Transplantation in combination with CAR T-cell therapy for refractory/relapsed aggressive B-cell lymphoma after failure of CD19 CAR-T cell therapy

Abstract

Abstract Background: The prognosis for patients with refractory/relapsed aggressive B-cell lymphoma (R/R B-NHL) who have failed CD19 CAR-T cell therapy is exceptionally poor. Aims: This study conducted a retrospective analysis of the treatment efficacy and survival of the patients who underwent autologous transplantation combined with another targeted CAR-T therapy(auto-HSCT+CAR-T) and allogeneic transplantation with donor-derived CAR-T therapy (allo-HSCT+donor CAR-T) after failing CD19 CAR-T therapy. Methods: From May 2020 to March 2024, 24 patients were included (Table 1). The median age was 39 years (range: 16-54). Diagnoses included DLBCL NOS (n=12), HGBL (n=9), PMBL (n=2), and MCL (n=1). The median IPI score was 3 (range: 2-5). Fourteen patients (58.3%) presented with extranodal lesions, and 8 (33.3%) had bulky disease (>7cm).After bridging therapy (BT), 7 of the 24 patients (29.2%) exhibited disease progression before transplantation. Twelve patients (50%) were selected for auto-HSCT+CAR-T and the other 12 (50%) for allo-HSCT+donor CAR-T, at a median of 8 months (range: 2-48) post-CD19 CAR-T infusion. Prior to the study, CD20/CD22 antigen expression in tumor tissue was confirmed by pathology, with the target selected based on antigen expression. The conditioning regimen for the auto-HSCT+CAR-T group was BEAM, while that for the allo-HSCT+donor CAR-T group consisted of a busulfan-fludarabine-based regimen. In the allo-HSCT+donor CAR-T group, there was 1 MSD, 1 MUD, and 10 HID. Tacrolimus,MMF, short-term MTX, and ATG were employed for GVHD prophylaxis. Results: The median number of CAR-T cells infused was 2.2×10^6/kg (range: 0.3-4.48×10^6/kg). The expansion of CAR-T cells was monitored in all patients, with the median time for both auto and donor CAR-T cells being 7 days post-infusion. The incidence of grade 3 CRS was 25% (6/24). Grade 1-2 neurotoxicity occurred in 4.2% (1/24) of patients. Nineteen patients experienced infections, with 16 (66.7%) suffering from grade 3 or higher severity. Among the patients who underwent allo-HSCT+donor CAR-T, 3 of 12 (25%) developed aGVHD(Table 2). The median follow-up period was 28.6 months (95% CI: 25.2-52.2). The ORR was 91.7%, with a CR of 83.3% and a PR of 8.3%. The median OS was 14.56 months (95% CI: 8.9-45.6), and the median PFS was 9.21 months (95% CI: 5.12-12.9). Among the 12 patients treated with autoHSCT+CAR-T therapy, 11 (91.7%) achieved CR, while 7 (63.6%) survived disease-free. In this cohort, 4 patients (33.3%) relapsed and died, while 1 patient (8.3%) died from an infection. In the alloHSCT+donor CAR-T group, 9 (75%) achieved CR and 2 (16.7%) achieved PR, with 4 (36.4%) surviving disease-free. In this group, 3 patients (25%) relapsed and died, while 5 (41.7%) died due to infections. Conclusion: Transplantation combined with CAR-T therapy presents an effective option for R/R B-cell lymphoma following the failure of CD19 CAR-T. Effective BT prior to transplantation significantly enhances survival rates.