A Phase II Study of Dual Epigenetic Agents Plus Obinutuzumab-Mitoxantrone Liposome in Relapsed/Refractory Diffuse Large B-Cell Lymphoma Patients Failure of Salvage Immunochemotherapy

Background: The prognoses of refractory/relapsed(R/R) diffuse large B-cell lymphoma(DLBCL) patients are extremely poor. We previously found that the overall response rate(ORR) and complete response rate(CRR) of dual epigenetic agents priming immunochemotherapy CD-R-GemOx(chidamide, decitabine, rituximab, gemcitabine and oxaliplatin) in R/R DLBCL failure of salvage treatment were 78.6% and 42.9%, respectively, which was highly effective. However, grade III/IV hematological toxicity was 92.7% and it is extremely important to modify dual epigenetic immunochemotherapy regimen.

Aims: This study aimed to evaluate the efficacy and safety of dual epigenetic priming immunochemotherapy CAGM regimen including chidamide, azacitidine, obinutuzumab and mitoxantrone liposome in R/R DLBCL patients.

Methods: Patients with R/R DLBCL failure of combined salvage immunochemotherapy were enrolled in this ongoing, prospective, multicenter, open-label phase II study(NCT05823701). The study started with an initial 2 cycles of induction therapy with CAGM containing chidamide(20 mg d1, d4, d8, d11 orally per cycle), azacitidine(100mg d1-d5 subcutaneous injection per cycle), obinutuzumab(1000mg d4 intravenous infusion per cycle) and liposomal mitoxantrone(20mg/m2 d5 intravenous infusion per cycle), following imaging examinations to evaluate response rates. Patients achieved complete remission(CR) or partial remission(PR) were followed by autologous stem cell transplantation(ASCT)/chimeric antigen receptor T cell therapy(CAR-T) for patients feasible to ASCT/CAR-T, while another 4 cycles of CAGM immunochemotherapy were given to patients who were unable to undergo ASCT/CAR-T. The primary endpoints were ORR and CRR at the end of cycle 2 of CAGM regimen for all patients. The secondary endpoints were ORR and CRR at the end of cycle 6 of CAGM regimen for patients infeasible to ASCT/CAR-T, 2-year overall survival(OS), 2-year progression free survival(PFS) and safety profiles for all patients.

Results: As of July 2024, 21 patients completed ≥2 cycles of CAGM and got at least one efficacy assessment. Among the 21 patients, the majority were non-GCB subtype and at III/IV stage. Almost half of patients received at least 3 lines of therapies and were refractory to prior therapy before CAGM. After 2 cycles of CAGM, 8 patients achieved CR, 7 patients achieved PR and 6 patients got disease progression who were withdrew from this trial. The ORR and CRR for a 2-cycle response were 71.4% and 38.1% respectively. Among the 15 responders, 3 patient received additional CAGM therapy, 3 patients were exposed to ASCT, 4 patients were exposed to CAR-T, and 5 patients received ASCT sequential CAR-T. The best ORR and CRR after consolidation therapy were 80% and 100% respectively. So far, 11 patients were alive with 9 patients maintained CR and 2 got PR. There were totally 4 deaths during the follow-up including 2 disease progression, 1 heart failure induced by severe hemolytic anemia and 1 severe COVID-19 infection. With a median follow-up time of 16.2 months ranged from 2.5 to 21.8 months, the one-year OS rate was 82.1% and the PFS rate was 80.9%. The median OS and PFS were not reached. During CAGM induction, the most common adverse events were hematological toxicities with 33.3% grade III/IV. All toxicities were transient and reversible.

Conclusions: This study demonstrates a favorable efficacy and significantly lower hematological toxicities of CAGM regimen in R/R DLBCL patients and expands therapeutic options for R/R DLBCL patients. More updated clinical data will be presented from this ongoing study.

No relevant conflicts of interest to declare.

Chidamide: Chidamide is the first subtype-selective histone deacetylase (HDAC) inhibitor available that can be administered orally, belonging to the class of epigenetic modulating drugs. The combination of chidamide and R-CHOP has been shown to significantly improve the complete response rate and deliver notable survival benefits for previously untreated diffuse large B-cell lymphoma (DLBCL) with positive expression of MYC and BCL2. Currently, this indication of chidamide has been granted approval in China.Azacitidine: Azacitidine is also an epigenetic modulating drug that has a synergistic effect with Chidamide. Previous studies have shown that dual epigenetic regulation has a potential therapeutic effect on DLBCL.Obinutuzumab: Obinutuzumab is a novel humanized anti-CD20 monoclonal antibody approved for follicular lymphoma. However, for patients with DLBCL who have failed rituximab treatment, Obinutuzumab has been reported to have some therapeutic effect.Mitoxantrone Liposome: Mitoxantrone liposomes use the high osmotic long retention (EPR) effect to passively target tumors and make tumor tissues have higher drug concentration. The current approved indications in China are relapsed/refractory (R/R) PTCL and extranodal NK/T cell lymphoma (NKTCL) patients, and clinical studies in the field of R/R DLBCL have also shown considerable efficacy.