Editorial Note: Large B-cell lymphoma (LBCL) is a common malignant hematologic disorder, representing 40% of all new non-Hodgkin lymphoma diagnoses. About 60% of patients respond to first-line standard immunotherapy, but the prognosis for high-risk patients is generally poor. Recently, chimeric antigen receptor T-cell (CAR-T) therapy has demonstrated controllable safety and significant efficacy in the treatment of relapsed/refractory B-cell lymphomas, including LBCL, follicular lymphoma (FL), and mantle cell lymphoma (MCL). The 50th European Society for Blood and Marrow Transplantation (EBMT) Annual Meeting took place in Glasgow, UK, from April 14th to 17th, 2024. During the conference, American researcher Alejandro Luna de Abia presented a retrospective study (Abstract No.: OS6-06) indicating that extranodal involvement significantly impacts the prognosis of LBCL patients undergoing CAR-T therapy, highlighting the need for personalized management strategies for these patients. “Oncology Frontier – Hematology Frontier” has invited Professor Liang Huang from the Institute of Hematology, Chinese Academy of Medical Sciences, to provide a comprehensive review of this study.
Research Background Extranodal involvement in large B-cell lymphoma (LBCL) is a known adverse prognostic factor. It is currently unclear whether extranodal involvement impacts the efficacy of chimeric antigen receptor T-cell (CAR-T) therapy. This study aims to clarify the impact of extranodal involvement sites in LBCL on the efficacy of CD19 CAR-T therapy.
Methods This is a single-center retrospective study that included adult LBCL patients treated with CD19 CAR-T therapy, excluding those with primary central nervous system (CNS) diseases. The study retrospectively reviewed the results of 921 18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) scans, including before and after leukapheresis, at the time of best response, and at relapse. The involvement of the CNS and bone marrow was assessed where data were available.
Results Of the 274 LBCL patients treated with CD19 CAR-T cells (axi-cel 54%, tisa-cel 26%, liso-cel 20%), 38% had transformed lymphoma, and most had received bridging therapy (78%). Before leukapheresis, 68% of patients had extranodal involvement, with 32% having only nodal involvement. At the last disease assessment before CAR-T therapy, the most common sites of extranodal involvement were bone/soft tissue (41%) and gastrointestinal/peritoneum (22%); 8% had CNS/orbital involvement. In patients with extranodal disease, worse prognostic factors, such as poor general condition (P=0.015) and larger tumor volume (P<0.001), were more common.
Compared to patients with only nodal involvement, those with extranodal involvement before CAR-T treatment exhibited higher levels of ≥grade 2 cytokine release syndrome (CRS, 45% vs. 32%, P=0.046), higher levels of ≥grade 2 immune effector cell-associated neurotoxicity syndrome (ICANS, 27% vs. 6%, P<0.001), and a lower complete response rate (55% vs. 78%, P<0.001). In a multivariate Cox regression model, after adjusting for related factors, patients without extranodal involvement before CAR-T had significantly improved progression-free survival (PFS) (HR 0.51 [95%CI: 0.34-0.77]) and overall survival (OS) (HR 0.49 [0.29-0.83]).
CAR-T remission rates by anatomical site of lesions were as follows: adrenal/urinary-genital system (12/32, 38%), gastrointestinal/peritoneum (23/68, 34%), lung/pleura/pericardium (19/56, 34%), and CNS/orbit (8/25, 32%). In the multivariate Cox regression model, involvement of the adrenal/urinary-genital system (HR=2.45, 95%CI: 1.59-3.77) and liver/biliary/pancreas (HR=1.9, 95%CI: 1.23-2.94) before CAR-T treatment was associated with an increased risk of relapse or progression post-CAR-T treatment. The analysis showed that patients with extranodal involvement had a worse 1-year OS rate (32%, 95%CI: 24%-43%) compared to those without extranodal involvement (63%, 95%CI: 46%-86%).
Conclusions The study results suggest that extranodal involvement significantly impacts the prognosis of LBCL patients receiving CAR-T therapy, necessitating personalized management strategies for these patients. Researchers advocate for organ-specific treatment approaches in future studies. Additionally, further research into the molecular biology characteristics of extranodal tumors is needed to enhance understanding and improve treatment interventions.
Expert Review
This study explored the impact of extranodal involvement sites on the efficacy of CD19 CAR-T therapy in LBCL patients. It included a retrospective analysis of 921 PET/CT scans from 274 LBCL patients, with 68% showing extranodal involvement. Common sites of involvement included bone/soft tissue (41%), gastrointestinal/peritoneum (22%), and CNS/orbit (8%). Extranodal involvement was associated with poorer physical scores and higher metabolic tumor volumes (MTV). Patients received axi-cel (54%), tisa-cel (26%), or liso-cel (20%) treatments. Before treatment, extranodal involvement correlated with higher incidences of grade 2+ CRS and ICANS, and a lower complete remission rate; however, multivariate analysis showed that only nodal involvement indicated benefits in PFS and OS. The results indicate the need to consider the anatomical sites of extranodal lesions in evaluating CAR-T therapy efficacy and establishing personalized treatment plans. However, it should be noted that this single-center retrospective study, limited in case numbers for specific sites, may introduce bias. Furthermore, the underlying biological mechanisms affecting treatment efficacy due to extranodal lesions, including specific genotypes and changes in the tumor immune microenvironment, were not explored and warrant further investigation.
