Lipo-MIT-based bridging therapy enables effective CAR-T treatment in high-risk relapsed or refractory B-cell lymphoma

Abstract

Abstract Background: Chimeric antigen receptor (CAR)-T cell therapy has significantly improved outcomes for relapsed or refractory (R/R) B-cell lymphoma. However, high tumor burden and bulky disease are risk factors of poor prognosis and severe adverse effects (AEs). Bridging therapy (BT) aims to reduce tumor burden and facilitate a smooth transition to CAR-T infusion. Mitoxantrone Hydrochloride Liposome (Lipo-MIT), a liposomal anthracycline with enhanced accessibility to mass tumor, has shown promising clinical efficacy in hematological malignancies. Here, we evaluated the efficacy and safety of R/G/Z-MINE regimen including CD20 antibody, Lipo-MIT, ifosfamide and etoposide as BT prior to CAR-T in patients (pts) with aggressive, bulky, or rapidly progressive R/R B-cell lymphoma. Methods: We retrospectively enrolled pts with R/R B-cell lymphoma who received at least one cycle of R/G/Z-MINE regimen before CAR-T administration in a single institution from Feb 2022 to Aug 2024. Anti-CD20 monoclonal antibodies were administered on day 0, including rituximab or zebrituzumab at 375 mg/m² or obinutuzumab at 1000 mg. Lipo-MIT was administered at a dose of 20 mg/m² on day 1. Ifosfamide was given at 1.33 g/m²/day and etoposide at 65 mg/m²/day on days 1–3. The response to BT was evaluated by CT or PET-CT imaging both before BT initiation and prior to CAR-T infusion. Results: A total of 22 pts was included, comprising 16 (72.7%) with de novo diffuse large B cell lymphoma, 3 (13.6%) with transformed follicular lymphoma, and 3 with Burkitt lymphoma. The median age at screening was 52 years (range, 18-66), and 15 (68%) pts were male. 72.7% have primary refractory disease, with a median prior treatment line of 2.5 (1-5). Nineteen pts (86.4%) had Ann Arbor stage III-IV disease with a median IPI score of 3. Extranodal involvement was observed in 21 pts (95.5%), including 5 (22.7%) with CNS disease and 8 (36.4%) with bulky disease (defined as any lesion >75 mm in diameter). The most common AEs during BT were hematotoxicity (95.5%), with grade≥3 treatment-related hematotoxicity observed in 17 pts (77.3%). All pts successfully proceeded to subsequent CAR-T therapy, and the median interval between leukapheresis and CAR-T was 43 days (range, 22-94). Among the 14 pts (63.6%) who responded to BT, 6 with bulky disease achieved lesion shrinkage to <75 mm after BT. The overall response rate (ORR) to CAR-T was 72.7% (16/22) with a complete response (CR) rate of 59.1% (13/22). Grade 3 cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were developed in 1 (4.5%) and 2 (9.1%) pts. Any grade immune effector cell-associated hematotoxicity were reported in 7 pts (31.8%), with no treatment related mortality events. Pts with bulky lesions showed comparable ORR and incidences of CRS and ICANS to those without . Significant reductions in the longest diameter and the sum of the product of the perpendicular diameters of measurable lesions were observed after BT and further decreased following CAR-T infusion, highlighting the effective tumor debulking achieved by the sequential approach (p<.001 for both) . Notably, there were statistically significant differences in ORR and CR rates between responders to BT and non-responders (ORR 92.9% vs. 37.5%, CR 78.6% vs. 37.5%; p<.05). Responders had also significantly longer PFS than non-responders (median NR vs. 1.95 months; p < .01) . CAR-HEMATOTOX scores were assessed pre- and post-BT, and the majority remained the same with 3 pts upgrading from low to high risk and 1 downgrading from high to low, suggesting no significant increase in hematotoxic risk associated with R/G/Z-MINE as BT regimen . Conclusions: In this pragmatic clinical study conducted in a cohort of pts with high tumor burden and rapidly progressive disease, R/G/Z-MINE regimen was shown to be a feasible bridging strategy that achieved effective tumor debulking and controllable safety profile, ultimately contributing to improved clinical outcomes following CAR-T therapy. These findings support the integration of intensive chemo-immunotherapy as a rational strategy to optimize CAR-T efficacy for pts with high-risk features.