Novel Targeted Agents in Combination with R-MINE (RMINE+X) Based on Different Molecular Subtypes in Relapsed/Refractory Diffuse Large B-Cell Lymphoma：a Phase 2 Multicenter Study

Background

The combination of gene-based chemotherapy and targeted therapy in the initial treatment of diffuse large B-cell lymphoma (DLBCL) has shown initial efficacy advantages (Mu-Chen Zhang, Cancer cell), but there have been fewer data in relapsed/refractory (R/R) DLBCL. Currently, the majority of subsequent treatments for these patients are salvage chemotherapy (such as the MINE regimen), but overall survival is poor and there is an unmet need. To replace the conventional mitoxantrone with its liposome formulation in R-MINE regimen, and incorporate new-targeted drugs (X) based on the different molecular subtypes in the R-MINE+X treatment of R/R DLBCL, and to explore its efficacy and safety.

Method

This study was a multicenter, single-arm, open-label study (NCT05784987) that enrolled R/R DLBCL patients aged ≥18 years. All patients received one cycle of R-MINE regimen treatment, followed by grouping and stratification based on gene subtype to receive different targeted drugs (X) in combination with R-MINE. The R-MINE+X regimen (rituximab 375 mg/m², d0; mitoxantrone hydrochloride liposome 12‒20 mg/m², d1; ifosfamide 1.33 g/m², d1‒3; etoposide 65 mg/m², d1‒3) was administered for up to 3 cycles (every 21 days is 1 cycle). The specific combination targeted drugs (X) are as follows: the MCD/BN2 group in combination with BTK inhibitors, the EZB group in combination with chidamide, the TP53 mutantion group in combination with PD-1 monoclonal antibody, and other types of groups in combination with lenalidomide or other targeted drugs (decided by the investigator). Patients who achieved complete response/partial response were assessed by the investigator for inclusion in the maintenance treatment group using targeted drug X, autologous stem cell transplantation (ASCT), allogeneic hematopoietic stem cell transplantation (allo-HSCT), or chimeric antigen receptor T-cell therapy (CAR-T). The primary endpoint was overall response rate (ORR), while secondary endpoints included complete response (CR) rate, duration of response (DoR), 1-year progression-free survival (PFS), 1-year overall survival (OS), and safety.

Result

From April 2022 to April 2024, a total of 39 R/R DLBCL patients were enrolled. The median age of all patients was 61 years (range 24‒79), and 22 (56.4%) patients were males. Among all patients, 33 (84.6%) patients had advanced-stage disease with stage III‒IV, and 21 (53.8%) patients had IPI scores of 3‒5. Twenty-five (64.1%) patients were refractory to the last-line therapy, and 12 patients (30.8%) were primary refractory.

As of the data cutoff date July 2024, a total of 27 patients had undergone at least one efficacy assessment, with the best ORR of 70.4% (19/27) and CR rate of 48.1% (13/27). In the patients with EZB group (n=2), 1 patient achieved CR and 1 patient achieved PR. There were 11 patients in MCD/BN2 group, with ORR of 63.6% (7/11) and CR rate of 45.5% (5/11). In the TP53 mutation group (n=1), 1 patient achieved CR. The best ORR and CR rate of the patients with Other group (n=13) were 69.2% (9/13) and 46.2% (6/13). Subgroup analysis showed efficacy in stage III‒IV patients, with ORR of 68.2% (15/22) and CR rate 40.9% (9/22). With a median follow-up of only 1.6 months, mPFS and mOS will be demonstrated after a longer follow-up. Grade ≥3 adverse events during study treatment (incidence ≥10%) were leucopenia (30.8%), neutropenia (30.8%), anemia (25.6%), thrombocytopenia (15.4%), and hypokalemia (12.8%).

Conclusion

R-MINE+X regimen therapy was well tolerated in all patients and showed clinically efficacy in patients with relapsed/refractory DLBCL. The study is ongoing and further results will be continuously released.