRR of 66.7% after 6 cycles of CAGM. Additionally, 4 patients underwent autologous stem cell transplantation (ASCT), 5 received CAR-T therapy, and 5 underwent sequential ASCT followed by CAR-T. Following consolidation therapy, the best ORR and CRR were 81.2% and 100%, respectively. At the time of analysis, 16 patients remained alive and all maintained CR. Four deaths were reported during follow-up, attributed to disease progression (2 cases), heart failure induced by severe hemolytic anemia (1 case), and severe COVID-19 infection (1 case). With a median follow-up of 28.5 months (range: 7.8-35.9 months), the 1-year overall survival (OS) and progression-free survival (PFS) rates were 80.2% and 56.7%, respectively, while the 2-year OS and PFS rates were 67.9% and 49.6%. The median OS was not reached, and the median PFS was 16.2 months. During CAGM induction, adverse events (AEs) were reported in 24 patients (92.3%). The most common AEs were hematological toxicities (88.5%), with 50.0% being grade III/IV. The most frequent non-hematological toxicities included elevated alanine aminotransferase/aspartate aminotransferase (19.2%), nausea (15.4%), mucositis (11.5%), fever (11.5%), pneumonia (3.8%), rash (3.8%), infusion-related reactions (3.8%) and COVID-19 infection (3.8%).

Conclusions: This study demonstrates the favorable efficacy and significantly lower hematological toxicities of the CAGM regimen in R/R DLBCL patients, offering a promising therapeutic option for this challenging population.