Background <p>Improving the prognosis of patients with relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) remains an unmet need. This multicenter, phase II study (NCT05784987) aimed to assess the efficacy and safety of a mitoxantrone hydrochloride liposome (Lipo-MIT)-based rituximab with mitoxantrone/ifosfamide/mesna/etoposide (R-MINE)-containing regimen, in which conventional mitoxantrone was replaced with Lipo-MIT, with or without a targeted agent.</p> Methods <p>Patients older than 18 years with histologically confirmed R/R DLBCL were enrolled. All enrolled patients received an R-MINE-containing regimen in 21-day cycles for up to four cycles. The addition of the targeted agent (X) was individualized according to prior treatment resistance and molecular subtype. The primary endpoint was objective response rate (ORR).</p> Results <p>From March 27, 2023, to July 10, 2025, 60 patients were enrolled. Of the 55 efficacy-evaluable patients, the ORR was 76.4% (95% confidence interval [CI]: 63.0%–86.8%), and the complete response rate was 52.7% (95% CI: 38.8%–66.3%). With the median follow-up of 13.9 months, the median PFS was 17.5 months (95% CI: 10.8–24.2), and the estimated PFS rate at 1 year was 58.5%. The median OS was not reached, with an estimated 1-year OS rate of 84.0%. Late relapse after the last-line therapy was identified as the only independent predictor for ORR, with an ORR of 86.4%. Grade ≥ 3 treatment-related adverse events (TRAEs) occurred in 46.7% of patients, with neutropenia (33.3%) being the most common. No serious TRAEs or TRAE-related deaths occurred.</p> Conclusions <p>The Lipo-MIT-based R-MINE-containing regimen showed encouraging efficacy and a manageable safety profile in R/R DLBCL, warranting further validation.</p> Clinical Trial Registration <p>This trial is registered with ClinicalTrials.gov (NCT05784987). URL https//clinicaltrials.gov/study/NCT05784987.</p>