Bendamustine combined with fludarabine/cyclophosphamide as a enhanced lymphodepletion regimen demonstrates favorable efficacy and safety in CAR-T therapy for extranodal/bulky R/R B-cell lymphoma

Abstract

Abstract Introduction： Bulky disease has been identified as an independent predictor of poor outcomes following CAR-T therapy. Although lymphodepletion (LD) critically affects CAR-T cell functionality and treatment response, its clinical significance remains undervalued, with no established protocols for standardized regimens. While bendamustine has gained traction as a standalone LD approach in commercial CAR-T products, its mechanistic basis and ideal combinatorial applications need further investigation. In this study, we investigated the combination of bendamustine with the standard fludarabine/cyclophosphamide (FC) regimen in patients exhibiting high tumor burden, particularly those with extranodal involvement or bulky disease, to assessed the clinical efficacy and safety . Methods A total of 38 adult patients with R/R BCL undergoing CAR-T therapy were enrolled. The LD regimen comprised bendamustine (70 mg/m²) on day -6 and FC (fludarabine 25 mg/m², cyclophosphamide 250 mg/m² daily for 3 days, days -5 to -3) before CAR-T cell infusion (day 0). Clinical outcomes were retrospectively analyzed. Primary endpoints included median absolute lymphocyte count (ALC) reduction from pre-LD to CAR-T infusion, complete response (CR) rate, 1-year overall survival (OS), progression-free survival (PFS), and adverse events (AEs) such as cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and hematologic toxicity. Results: From March 2022 to March 2025, 38 patients were enrolled, with a median age of 56 years (range: 30–79). Among them, 35 (92.11%) had bulky disease (>5 cm) and/or extranodal involvement, 42.11% (16/38) were aged ≥60 years, 73.68% (28/38) had a CAR-HEMATOTOX score ≥3, and 50.0% (19/38) had an International Prognostic Index (IPI) score ≥3. The median ALC at CAR-T infusion was 0.04 × 10⁹/L (range: 0–0.23), with a median ALC reduction of -0.53 × 10⁹/L (range: -2.18 to 0.07) from pre-LD to infusion. The best response was evaluated at 1 to 6 months after CAR-T cell infusion. CR was achieved in 55.26% (21/38) of patients, and PR was observed in 26.31% (10/38), yielding an overall response rate (ORR) of 81.57%. With a median follow-up of 21.5 months (note: some patients had shorter enrollment durations), the median OS was not reached, while the median PFS was 10.3 months. Survival analysis demonstrated 12-month, 24-month, and 36-month OS rates of 79.14%, 67.04%, and 54.93%, respectively. The 12-month PFS rate was 52.37%. Safety assessment showed CRS of any grade/≥grade 3 in 63.1%/5.3% of patients, ICANS of any grade/≥grade 3 in 5.3%/2.6%, and hematologic toxicity including neutropenia (60.53%, 23/38) and grade 4 thrombocytopenia (28.95%, 11/38). Conclusion The B-FC regimen demonstrates promising efficacy and safety in elderly patients with high tumor burden and elevated CAR-HEMATOTOX scores. Further investigation is warranted to elucidate the mechanistic impact of B-FC on CAR-T cell kinetics.