Site-Specific Response Rates in Large B-Cell Lymphomas Treated with CD19-CART Therapy.

Introduction Patients with relapsed or refractory large B-cell lymphoma (LBCL) frequently manifest systemic disease prior to CD19-directed chimeric antigen T-cell (CAR-T) therapy. However, it remains unclear whether specific nodal (ND) and extranodal (EN) sites act as sanctuaries, facilitating resistance against CAR-T activity. Therefore, our study aims to elucidate the dynamics of anatomical disease involvement before and after CD19-CAR-T therapy. Methods Adults with LBCL treated with CD19-CAR-T were included; primary central nervous system (CNS) disease was an exclusion criterion. We retrospectively reviewed 628 18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET) scans performed before apheresis, after apheresis, at the time of best response, and at relapse; CNS and bone marrow involvements were evaluated when available. For CAR-T refractory disease, relapse and best response PET assessments were considered as the same. Results Among 191 LBCL patients treated with CD19-CAR-T cells (axi-cel 55%, tisa-cel 26%, liso-cel 19%), 35% had transformed lymphoma, and the majority received bridging therapy (81%). EN involvement (with/without ND disease) before apheresis was observed in 62% of cases, with only 38% presenting exclusively with ND disease. In the most recent assessment before CAR-T, the most common EN sites involved were bone/soft tissue (35%) and lungs/pleura/pericardium (17%) (figure 1); 8% had CNS involvement. Poor prognostic factors, including lower performance status (p=0.017), higher pre-apheresis metabolic tumor volume (p=0.004), and higher pre-lymphodepletion LDH levels (p=0.028), were more prevalent in patients with EN involvement compared to exclusive ND involvement.Complete response (CR) rates in patients with EN and exclusive ND involvement at best response were 56% vs 82%, respectively (p<0.001). Among EN sites, site-specific CR rates (figure 2) were lowest in hepatobiliary/pancreas (2/11 [18%]), adrenal/kidney (4/14 [29%]), and CNS (5/15 [33%]) sites. At the time of progression or relapse after CAR-T therapy 71/87 (82%) and 68/87 (78%) of patients had EN and ND involvement, respectively; commonly involved EN sites were bone/soft tissue (41/87 [47%]) and lungs/pleura/pericardium (26/87 [30%]). Finally, 1 year after relapse or progression, the overall survival rates measured from the time of relapse post-CAR-T were similar regardless of EN involvement (EN: 51% [95%CI: 40-65]) or exclusive ND involvement (56% [33-96], p=0.11). Conclusion This first-in-kind, large-scale analysis of site-specific dynamics in CAR-T patients identified lower response rates in the hepatobiliary/pancreatic, adrenal/kidney, and central nervous system organs. These findings suggest that pre- and post-CAR-T interventions may be optimized based on organ involvement.